Hyperkinetic Movement Disorders Differential Diagnosis and Treatment

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Hyperkinetic Movement Disorders Differential diagnosis and treatment

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Albanese_ffirs.indd ii 1/23/2012 10:47:45 AM Hyperkinetic Movement Disorders Differential diagnosis and treatment

EDITED BY

Alberto Albanese MD Professor of Neurology Fondazione IRCCS Istituto Neurologico Carlo Besta Università Cattolica del Sacro Cuore, Milan, Italy

Joseph Jankovic MD Professor of Neurology Director, Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, TX, USA

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Library of Congress Cataloging-in-Publication Data Hyperkinetic movement disorders : differential diagnosis and treatment / edited by Alberto Albanese, Joseph Jankovic. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4443-3352-7 (hard cover : alk. paper) ISBN-10: 1-4443-3352-6 (hard cover : alk. paper) ISBN-13: 978-1-4443-4615-2 (ePDF) ISBN-13: 978-1-4443-4618-3 (Wiley Online Library) [etc.] 1. Hyperkinesia. 2. Diagnosis, Differential. I. Albanese, Alberto. II. Jankovic, Joseph. [DNLM: 1. Hyperkinesis. 2. Movement Disorders. 3. Diagnosis, Differential. WL 390] RC376.5.H96 2012 616.85′89–dc23 2011020595 A catalogue record for this book is available from the British Library.

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Albanese_ffirs.indd iv 1/23/2012 10:47:46 AM Contents

Preface, vii List of Contributors, viii List of Videos, x

Part 1 General Issues in Hyperkinetic Disorders, 1

1 Distinguishing Clinical Features of Hyperkinetic Disorders, 3 Alberto Albanese and Joseph Jankovic 2 Pathophysiology and Molecular Pathology of Dystonia and Tics, 15 Marie Vidailhet, Michael Schupbach, and David Grabli 3 Pathophysiology and Molecular Pathology of Tremor, Myoclonus, and Chorea, 26 Johannes D. Speelman, Elisabeth M. Foncke, Anne-Fleur van Rootselaar, and Marina A. Tijssen 4 Overview of the Medical Treatments of Hyperkinetic Disorders, 40 William Ondo 5 Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders, 49 Vinata Vedam-Mai, Oscar Bernal, and Michael S. Okun

Part 2 Tremor Syndromes, 71

6 Essential Tremor, 73 Julián Benito-León and Elan D. Louis 7 Other Tremors, 95 Claustre Pont-Sunyer, Eduardo Tolosa and Judith Navarro-Otano

Part 3 Dystonia Syndromes, 113

8 Primary Dystonias, 115 Antonio E. Elia and Alberto Albanese 9 Secondary Dystonias, 135 Susanne A. Schneider

Part 4 Chorea Syndromes, 147

10 Huntington Disease and Other Genetic Choreas, 149 Ainhi Ha and Joseph Jankovic

Albanese_ftoc.indd v 1/23/2012 10:59:08 AM vi Contents

11 Acquired Choreas, 175 Ruth H. Walker 12 Tics and Tourette Syndrome, 188 Joseph Jankovic 13 Secondary Tics, 200 Francisco Cardoso

Part 5 Myoclonus Syndromes, 207

14 Inherited Myoclonus Syndromes, 209 Emmanuel Roze and Emmanuelle Apartis 15 Segmental Myoclonus, 221 John Nathaniel Caviness 16 Other Jerks and Startles, 236 Codrin Lungu and Mark Hallett

Part 6 Ataxias, 257

17 Clinical and Pathophysiological Features of Cerebellar Dysfunction, 259 Giuliana Grimaldi and Mario Manto 18 Inherited and Sporadic Ataxias, 279 Hélio A.G. Teive, Renato P. Munhoz, and Tetsuo Ashizawa

Part 7 Other Hyperkinetic Disorders, 297

19 Dyskinesias in Parkinsonian Syndromes, 299 S. Elizabeth Zauber and Christopher G. Goetz 20 Restless Legs Syndrome, 311 Pamela Hamilton-Stubbs and Arthur S. Walters 21 Tardive Dyskinesias, 331 Gonzalo J. Revuelta, Leslie Cloud, Pratibha G. Aia, and Stewart A. Factor 22 Stereotypies and Other Developmental Hyperkinesias, 353 Jayasri Srinivasan and Jonathan W. Mink 23 Paroxysmal Dyskinesias, 363 Miryam Carecchio, João Massano, and Kailash P. Bhatia 24 Psychogenic Movement Disorders, 375 Stanley Fahn

Index, 385

A companion site with all the videos cited in this book can be found at: www.wiley.com/go/albanese/movement

Albanese_ftoc.indd vi 1/23/2012 10:59:08 AM Preface

Hyperkinetic movement disorders have always effective and safe medical and surgical treatment puzzled neurologists and other clinicians because of strategies. Appropriate diagnosis, however, is criti- uncertainties about their classification and treat- cal before the most suitable disease-specific treatment. At first sight, many hyperkinetic disorders ment is selected and offered to the patient. may look alike, but a closer examination of their Because of diagnostic challenges in the field of phenomenology, including pattern, rhythm, and hyperkinetic movement disorders many patients anatomic distribution, usually allows for their seek multiple opinions. These consultations are proper categorization. Although in general sometimes done informally and facilitated by neurology, clinical anatomical correlates are the exchanging patient videos. Personal experience cornerstone of diagnosis, in movement disorders and expert knowledge are perhaps more important phenomenology has an essential role. In our training in this field than other neurological disciplines. and mentoring experience we enjoy the enthusi- Hence, the idea to assemble a unique volume dedi- asm of young residents and fellows who begin to cated to hyperkinetic movement disorders, accom- explore the many facets of hyperkinetic disorders. panied by instructive videos, was the impetus for They soon recognize that proper phenomenologi- this book. cal categorization is an essential element in the In planning this book we carefully selected true diagnosis of movement disorders, which then leads authorities in each field and, fortunately, they have to finding the most likely etiology and treatment. accepted our invitation. As a result, we assembled Thus, as an example, if the clinician does not recog- the most outstanding, internationally renowned, nize patient’s chorea, the appropriate tests, such as faculty. We wish to thank the authors for their Huntington disease DNA test, may not be ordered scholarly contributions. We also wish to thank the and the diagnosis may be delayed. Similarly, if one editorial and management staff of Wiley, particu- does not recognize a particular hyperkinesia as larly Michael Bevan, Julie Elliott, and Martin stereotypy, prior use of dopamine receptor blocking Sugden. Finally, we express our deep appreciation drugs may not be investigated and the diagnosis of to our families, who allowed us to dedicate our tardive dyskinesia can be missed. time and effort to this project. Until few years ago treatment options for hyperkinetic movement disorders were limited, but in Alberto Albanese Joseph Jankovic recent years there has been a remarkable growth in Milan, Italy Houston, Texas

vii

Albanese_fpref.indd vii 12/24/2011 4:14:32 AM List of Contributors

Pratibha G. Aia Francisco Cardoso Christopher G. Goetz Department of Neurology Neurology Service, Department of The Parkinson Disease and Movement Emory University School of Medicine Internal Medicine Disorder Center Atlanta, GA, USA The Federal University of Minas Gerais Rush University Medical Center Belo Horizonte, Brazil Chicago, IL, USA Alberto Albanese Fondazione IRCCS Istituto Miryam Carecchio David Grabli Neurologico Carlo Besta Sobell Department of Motor Department of Neurology Università Cattolica del Sacro Cuore Neuroscience and Movement Disorders Salpetrière Hospital Milan, Italy Institute of Neurology Pierre and Marie Curie University University College London Paris, France Emmanuelle Apartis London, UK Service de Physiologie Giuliana Grimaldi Hôpital Saint-Antoine John Nathaniel Caviness Fonds National de la Recherche Paris, France Department of Neurology Scientifique (FNRS) Mayo Clinic College of Medicine Neurologie ULB-Erasme Tetsuo Ashizawa Mayo Clinic Scottsdale Brussels, Belgium Department of Neurology AZ, USA University of Florida Ainhi Ha Gainesville, FL, USA Leslie Cloud Parkinson’s Disease Center and Department of Neurology Movement Disorders Clinic Julián Benito-León Emory University School of Medicine Department of Neurology Department of Neurology, University Atlanta, GA, USA Baylor College of Medicine Hospital “12 de Octubre,” and Houston, TX, USA Centro de Investigación Biomédica Antonio E. Elia en Red sobre Istituto Neurologico Carlo Besta, Mark Hallett Enfermedades Neurodegenerativas Milan, Italy National Institute of Neurological (CIBERNED) Disorders and Stroke Madrid, Spain Stewart A. Factor Bethesda, MD, USA Department of Neurology Oscar Bernal Emory University School of Medicine Pamela Hamilton-Stubbs Movement Disorders Center Atlanta, GA, USA Sleep Clinic for Children and Adults & Department of Neurology Richmond, VA, USA University of Florida Stanley Fahn Gainesville, FL, USA Department of Neurology Joseph Jankovic Columbia University College of Parkinson’s Disease Center and Kailash P. Bhatia Physicians Surgeons Movement Disorders Clinic Sobell Department of Motor New York, NY, USA Department of Neurology, Baylor Neuroscience and Movement College of Medicine Disorders Elisabeth M. Foncke Houston, TX, USA Institute of Neurology, Department of Neurology University College London Free University Medical Center London, UK (VUmc) Amsterdam, the Netherlands

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Albanese_flast.indd viii 1/23/2012 12:45:55 PM List of Contributors ix

Elan D. Louis William Ondo Marina A. Tijssen The G.H. Sergievsky Center, Department of Neurology Department of Neurology Department of Neurology, and Taub Baylor College of Medicine Academic Medical Center Institute for Research on Alzheimer’s Houston, TX, USA University of Amsterdam Disease and the Aging Brain Amsterdam, the Netherlands College of Physicians and Surgeons Claustre Pont-Sunyer and Department of Epidemiology Neurology Service Eduardo Tolosa Mailman School of Public Health Hospital Clinic de Barcelona Neurology Service Columbia University, New York University of Barcelona Hospital Clinic de Barcelona NY, USA Barcelona, Spain University of Barcelona Barcelona, Spain Codrin Lungu Gonzalo J. Revuelta National Institute of Neurological Department of Neurology Anne-Fleur van Rootselaar Disorders and Stroke Emory University School of Medicine Department of Neurology Bethesda, MD, USA Atlanta, GA, USA Academic Medical Center University of Amsterdam Mario Manto Emmanuel Roze Amsterdam, the Netherlands Fonds National de la Recherche Fédération des Maladies du Système Scientifique (FNRS) Nerveux Vinata Vedam-Mai Neurologie ULB-Erasme Hôpital Pitié-Salpêtrière Department of Neurological Surgery Brussels, Belgium Paris, France University of Florida Gainesville, FL, USA João Massano Susanne A. Schneider Sobell Department of Motor Schilling Section of Clinical and Marie Vidailhet Neuroscience and Movement Molecular Neurogenetics at the Department of Neurology, ICM-CRICM Disorders Department of Neurology Research Center Institute of Neurology University Luebeck Salpetrière Hospital University College London Luebeck, Germany Pierre and Marie Curie University London, UK Paris, France Michael Schupbach Jonathan W. Mink Department of Neurology Ruth H. Walker Department of Neurology Salpetrière Hospital Department of Neurology Division of Child Neurology Pierre and Marie Curie University James J. Peters Veterans Affairs University of Rochester Paris, France Medical Center, Bronx, NY Medical Center and Mount Sinai School of Medicine Rochester, NY, USA Johannes D. Speelman New York, NY, USA Department of Neurology Renato P. Munhoz Academic Medical Center Arthur S. Walters Neurology Service University of Amsterdam Department of Neurology Department of Internal Medicine Amsterdam, the Netherlands Vanderbilt University School of Hospital de Clínicas Medicine Federal University of Paraná Jayasri Srinivasan Nashville, TN, USA Curitiba, Brazil Department of Neurology Division of Child Neurology S. Elizabeth Zauber Judith Navarro-Otano University of Rochester Department of Neurology Neurology Service Medical Center Indiana University School Medicine Hospital Clinic de Barcelona Rochester, NY, USA Indianapolis, IN, USA University of Barcelona Barcelona, Spain Hélio A.G. Teive Neurology Service Michael S. Okun Department of Internal Medicine Departments of Neurology Hospital de Clínicas & Neurological Surgery Federal University of Paraná Movement Disorders Center Curitiba, Brazil University of Florida Gainesville, FL, USA

Albanese_flast.indd ix 1/23/2012 12:45:55 PM List of Videos

The videos in this book can be accessed either by scanning the QR (Quick Response) codes within this book using a QR reader app and the camera on your smart phone, or alternatively, copying the web link (listed under the QR code) into your web browser. QR code reader apps can be obtained from the app store market for your smartphone not from the publisher.

Video 6.1 Essential tremor, 74 Video 7.1 Task-specific tremor (“handbag” tremor), 96 Video 7.2 Dystonic head tremor, 99 Video 7.3 Holmes tremor, 101 Video 7.4 Drug-related tremor in a patient with segmental dystonia, 101 Video 8.1 Primary cervical dystonia, 118 Video 8.2 Primary dystonia: DYT1 phenotype, 121 Video 8.3 Primary dystonia: DYT6 phenotype, 122 Video 8.4 Primary dystonia: DYT13 phenotype, 124 Video 9.1 Hemidystonia following basal ganglia lesion, 136 Video 9.2 Dystonia in PKAN, 137 Video 9.3 Complex regional pain syndrome, 138 Video 9.4 Creutzfeldt–Jakob disease, 139 Video 10.1 Mild generalized chorea in Huntington disease, 150 Video 10.2 Moderate chorea in Huntington disease, 150 Video 10.3 Chorea in Huntington disease, 151 Video 10.4 Juvenile-onset Huntington disease, 151 Video 10.5 Features associated with Huntington disease, 152 Video 10.6 Progression of motor impairment in Huntington disease, 152 Video 10.7 Chorea in ataxia telangectasia, 163 Video 10.8 Chorea in Neuroacanthocytosis, 164 Video 11.1 Hemichorea due to vascular hypoperfusion, 178 Video 11.2 Movement disorder of acquired hepatocerebral degeneration, 179 Video 11.3 Celiac dyskinesia, 180 Video 12.1 Phenomenology of tics in Tourette syndrome, 189 Video 12.2 Phenomenology of tics in Tourette syndrome, 189 Video 12.3 Phenomenology of tics in Tourette syndrome, 190 Video 12.4 Phenomenology of Tourette syndrome, 190 Video 12.5 Phenomenology of Tourette syndrome, 190 Video 12.6 Phenomenology of Tourette syndrome, 191

Albanese_flast.indd x 1/23/2012 12:45:55 PM List of Videos xi

Video 13.1 Tics following peripheral injury, 202 Video 14.1 Myoclonus-dystonia phenomenology, 211 Video 14.2 Myoclonus-dystonia phenomenology, 212 Video 14.3 Myoclonus-dystonia: lightning jerks, 212 Video 14.4 Myoclonus-dystonia: deep brain stimulation, 214 Video 14.5 Myoclonus in Unverricht–Lundborg disease, 217 Video 14.6 Myoclonus in Lafora body disease, 217 Video 15.1 Palatal myoclonus, 222 Video 15.2 Segmental myoclonus, 226 Video 15.3 Segmental myoclonus, 226 Video 16.1 Focal myoclonus, 237 Video 16.2 Generalized myoclonus, 240 Video 16.3 Belly dancer’s dyskinesia, 247 Video 16.4 Painful legs and moving toes, 248 Video 18.1 Ataxia phenomenology, 279 Video 18.2 Friedreich ataxia, 280 Video 18.3 SCA2 ataxia, 290 Video 18.4 SCA3 ataxia, 290 Video 19.1 Peak dose dyskinesia, 300 Video 19.2 Diphasic dyskinesia, 301 Video 19.3 Off dyskinesia, 302 Video 19.4 On-state dyskinesia, 302 Video 20.1 Periodic limb movements in sleep, 312 Video 20.2 Restless leg syndrome, 315 Video 21.1 Phenomenology of tardive dyskinesias, 334 Video 21.2 Phenomenology of tardive dyskinesias, 336 Video 21.3 Phenomenology of tardive dyskinesias, 336 Video 21.4 Phenomenology of tardive dyskinesias and response to treatment, 341 Video 22.1 Stereotypies in Rett syndrome, 356 Video 22.2 Tardive stereotypies, 357 Video 22.3 Stereotypies in suspected taupathy, 358 Video 23.1 Infantile paroxysmal kinesigenic dyskinesia, 363 Video 23.2 Paroxysmal kinesigenic dyskinesia while standing, 364 Video 23.3 Autosomal dominant paroxysmal kinesigenic dyskinesia, 364 Video 23.4 Ballic paroxysmal kinesigenic dyskinesia, 364 Video 23.5 GLUT1 deficiency, 367 Video 23.6 Paroxysmal dyskinesia in patient with cerebral palsy, 370 Video 24.1 Psychogenic tremor, 378 Video 24.2 Psychogenic tremor, 379 Video 24.3 Psychogenic dystonia, 380 Video 24.4 Psychogenic myoclonus, 380 Video 24.5 Psychogenic gait disorder, 381 Video 24.6 Psychogenic tic disorder, 382

Albanese_flast.indd xi 1/23/2012 12:45:55 PM Plate 5.1 An example of the basal ganglia anatomy on a MRI with a morphable atlas. Blue is striatum, green is thalamus/GPe, red is STN/GPi, yellow is optic tract, and black is substantia nigra.

Albanese_bins.indd 1 12/24/2011 7:36:25 AM Plate 5.2 The trajectory shows an approach that will place a lead on the VIM/VE border. Usually a single VIM lead is placed at the VIM/VOP border, and if a dual lead is attempted a second lead may be placed in ZI or in VOA/VOP.

Albanese_bins.indd 2 12/24/2011 7:36:27 AM Plate 5.3 This MRI shows a typical trajectory for GPi DBS.

Plate 5.4 This MRI reveals a sample trajectory for STN DBS. This trajectory would be the far anterior border of STN by microelectrode mapping and the optimal lead position would be posterior to this trajectory.

Albanese_bins.indd 3 12/24/2011 7:36:28 AM Plate 6.2 Cerebellar cortical section of an ET case (Bielschowsky stain). The red arrows indicate the abundance of Purkinje cell axonal swellings (torpedoes).

Plate 18.1 Telangiectasia in the sclera in ataxia telangiectasia.

Albanese_bins.indd 4 12/24/2011 7:36:31 AM PART 1 General Issues in Hyperkinetic Disorders

Albanese_p01.indd 1 12/24/2011 6:00:47 AM CHAPTER 1 Distinguishing Clinical Features of Hyperkinetic Disorders

Alberto Albanese1 and Joseph Jankovic 2 1 Fondazione IRCCS Istituto Neurologico Carlo Besta, Università Cattolica del Sacro Cuore, Milan, Italy 2 Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Introduction isolation or in variable combinations: tremor, chorea, tics, myoclonus, dystonia, and stereotypies. Movement abnormalities can be dichotomized into In addition to these six categories there are other the two broad categories of hypokinetic and abnormalities of motor control that are also hyperkinetic syndromes. The hallmark of hypoki- included within the field of movement disorders, nesias is the loss of voluntary and automatic such as akathisia, amputation stumps, ataxia, movements (akinesia), which is combined with athetosis, ballism, hyperekplexia, mannerisms, slowness (bradykinesia) and stiffness or increased myorhythmia, restlessness, and spasticity. The term muscle tone (rigidity) in akinetic-rigid or parkin- “dyskinesia” is commonly used to indicate any or a sonian syndromes [1]. In contrast, hyperkinesias combination of abnormal involuntary movements, are manifested by abnormal, uncontrollable, and such as tardive or paroxysmal dyskinesias or unwanted movements. This term should not be levodopa-induced dyskinesia, but more specific confused with “hyperkinetic disorders” used in phenomenological categorization should be used ICD 10 [2] to describe a behavioral abnormality – whenever possible. In addition, there is a large and typically labeled attention deficit disorder with important group of peripherally-induced movement hyperactivity, occurring particularly in children disorders, exemplified by hemifacial spasm [4], and often associated with attention deficit and a although any hyperkinetic movement disorder can tendency to move from one activity to another be triggered or induced by peripheral injury [5]. without completing any one. This is often associated Some conditions combine hypokinetic and with disorganized, ill-regulated, and scattered hyperkinetic features, as exemplified by the activity and thinking. This is not the only coexistence of bradykinesia and tremor in Parkinson inconsistency between terminology in adult and disease (PD) often referred to by the oxymora “gait childhood disorders, and efforts have been recently disorder with acceleration” [6] or “shaking palsy” undertaken to unify the nosology and diagnostic [7]. Probably the best examples of coexistent hyper- recommendations in pediatric and adult movement and hypokinesia is levodopa-induced dyskinesia in disorders [3]. patients with PD and chorea or dystonia in patients Hyperkinetic movement disorders include six with Huntington disease, many of whom have an main phenotypic categories, which can appear in underlying hypokinesia [8].

Hyperkinetic Movement Disorders: Differential Diagnosis and Treatment, First Edition. Edited by Alberto Albanese and Joseph Jankovic. © 2012 Blackwell Publishing Ltd. Published 2012 by Blackwell Publishing Ltd.

Albanese_c01.indd 3 12/24/2011 6:01:55 AM 4 Chapter 1

We describe here the hallmark features and Table 1.1 Chronology of first description of the main phenomenology of the main hyperkinetic disorders, hyperkinetic disorders. which are listed according to the time of their Date Name First usage medical recognition. Ancient Greece Tremor τρεμω (to tremble, to fear) XI Century Chorea Choreomania (ritual Historical background dance) XVII Century Tic French horse breeders 1871 Athetosis Hammond [71] The importance of recognizing the appropriate 1881 Myoclonus Friedreich [21] phenomenology, not only as a guide to diagnosis 1885 Ballism Kussmaul [72] but also as a means to study the pathophysiology 1911 Dystonia Oppenheim [24] of the disorder, is highlighted by the following 1953 Asterixis Adams [23] statement attributed to Sir William Osler: “To study the phenomenon of disease without books is to sail an uncharted sea, while to study books without and was later recognized to be a manifestation of patients is not to go to sea at all” [9]. rheumatic fever. Adult-onset hereditary chorea The characterization and classification of the was described in the 19th century [16] and later various hyperkinetic disorders has evolved over a renamed Huntington chorea. long period of time (Table 1.1). Tremor was a com- The term “tic” arose in France in the 17th century mon language word before becoming a medical to describe shivers in horses, particularly of certain term. In ancient Greek, the root TRE is a lexical breeds, which affect primarily the muscles of the unit to indicate at the same time fear and shaking. pelvic region, pelvic limbs, and tail [17]. The Tremor was defined by Galen as an “involuntary word was later used by French doctors by alternating up and down motion of the limbs.” analogy. The first medical report on human tics is Involuntary movements present during action or probably the description of the Marquise of at rest were also mentioned by Sylvius [10]. Dampierre, who started having tics at 7 years of Parkinsonian tremor was later described by James age [18]. Later, Trousseau listed tics among Parkinson [7] and further differentiated from choreatic disorders [19] and Gilles de la Tourette kinetic “intentional tremor” by Charcot [11]. The provided a separate taxonomic categorization of familial occurrence of postural action tremor was these phenomena [20]. recognized shortly afterwards [12]. Essential myoclonus was first described by Epidemics of “dancing mania” emerged in Friedrich [21], who reported a 50-year-old man central Europe in the late Middle Ages as local phe- with a 5-year history of multifocal muscle jerks nomena [13] or in connection with pilgrimages. affecting both sides of the body symmetrically, but Coincident with the Black Plague in 1348–50, asynchronously. The syndrome was defined as St Vitus was called upon to intercede, leading to “paramyoclonus multiplex” because of the reported the term “chorea Sancti Viti” (St Vitus dance) to symmetry. Forms of myoclonic epilepsy were later indicate at the same time a request for intercession described and Lundborg [22] proposed a classification and a means to expiate. This terminology has of myoclonus that remains largely in use today. entered medical literature after Paracelcus Asterixis was observed in patients with hepatic described this syndrome among one of the five encephalopathy [23] and later recognized to be a that “deprive man of health and reason.” He form of negative myoclonus. adopted the term “chorea” into medical jargon and Dystonia was the last main hyperkinetic disorder proposed using the expression “chorea lasciva” to to be recognized: its name derives from a supposed describe the epidemics [14]. One century later, alteration of muscle tone in patients with generalized Thomas Sydenham observed an epidemic affecting distribution [24]. The hereditary nature was noted at only children which he called “chorea minor” [15] about the same time [25].

Albanese_c01.indd 4 12/24/2011 6:01:55 AM Distinguishing Clinical Features of Hyperkinetic Disorders 5

Table 1.2 Tremor types can be differentiated based on frequency, amplitude and onset in relation to voluntary movements.

Frequency Tremor type Amplitude Prevalent site Relation to voluntary movement

1–4 Hz Cerebellar tremor Medium–high Limbs Postural, action 3–5 Hz Task-specific tremor Low–medium Hand Writing, feeding, playing an instrument 4–5 Hz Parkinsonian tremor Medium–high Limbs, jaw Rest 5–8 Hz Essential tremor Medium–high Limbs, head, voice Postural 8–12 Hz Physiologic tremor Medium Limbs Postural 14–16 Hz Orthostatic tremor Low–medium (may not be Legs, trunk Standing visible, but can be palpated or auscultated)

Phenomenology and classification with cerebellar dysfunction, is characterized by the worsening of tremor on approach to a target, Although at first sight involuntary movements as in a finger-to-nose maneuver. The typical rest resemble each other, each hyperkinetic disorder tremor of PD has a frequency of 4 to 6 Hz, and is has a specific phenomenology (signature) that most prominent distally. Its characteristic appearance can be identified by direct observation of the in the hand is also referred to as a pill-rolling patient or videotaped examination. Duration, tremor. Parkinsonian rest tremor also typically rhythmicity, topography, and other features involves the chin, jaw, and legs, but almost never must be carefully analyzed and noted in order to involves the neck. Indeed, head oscillation make a specific phenomenological diagnosis [26] should suggest essential tremor or dystonic (Table 1.2). tremor rather than PD. True rest tremor, however, disappears during complete rest, such as sleep, Tremor and is reduced or disappears with voluntary mus- Tremor is an involuntary, rhythmic, oscillation of a cle contraction, or during movement. Postural body region about a joint axis. It is usually tremor is present with the maintenance of a produced by alternating or synchronous contrac- particular posture, such as holding the arms tions of reciprocally innervated agonistic and outstretched in front of the body. It is commonly antagonistic muscles that generate a relatively seen in physiological and essential tremor. symmetric velocity in both directions about a Re-emergent tremor refers to a postural tremor midpoint of the movement [27, 28]. The oscillation that occurs after a variable latency period during produced by tremor can be represented by a which time no observable postural tremor is sinusoidal curve; it is generated by rhythmical present [30]. This typically occurs in the setting discharges in an oscillating neuronal network and of PD, and most likely represents a parkinsonian maintained by feedback and feed-forward loops. rest tremor that has been “reset” during the The resulting movement is patterned and rhythmic, maintenance of a posture [31]. characteristics that distinguish tremor from other Task-specific tremor occurs only during execu- hyperkinesias [29]. tion of a particular task, such as writing, and is Tremor varies when different voluntary considered by many to be a variant of dystonic movements are performed or postures are held: it tremor. Dystonic tremor may occur in the setting is labeled as a rest tremor, postural tremor, or of dystonia, and is a rhythmic, oscillation-like, action tremor according to the condition of greatest dystonic movement [32]. Position-specific tremors severity. Intention tremor, typically associated only occur when the affected body part is placed in

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a particular position or posture. Orthostatic tremor Ballism is characterized by high amplitude, is an example of a position-specific tremor, and almost violent, movements that mainly involve the refers to a fast (14–16 Hz) tremor, mainly affecting proximal limb joints. It is considered an extreme the trunk and legs, that occurs after standing for a phenomenological expression of the spectrum of certain period of time [33]. chorea that affects proximal joints such as shoulder or hip. This leads to large amplitude movements of Chorea the limbs, sometimes with a flinging or flailing Chorea is an irregular, unpredictable, involuntary quality. As patients recover from acute ballism, random-appearing sequence of one or more, frequently associated with a stroke in the discrete, involuntary jerk-like movements or contralateral subthalamic nucleus, the ballistic movement fragments. Movements appear ran- movements often gradually evolve into chorea or dom due to the variability in timing, duration, dystonia (see Chapters 10 and 11). direction, or anatomic location. Each movement may have a distinct start and end point, although Tics these may be difficult to identify since movements Tics are repeated, individually recognizable, are often strung together, one immediately intermittent movements or movement fragments following or overlapping another. Movements that are almost always briefly suppressible and may, therefore, appear to flow randomly from one are usually associated with the awareness of an muscle group to another, and can involve trunk, urge to perform the movement, the so-called neck, face, tongue, and extremities. Infrequent “premonitory sensation.” Motor tics often result and mild chorea may appear as isolated, in either a simple jerk-like movement such as a small-amplitude brief movements. It may resem- blink, facial grimace, head jerk, or shoulder shrug, ble restless, fidgety, or anxious behavior. When or more complex, stereotyped, semivoluntary, chorea is more severe, it may appear to be almost intermittent movements. Tics are usually abrupt continuous, flowing from one site of the body to in onset, fast and brief (clonic tics), slow and another (Figure 1.1). sustained (dystonic tics), or manifested by sudden Although chorea may be worsened by movement, cessation of movement because of isometric muscle it usually does not stop with attempted relaxation. contractions (tonic tics), or inhibition of voluntary Chorea is distinguished from tremor and dystonia movement (blocking tics). The duration of each by its lack of rhythmicity and predictability. Chorea tic movement is characteristic of that tic, and the may be difficult to differentiate from myoclonus, duration does not generally vary between different but the latter is more intermittent rather than repetitions [34]. Tics can occur during all stages continuous. Chorea is typically a fluent disorder of sleep. involving contiguous body parts in variable order Characteristic features include predictability of and direction. It may be associated with hypotonia, both the nature of the movement and its onset, hung-up and pendular reflexes, and motor suggestibility, exacerbation during excitement or impersistence (inability to maintain a sustained stress and also after stress (rebound), and brief contraction). Examples of impersistence include voluntary suppressibility. Complex motor tics may an inability to maintain prolonged tongue protru- resemble normal motor acts or gestures, but are sion or handgrip (“milkmaid grip”). The term generally inappropriately intense and timed [34]. “parakinesia” refers to the incorporation of the The movements can appear purposeful, such as involuntary movements into semipurposeful touching, throwing, hitting, jumping, and kicking, movements, in a semiconscious attempt to or non-purposeful, such as head shaking or trunk camouflage the chorea. Examples of parakinesia bending. Occasionally tics can be so severe as to include touching one’s face, adjusting glasses, and cause neurological sequels, with reports of other mannerisms that often served to delay the compressive cervical myelopathy resulting from recognition of the involuntary movement. recurrent head thrusting and violent neck

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(a) (b) (c) (d)

2 sec (e) (f) (g) (h)

(i) (j) (k) (l)

Figure 1.1 This photographic sequence (1.5 frames per second) permits an appreciation of the rapid flow of chorea motor fragments in a patient with Huntington disease.

hyperextension tics [35]. Complex motor tics can occurrences of sniffing, throat clearing, grunting, also include copropraxia (grabbing or exposing screaming, coughing, blowing, or sucking sounds. one’s genitals) or echopraxia (imitating gestures). Pathological laughter has also been reported as a Motor tics are almost invariably accompanied by manifestation of a simple phonic tic [36]. In contrast, vocal or phonic tics and many experts view motor and complex phonic tics are semantically meaningful phonic tics are having the same pathophyiological utterances and include coprolalia, or shouting of mechanism. Simple phonic tics can involve brief obscenities, profanities, or other insults. Other

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complex phonic tics include echolalia (repeating These “lightning-like” movements differ from someone else’s words or phrases) and palilalia epileptic myoclonus and do not affect consciousness (repeating one’s own utterances, particularly the [41]. Myoclonus may be synchronous (several mus- last syllable, word, or phrase in a sentence). Rarely, cles contracting simultaneously), spreading (several tics may be continuous and disabling, resulting in a muscles contracting in a predictable sequence), or so-called “tic status” [37] or in severe, self-injurious, asynchronous (several muscles contracting with var- even life-threatening behaviors, so called “malignant ying and unpredictable relative timing). When myo- Tourette syndrome” [38]. Because of the broad clonus affects more than one muscle in an apparently expression of Tourette syndrome, manifested not random and varying pattern it is called multifocal; it is only by motor and phonic tics but by a variety of called generalized when many muscles through the behavioral comorbidities (such as attention deficit body are involved simultaneously. Myoclonus is with hyperactivity, obsessive-compulsive disorder, characterized by a sudden unidirectional movement and impulsivity), the management depends on due to agonist contraction (positive myoclonus) or establishing an appropriate hierarchy of the various by sudden brief muscle relaxation (negative myo- symptoms and targeting the therapeutic strategies to clonus) [42]. The latter is exemplified by asterixis, the most troublesome problems [39]. (See Chapters which typically presents in patients with hepatic and 12 and 13). other encephalopathy. The distinction between myoclonus and other involuntary disorders – particularly tics, chorea, Athetosis and different varieties of jerks – is not always clear. Athetosis is a slow, continuous, involuntary writhing Tics are usually associated with a generalized, movement that (1) prevents the maintenance of a conscious, urge or local premonitory sensation to stable posture; (2) involves continuous smooth move and a feeling of relief of tension after the movements that appear to be random and are not movement. In addition, many tics are suppressible, composed of recognizable movement fragments; in contrast to myoclonus. Brief muscle movements (3) typically involves the distal extremities (hands in dystonia are often associated with dystonic or feet) more than the proximal and can also posturing. Mild chorea may be difficult to distin- involve the face, neck, and trunk; and (4) may guish from myoclonus. Sometimes myoclonus is worsen with attempts at movement or posture, but rhythmic and can resemble tremor. When myo- can also occur at rest. clonus is repeated rhythmically it is also called Athetosis rarely occurs in isolation but is much “myoclonic tremor”, but this is a misnomer as more commonly associated with chorea and rhythmical myoclonus, such as palatal myoclonus dystonia. In fact, it is considered a variant of distal [43], is caused by contractions of agonists only, not chorea or dystonia. Phenomenologically, athetosis alternating contractions of antagonist muscles as is at the opposite end of ballism, resulting in a seen in tremor. slow, gentle, and distal motion, resembling slow Myoclonus can be caused or worsened by chorea. The recognition of athetosis often leads to movement and can sometimes occur during consideration of cerebral palsy or paroxysmal sleep. Myoclonus can be categorized as action choreoathetosis. Pseudoathetosis refers to a severe myoclonus, postural myoclonus, or rest distal sensory loss syndrome whereby involuntary, myoclonus on the basis of the condition in which slow, writhing movements are due to loss of it is observed [44]. It can also be categorized on proprioception [40]. the basis of the presumed anatomic origin as cortical, subcortical, brainstem, propriospinal, or Myoclonus spinal. Myoclonus may coexist with dystonia (as Myoclonus consists of repeated, often non-rhythmic, in myoclonus-dystonia syndrome) or with tremor brief shock-like jerks due to the sudden involuntary (as in essential myoclonus) [45]. (See Chapters contraction or relaxation of one or more muscles. 14, 15, and 16).

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Dystonia Severity Activation In dystonia, involuntary sustained or intermittent muscle contractions cause twisting and repetitive Mild Task-specific movements, abnormal postures, or both. The combination of postures and dystonic movements is typical of dystonia [46]. Dystonic postures are repeated and particular Moderate Movement-specific patterns or postures are characteristic of each patient at a given point in time. Similar dystonic postures may occur in different patients. Postures Severe Independent of voluntary movement can be sustained, particularly at the peak of dystonic Figure 1.2 Increasing severity of dystonia is often movements, or may occur during very brief associated with loss of task-specificity and relation intervals. Dystonic postures are often triggered by to voluntary movement. attempts at voluntary movement or voluntary posture, and in some cases they are triggered only in particular body positions or by particular or longer, dystonia may lead to fixed contractures. movements as may occur in task-specific dystonia. Fixed dystonia is often associated with painful With the exception of certain seizure disorders [47], contracture, as in post-traumatic, chronic regional dystonic movements or postures are not typically pain syndrome [53] or sustained voluntary seen during sleep, possibly due to inhibition of contraction as in psychogenic dystonia. (see movements by spinal mechanisms [48]. Postures Chapter 24). tend to occur at intervals determined by voluntary Dystonia is typically associated with the movement and can be sustained for variable lengths occurrence of gestes antagonistes (or sensory of time. Relaxation may be impaired so that the tricks), mirror phenomena and overflow [54–56]. dystonic posture may be maintained well beyond Their recognition supports the clinical diagnosis of the end of the attempted voluntary movement that dystonia [46]. Dystonia can affect any body part, triggered it. There may be multiple dystonic postures with a wide range in severity from very mild to in the same patient, so that different dystonic extremely severe cases (see Chapters 8 and 9). postures may be combined. Dystonic movements may vary in terms of Stereotypies speed, amplitude, rhythmicity, forcefulness, and Stereotypies are involuntary or unvoluntary (in distribution in the body, but the same muscles are response to or induced by inner sensory stimulus or usually involved; hence the term “patterned” unwanted feeling), coordinated, patterned, repetitive, movement disorder. Dystonia may occur at rest, rhythmic, seemingly purposeless movements or during activity or only during a specific motor utterances [57]. Although stereotypies typically movement or posture, so-called task- or occur in children with autism or other pervasive position-specific dystonia (Figure 1.2) [49]. The developmental disorders, they can also occur in most common adult-onset upper limb task-specific adults. Typical motor stereotypies encountered in dystonia is writer’s cramp [50]. Musician’s cramp children with autism include body rocking, head occurs while playing a musical instrument [51]. nodding, head banging, hand washing and waving, Embouchure dystonia affects the control of the lip, covering ears, fluttering of fingers or hands in front jaw, and tongue muscles, and may be seen in of the face, repetitive and sequential finger woodwind and brass players [52]. movements, eye deviations, lip smacking, and The term “fixed dystonia” is used to indicate chewing movements, pacing, object fixation, and persistent, abnormal posture, without a dynamic skin picking. Phonic stereotypies include grunting, component. When present but untreated for weeks moaning, and humming. In adults, stereotypies are

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usually encountered in patients with tardive Behavioural features associated with hyperki- dyskinesias. In this setting stereotypies are usually netic disorders should not be confounded with in the form of orofacial or lingual chewing psychogenic movement disorders, which are movements, pelvic rocking movements and other abnormal movements thought to be due to pre- repetitive coordinated movements. They are often existing psychological or psychiatric disturbances. accompanied by akathisia, manifested by motor The borderland between movement disorders and and sensory restlessness (see Chapters 21 and 22). psychiatry is a difficult diagnostic area. It is remarkable that most movement disorders were initially Non-motor features considered psychogenic due to the inexplicability of Psychiatric morbidity is higher in patients with their phenomenology, such as the paradigmatic hyperkinetic movement disorders than in case of primary dystonia, featuring bizarre postural community samples or in patients with other forms abnormalities, relief by gestes antagonistes, task of chronic disease. Behavioral abnormalities specificity, and normal brain morphology. The have been reported in patients with Tourette syn- organic nature of primary hyperkinetic movement drome [58], Wilson disease [59], dystonia [60], disorder is now unequivocally recognized, although essential tremor [61], Sydenham chorea [62] and they may not always be easily differentiated from Huntington disease gene carriers [63]. Age at onset psychogenic hyperkinesias. Chronicity, social is likely to be an important determinant of suscep- impairment, and stigma, however, can affect the tibility to psychiatric morbidity in many of these ability of patients with hyperkinetic disorders to conditions. develop or continue many of their key social roles, Given the complexity of basal ganglia functions, it such as marital or employment status, thus engen- is not surprising that hyperkinetic disorders are dering reactive depression or other secondary frequently associated with behavioral or psychological behavioral consequences. changes that, in many cases, are considered to have a pathogenic commonality with the motor disturbance. Basal ganglia pathology engenders a wide Clinical examination spectrum of neuropsychiatric symptoms [64], which and medical recording are thought to involve the associative circuit (focused on the dorsolateral caudate nucleus and the cau- Although the expert clinician can quickly attempt doventral putamen) and the emotional circuits (cen- to recognize the features of hyperkinetic disorders tered in the ventral caudate nucleus, the nucleus (Figure 1.3) it is necessary to accomplish a thorough accumbens, and the amygdala) [65, 66]. documentation of the observed features to avoid Particularly chorea, tics, and dystonia are mistakes and allow review and comparison of the coincident with obsessive-compulsive traits, anxiety, phenotype [26, 57]. or depression in different combinations and with Examination of patients with a hyperkinetic variable severity. Such coincidence may be due to movement disorder must include a full examination an underlying basal ganglia dysfunction produc- for associated neurological findings. It must also ing both motoric and behavioral expressivity. Of include an assessment of the effect of the movement particular interest is the finding that depression, disorder on overall motor function and quality of attention-deficit hyperactivity disorder and vocal tics life. Observation of the disorder itself should are significantly more common in children with include several components, including the Sydenham chorea, compared to children who had phenomenology of the disorder, the time-course, rheumatic fever without Sydenham chorea [67]. triggers and suppressibility, and the somatic Medication-related adverse effects may be an distribution (focal, segmental, multifocal, and additional source of depression or anxiety in patients generalized). The phenomenology should be with hyperkinetic movement disorders and cause described in terms of duration, speed, amplitude, akathisia or additional hyperkinesias [68–70]. jerkiness, repeatability, or stereotyped quality, and

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Figure 1.3 Flow chart for a quick Abnormal orientation in the differential diagnosis movements of the five main hyperkinetic disorders.

Rhythmic Arrhythmic

Tremor Sustained Rapid

Non Dystonia Suppressible suppressible

Chorea Tics

Myoclonus

Table 1.3 General features of hyperkinetic disorders.

Regularity Rhythmicity Speed Suppressibility Duration Triggerability

Tremor Yes Yes 1–16 Hz Sometimes Transient or Position, posture, briefly permanent voluntary movement Chorea No No Fast No Transient or Voluntary movement permanent Tics No No Slow Usually Transient or Sensory stimuli, stress, or fast permanent thoughts Myoclonus Sometimes Sometimes Fast No Transient or Sensory or permanent proprioceptive stimuli Dystonia No Rarely Slow Partial or only Transient, Specific motor tasks or fast briefly permanent or paroxysmal

the number of different identifiable movements or Distractibility evaluates whether unrelated mental postures. The time-course should be described in or physical tasks (as opposed to asking the patient terms of rhythmicity, whether it is intermittent to voluntarily suppress) result in movement with intervening more normal movement, whether suppression. Distractibility can be seen in tics, movements are sustained or ongoing, and whether stereotypies, and psychogenic movements. there are discrete submovements or movement Given the patient’s consent, it is valuable to take fragments or whether the movement appears to be a video of the clinical interview and medical continuously flowing. Possible triggers should be examination. This allows the examiner to review the assessed from the history and examination, phenomenology of the hyperkinetic disorder, to including attempted movement, posture, rest, and seek expert consultation and visually compare emotional state. Suppressibility can be tested in phenomenology changes during natural course of clinic or assessed from the history, and the presence the condition. It is particularly important to show as of an urge to move should be determined. clearly as possible on the video clip the features listed

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Table 1.4 Distinctive features of hyperkinetic disorders.

Hyperkinetic Clinical pattern Typical features Associated features disorder

Tremor Rhythmic oscillation of a body Regular, Cog-wheeling part around one or more joints oscillatory (postural tremor) Chorea Brief purposeless and quick Random, Hypotonia, motor movements that often progress arrhythmic, rapid, impersistence from proximal to distal segments occasionally (fluency) suppressible Ballism Violent flinging (usually Arrhythmic, Hypotonia unilateral) movements involving rapid, one limb and the shoulder in a non-suppressible coordinated way Tics Stereotyped intermittent Arrhythmic, Temporarily movements (motor tics) or sounds rapid, suppressible by will (phonic tics) with abrupt onset suppressible Athetosis Slow writhing movement or Arrhythmic, slow, sequence of postures involving sustained, the fingers, hand and wrist non-suppressible Myoclonus Sudden brief muscle jerks Arrhythmic, (positive myoclonus) or releases rapid, (negative myoclonus) of one or non-suppressible more motor units Dystonia Sustained patterned repetitive Arrhythmic, Gestes movements, often torsional, sustained, antagonistes, occasionally rhythmic, associated patterned, mirroring with abnormal postures non-suppressible

in Tables 1.3 and 1.4, allowing the specifics of the 4 Yaltho TC, Jankovic J. The many faces of hemifacial observed phenomena to be visually evaluated. spasm: differential diagnosis of unilateral facial A well-constructed video recording can convey more spasms. Mov Disord 2011; 26:1582–92. accurate information than standard clinical notes. 5 Jankovic J. Peripherally induced movement disorders. Neurol Clin 2009; 27:821–32. 6 Boissier de Sauvages F. Nosologia methodica sistens References morborum classes juxtà Sydenhami mentem & botanicorum ordinem. Amsterdam: De Tournes 1768. 1 Zaidel A, Arkadir D, Israel Z, Bergman H. Akineto-rigid 7 Parkinson J. An essay on the shaking palsy. London: vs. tremor syndromes in Parkinsonism. Curr Opin Sherwood, Neely and Jones 1817. Neurol 2009; 22:387–93. 8 Del Sorbo F, Albanese A. Levodopa-induced 2 World Health Oranization. International Statistical dyskinesias and their management. J Neurol 2008; Classification of Diseases and Related Health Problems. 255(Suppl 4):32–41. Tenth revision 2nd edition. Geneva: World Health 9 Bean WB. Sir William Osler Aphorisms. New York: Organization 2007. Henry Schuman, Inc 1950. 3 Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, 10 de la Boë F. Disputationes medicarum pars prima, Mink JW, et al. Definition and classification of hyperki- primarias corporis humani functiones naturales en netic movements in childhood. Mov Disord 2010; anatomicis, practicis et chymicis experimentiis deductas 15(25):1538–49. complectens. Amsterdam: van den Bergh 1663.

Albanese_c01.indd 12 12/24/2011 6:01:59 AM Distinguishing Clinical Features of Hyperkinetic Disorders 13

11 Charcot JM. Leçons sur les maladies du système 29 Jankovic J, Fahn S. Physiologic and pathologic nerveux. Paris: A. Delahaye 1872. tremors. Diagnosis, mechanism, and management. 12 Dana CL. Hereditary tremor: a hitherto undescribed Ann Intern Med 1980; 93:460–5. form of motor neurosis. Am J Med Sci 1887; 30 Jankovic J, Schwartz KS, Ondo W. Re-emergent 94:386–93. tremor of Parkinson’s disease. J Neurol Neurosurg 13 Waller J. A forgotten plague: making sense of dancing Psychiat 1999; 67:646–50. mania. Lancet 2009; 21(373):624–5. 31 Fekete R, Jankovic J. Revisiting the relationship 14 von Hohenheim P. Von den Krankheiten, so die between essential tremor and Parkinson’s disease. Vernunfft berauben. Basel: Adam of Bodenstein. Mov Disord 2011; 26:391–8. 1567. 32 Lalli S, Albanese A. The diagnostic challenge of 15 Sydenham T. Schedula monitoria de novae febris primary dystonia: evidence from misdiagnosis. Mov ingressu. London: G. Kettilby. 1686. Disord 2010; 15:1619–26. 16 Huntington G. On chorea. Medical and Surgical 33 Piboolnurak P, Yu QP, Pullman SL. Clinical and Reporter (Philadelphia) 1872; 26:317–21. neurophysiologic spectrum of orthostatic tremor: case 17 DeLahunta A, Glass E. Veterinary neuroanatomy and series of 26 subjects. Mov Disord 2005; 20:1455–61. clinical neurology 3rd ed. St. Louis: Saunders Elsevier. 34 Jankovic J. Tourette syndrome. Phenomenology and 2008. classification of tics. Neurol Clin 1997; 15:267–75. 18 Itard JMG. Mémoire sur quelques fonctions involon- 35 Krauss JK, Jankovic J. Severe motor tics causing taires des appareils de la locomotion, de la préhension cervical myelopathy in Tourette’s syndrome. Mov et de la voix. Archives Générales de Médecine 1825; Disord 1996; 11:563–6. 8:385–407. 36 Cavanna AE, Ali F, Leckman JF, Robertson MM. 19 Trousseau A. Clinique médicale de l’Hôtel-Dieu de Pathological laughter in Gilles de la Tourette syn- Paris 5 edn. Paris: J.-B. Baillière 1877. drome: an unusual phonic tic. Mov Disord 2010; 20 Gilles de la Tourette GE. La maladie des tics convulsifs. 15(25):2233–9. La Semaine Médicale 1899; 19:153–6. 37 Kovacs N, Herold R, Janszky J, Komoly S, Nagy F. Tics 21 Friedreich N. Neuropathologische Beobachtung beim status: a movement disorder emergency: observations. Paramyoklonus multiplex. Virchows Arch Path Anat J Neurol 2011; 258:143–5. 1881; 86:421–9. 38 Cheung MY, Shahed J, Jankovic J. Malignant Tourette 22 Lundborg H. Die progressive Myoklonus-Epilepsie syndrome. Mov Disord 2007; 15:1743–50. (Unverricht’s Myoklonie). Upsala: Almqvist & Wiksell 39 Jankovic J, Kurlan R. Tourette syndrome: evolving 1903. concepts. Mov Disord 2011; 26:1149–56. 23 Adams RD, Foley JM. The neurological disorders 40 Spitz M, Costa Machado AA, Carvalho Rdo C, Maia FM, associated with liver disease. Res Publ Assoc Res Nerv Haddad MS, Calegaro D, et al. Pseudoathetosis: report Ment Dis 1953; 32:198–237. of three patients. Mov Disord 2006; 21:1520–2. 24 Oppenheim H. Über eine eigenartige Krampfkrankheit 41 Halliday AM. The electrophysiological study of des kindlichen und jugendlichen Alters (Dysbasia myoclonus in man. Brain 1967; 90:241–84. lordotica progressiva, Dystonia musculorum defor- 42 Shibasaki H, Hallett M. Electrophysiological studies of mans). Neurolog Centralb 1911; 30:1090–7. myoclonus. Muscle Nerve 2005; 31:157–74. 25 Flatau E, Sterling W. Progressiver Torsionspasm bie 43 Deuschl G, Wilms H. Clinical spectrum and physiology Kindern. Z ges Neurol Psychiat 1911; 7:586–612. of palatal tremor. Mov Disord 2002; 17(Suppl 2), 26 Jankovic J, Lang AE. Movement disorders: diagnosis S63–S66. and assessment. In: Bradley WG, Daroff RB, Fenichel 44 Caviness JN, Brown P. Myoclonus: current concepts GM, Jankovic J, editors. Neurology in clinical practice, and recent advances. Lancet Neurol 2004; 3:598–607. 5th edn. Philadelphia, PA: Butterworth-Heinemann 45 Dijk JM, Tijssen MA. Management of patients with myo- (Elsevier) 2008; pp 293–325. clonus: available therapies and the need for an 27 Hallett M. Classification and treatment of tremor. evidence-based approach. Lancet Neurol 2010; 9:1028–36. JAMA 1991; 28(266):1115–17. 46 Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; 28 Deuschl G, Bain P, Brin M. Consensus statement of the 24:1725–31. Movement Disorder Society on Tremor. Ad Hoc 47 Meierkord H, Fish DR, Smith SJ, Scott CA, Shorvon SD, Scientific Committee. Mov Disord 1998; 13(Suppl 3): Marsden CD. Is nocturnal paroxysmal dystonia a form 2–23. of frontal lobe epilepsy? Mov Disord 1992; 7:38–42.

Albanese_c01.indd 13 12/24/2011 6:01:59 AM 14 Chapter 1

48 Fish DR, Sawyers D, Smith SJ, Allen PJ, Murray NM, 62 Maia DP, Teixeira AL, Jr., Quintao Cunningham MC, Marsden CD. Motor inhibition from the brainstem is Cardoso F. Obsessive compulsive behavior, hyperactiv- normal in torsion dystonia during REM sleep. J Neurol ity, and attention deficit disorder in Sydenham chorea. Neurosurg Psychiat 1991; 54:140–4. Neurology 2005; 24:1799–801. 49 Fahn S. Concept and classification of dystonia. Adv 63 van Duijn E, Kingma EM, van der Mast RC. Neurol 1988; 50:1–8. Psychopathology in verified Huntington’s disease gene 50 Pont-Sunyer C, Marti MJ, Tolosa E. Focal limb carriers. J Neuropsychiat Clin Neurosci 2007; 19:441–8. dystonia. Eur J Neurol 2010; 17(Suppl 1):22–7. 64 Saint-Cyr JA, Taylor AE, Nicholson K. Behavior and 51 Jankovic J, Ashoori A. Movement disorders in the basal ganglia. Adv Neurol 1995; 65:1–28. musicians. Mov Disord 2008; 30(23):1957–65. 65 de Olmos JS, Heimer L. The concepts of the ventral 52 Frucht SJ, Fahn S, Greene PE, O’Brien C, Gelb M, striatopallidal system and extended amygdala. Ann N Truong DD, et al. The natural history of embouchure Y Acad Sci 1999; 29(877):1–32. dystonia. Mov Disord 2001; 16:899–906. 66 Garcia-Cairasco N, Miguel EC, Rauch SL, Leckman JF. 53 Schrag A, Trimble M, Quinn N, Bhatia K. The Current controversies and future directions in basal syndrome of fixed dystonia: an evaluation of 103 ganglia research. Integrating basic neuroscience and patients. Brain 2004; 127:2360–72. clinical investigation. Psychiatr Clin North Am 1997; 54 Albanese A. The clinical expression of primary 20:945–62. dystonia. J Neurol 2003; 250:1145–51. 67 Marques-Dias MJ, Mercadante MT, Tucker D, 55 Sitburana O, Jankovic J. Focal hand dystonia, mirror Lombroso P. Sydenham’s chorea. Psychiat Clin North dystonia and motor overflow. J Neurol Sci 2008; Am 1997; 20:809–20. 15(266):31–3. 68 Kane JM, Fleischhacker WW, Hansen L, Perlis R, 56 Sitburana O, Wu LJ, Sheffield JK, Davidson A, Pikalov A, III, Assuncao-Talbott S. Akathisia: an Jankovic J. Motor overflow and mirror dystonia. updated review focusing on second-generation Parkinsonism Relat Disord 2009; 15:758–61. antipsychotics. J Clin Psychiat 2009; 70:627–43. 57 Fahn S, Jankovic J, Hallett M. Principles and practice 69 Sinclair LI, Christmas DM, Hood SD, Potokar JP, of movement disorders. Philadelphia, PA: Churchill Robertson A, Isaac A, et al. Antidepressant-induced Livingstone Elsevier 2011. jitteriness/anxiety syndrome: systematic review. 58 Gaze C, Kepley HO, Walkup JT. Co-occurring Br J Psychiat 2009; 194:483–90. psychiatric disorders in children and adolescents 70 Madhusoodanan S, Alexeenko L, Sanders R, with Tourette syndrome. J Child Neurol 2006; 21: Brenner R. Extrapyramidal symptoms associated with 657–64. antidepressants–a review of the literature and an 59 Brewer GJ. Behavioral abnormalities in Wilson’s analysis of spontaneous reports. Ann Clin Psychiat disease. Adv Neurol 2005; 96:262–74. 2010; 22:148–56. 60 Jahanshahi M. Behavioral and psychiatric manifesta- 71 Hammond WA. A treatise of diseases of the nervous tions in dystonia. Adv Neurol 2005; 96:291–319. system. New York: Appleton Century Crofts 1871. 61 Louis ED. Behavioral symptoms associated with 72 Kussmaul A. Ziemssen’s Handbuch der Speciellen essential tremor. Adv Neurol 2005; 96:284–90. Pathologie und Therapie. Leipzig: Vogel 1885.

Albanese_c01.indd 14 12/24/2011 6:01:59 AM CHAPTER 2 Pathophysiology and Molecular Pathology of Dystonia and Tics Marie Vidailhet, Michael Schupbach, and David Grabli Department of Neurology, ICM-CRICM Research Center, Salpetrière Hospital and Pierre and Marie Curie University, Paris, France

Introduction molecular pathology and dystonic phenotype is far from being bridged, identification of the functions In this chapter we focus on dystonia and tics as they of the mutated genes has been possible for some may share similarities in the pathophysiology:they primary dystonia forms providing new insight into can be considered as models of: dysfunction of the the pathophysiological processes underlying the basal ganglia-cortical pathways; the sensorimotor expression of these different clinical patterns loop for dystonia; and the motor, associative, and lim- (Table 2.1). Interestingly, several recent works have bic loops for tics and Gilles de la Tourette syndrome. highlighted functional links between the proteins encoded by these genes. DYT1 dystonia is related to mutations in the Dystonia TOR1A gene. Torsin A, an AAA+ ATPase, is a protein whose exact cellular function is not yet known. Dystonia is defined as involuntary, sustained and This protein may play a role in cellular membranes often repetitive, muscle contractions of opposite (nuclear envelope and endoplasmic reticulum) muscles that lead to abnormal movements or pos- homeostasis and may be involved in proteins ture. This definition, although commonly accepted, processing/trafficking and excretory pathways. does not reflect the complexity and variety of syn- Other potential functions include synaptic dromes enclosed within the denomination of dysto- vesicles recycling, neurite outgrow and postnatal nia. Here, we attempt to update the implication of maturation events involving neurons (especially at genetic forms in the pathophysiology of dystonia, the synaptic level) [2] and glia [3]. explore the animal models, and summarize recent DYT3 dystonia is caused by complex changes in advances in neuroimaging and neurophysiology. TAF1/DYT3 transcripts. TAF1/DYT3 comprises at least 43 exons that are alternatively spliced. Molecular pathology Alternative splicing of exon 1–38 encodes isoform Up to 20 genetic forms of dystonia have been of TATA box binding protein-associated factor identified to date [1]. The phenotype of these forms I (TAF1]. Exons d1–d5 located downstream to is presented in Chapter 7. Although the gap between exon 38 can either form separate transcripts

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Table 2.1 DYT coding for dystonia genes and locus.

Locus Inheritance Chromosome Gene Phenotype OMIM name

DYT1 AD 9q34 TOR1A Early onset idiopathic AAA+ ATPase: cellular 128100 torsion dystonia membranes homeostasy, protein trafficking and processing, neurite outgrow and vesicles recycling DYT2 AR NK NK AR torsion dystonia NK 224500 DYT3 XL Xq13.1 TAF1 X-linked dystonia- TATA box binding 314250 parkinsonism (Lubag) protein-associated factor I: regulation of transcription DYT4 AD Inconnu NK Hereditary whispering NK 128101 dystonia DYT5a AD 14q22.1-q22.2 GCH1 Dopa-responsive GTP-cyclohydrolase 1: first 128230 dystonia (DRD); Segawa and rate limiting enzyme syndrome; hereditary of pterines biosynthesis progressive dystonia with marked diurnal fluctuation DYT5b AR 11p15.5 TH Autosomal recessive Tyrosine hydroxylase: 605407 DRD; AR Segawa rate limiting enzyme of syndrome dopamine biosynthesis DYT6 AD 8p11.21 THAP1 Idiopathic torsion Thanatos associated 602629 dystonia of ‘mixed’ protein domain- type containing apoptosis- associated protein1: cell proliferation and survival; apoptosis; interaction with transcription factor DYT7 AD 18p NK Adult-onset focal NK 602124 dystonia DYT8 AD 2q35 MR1 Non-kinesigenic Myofibrillogenesis 118800 paroxysmal regulator 1: function not choreoathetosis clearly understood (PNKD1) DYT9 = AD 1p SLC2A1 Episodic NK 601042 DYT18 choreoathetosis/ spasticity and ataxia DYT10 AD 16q11.2-q12.1 NK Paroxysmal kinesigenic NK 128200 dyskinesia (PKD1) DYT11 AD 7q21 SGCE Myoclonus dystonia ε-sarcoglycan: function 159900 not known DYT12 AD 19q12-q13.2 ATP1A3 Rapid-onset Na/K ATPase subunit α3: 128235 dystonia-parkinsonism involvement in ion transfers through neurons membranes DYT13 AD 1p63.32-p36.13 NK Early onset cranio-facial NK 607671 dystonia DYT15 AD 18p11 NK Myoclonus dystonia NK 607488

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Table 2.1 (cont’d).

Locus Inheritance Chromosome Gene Phenotype OMIM name

DYT16 AR 2q31.3 PRKRA Early onset AR Protein kinase, interferon- 612067 dystonia–parkinsonism inducible double-stranded RNA-dependent activator: signal transduction, cellular proliferation and differentiation; apoptosis DYT17 AR 20p11.2-q13.12 NK AR torsion dystonia Glucose transporter 612406 (focal) 1 (Glut1): transport of glucose through blood brain barrier DYT18 AD 1p35-p31.3 SLC2A1 Paroxysmal exertion- NK 612126 induced dyskinesia DYT19 AD 16q13-q22.1 NK Paroxysmal kinesigenic NK 611031 dyskinesia (PKD2) DYT20 AD 2q31 NK Non-kinesigenic NK 611147 paroxysmal choreoathetosis (PNKD2) DYT21 AD 2q14.3-q21.3 NK late onset, focal, NK segmental,generalized dsytonia protein

AD: autosomal dominant; AR: autosomal recessive, XL: X-linked; NK: not known.

regulated by separate promoters [4]. or transcripts cellular processes as transcriptional regulation, spliced to some of exons 1–37 of TAF1 [5]. It is not signaling, proteasomal degradation and organelle clear how these changes in TAF1/DYT3 transcript trafficking [9]. system cause the disease but several lines of DYT11 dystonia is related to mutations in the evidence point to modifications of D2 receptors SGCE gene. They result in the synthesis of either expression or disruption of various gene expres- aberrant e-sarcoglycan molecules or none at all, sion in the striatum [1]. and are “loss of function” [10]. The spectrum of DYT6 dystonia is caused by mutations in the gene myoclonus dystonia-DYT11 associated with muta- that encodes THAP (thanatos- associated protein) tions within the SGCE gene [11] has been expanded domain-containing apoptosis-associated protein to microdeletion [12] and Silver–Russel syndrome 1 (THAP1] [6, 7]. In addition to the identified (uniparental disomy of chromosome 7). mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia [6]. The Outline of a dystonia molecular THAP1 protein is a sequence-specific DNA-binding network factor which regulates cell proliferation and plays Links between DYT1 and DYT6 roles in cell survival and/or apoptosis. [8]. Recently, Recent evidence suggests that THAP1 is able to THAP1 was found to bind two proteins: HCF–1 interact with the promoter of DYT1/TOR1A and protein, a potent transcriptional coactivator and that THAP1 mutations causing dystonia alter this cell cycle regulator, and OGT protein, a O-linked interaction. However, it was not possible to prove N-acetylglucosamine (O-GlcNAc) transferase, an in blood cells or fibroblast lines that DYT1 expres- enzyme which plays an role in a whole host of sion was reduced in THAP1-mutated patients or

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increased by THAP1 overexpression. This direct perfectly mimic the complexity of the clinical fea- interaction may thus only occur in specific region tures observed in humans. These various models of the brain or at key developmental steps [13]. basically display dysfunctions within the main motor networks. Links between DYT6 and DYT3 THAP1 shares sequence characteristics, in vivo Cortex–basal ganglia loops expression patterns and protein partners with Various types of dystonia, from abnormal postures THAP3 [9]. Transcriptional dysregulation leading to to phasic movements or myoclonic dystonia [21], increased neuronal vulnerability, may contribute have been produced after microinjections of bicuc- to diseases such as DYT6 and DYT3 (X-linked ulline (antagonist of GABA-A receptors) into the dystonia-parkinsonism) caused by reduced expres- posterior putamen, corresponding to the sensori- sion of RNA polymerase II TATA box-binding motor territory [22] and the sensorimotor territory protein- associated factor 1 (TAF1). In these two of the external globus pallidus (GPe) [23]. Injections diseases, THAP1 (DYT6) and TAF1 (DYT3) are cru- within the thalamus [ventral lateralis, nucleus pars cial to cell-cycle progression in dividing cells and oralis (VLo) and ventral anterior nucleus (VA)] mutations in either protein is likely to favor cell- induced contralateral dystonic postures, whereas cycle arrest and probably cell death [14]. In addi- injections in the caudal part [ventral posterolateral tion, THAP3 interacts with HCF–1 through a nucleus, pars oralis (VPLo) and ventralis lateralis consensus HCF–1-binding motif (HBM), a motif nucleus, pars caudalis (VLc] induced myoclonic that is also present in THAP1 and the gene encod- dystonia. This suggested that dystonia might result ing the THAP1/DYT6 protein partner OGT maps from a dysfunction of the motor pallidal relay (ros- within the DYT3 critical region on Xq13.1 [9]. tral) but also points to the cerebellar relay (caudal) A link may also exist between DYT1 and DYT6. of the thalamus [21]. Impairment of synaptic plasticity in the striatum is a critical point and has Dopamine dysfunction: a link between been demonstrated in DYT1 mice models. Abnormal DYT1, DYT11 plasticity in the cortex-basal ganglia loop is under- A beneficial effect of levodopa has been observed in lined by aberrant long-term potentiation (LTP) and some myoclonus-dystonia patients [15]. The SCGE depression (LTD) phenomena [24, 25] with an gene is also strongly expressed in dopaminergic unbalanced cholinergic transmission. Systemic neurons. Dysregulation of dopamine release has 3-NP increased NMDA receptor-dependent LTP at been observed in animal models and reduced dopa- the level of the corticostriatal synapses [26]. At the mine D2 receptor availability was found in patients. cortical level, in the SMA proper, there is also an The role of dopamine dysfunction in DYT1 dystonia increase in excitability and loss of selectivity [21]. has been emphasized [16–18]: dopamine trans- Lesions and pharmacological manipulations of the porter activity is reduced in DYT1 animal models, brainstem (e.g. interstitial nucleus of Cajal, pedun- with altered dynamics of reuptake and release of culopontine nucleus, and red nucleus that receives dopamine [19]. In addition, reduced striatal D2 input from the basal ganglia and the cerebellum) receptor binding was found in DYT11 [20]. Finally, may elicit dystonic movements [27]. TAF1, implicated in Lubag (DYT3 dystonia) may also play a role in the regulation of the DRD2 gene, Cerebellum–basal ganglia-cortex and a decreased expression of the DRD2 gene has Based on two animal models with dystonic move- been found. Together, these results suggest that ments originating from cerebellar dysfunctions, the alteration in the dopamine signaling pathway may role of the cerebellum in the pathophysiology of be crucial in various forms of dystonia. dystonia has been emphasized [28]. Additional subclinical lesions of the striatum exaggerated the Animal models dystonic attacks [29]. Moreover, in normal mice, Several animal models have been developed when dystonic movements were triggered by a throughout the years, although none of them can local application of kainic acid on the cerebellar

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cortex, microdialysis revealed a reduction in striatal (manifesting and non-manifesting carriers), whereas dopamine release [29] Taken together, these various DYT6 individuals had normal performance. This results in mice support the hypothesis that dystonia interaction between phenotype (dystonia) and may arise from the dysfunction of a motor network genotype (DYT1 status) was further explored by involving the basal ganglia, the cerebellum, the comparing symptomatic and asymptomatic DYT1 cortex, and the dopaminergic system. Apart from carriers with non-DYT1 dystonic patients (either the interaction at the cortical level, a disynaptic sporadic or with a family history) [41]. The functional pathway linking an output stage of cerebellar activation was predominant in the lateral cerebellum processing (dentate nucleus) with an input stage of with relative activation deficits in the bilateral basal ganglia processing (striatum) was recently dorsolateral prefrontal cortex, and the left cingulated demonstrated [30]. Cortical areas (the SMA and the and dorsal premotor cortex [42], suggesting a shift pre-SMA) are also the targets of disynaptic from the cortico-striato-pallida-thalamocortical to projections from the dentate nucleus of the cerebellar pathways. Whether this balance between cerebellum and from the GPi [31, 32]. striatal and cerebellar processing is secondary to functional or structural abnormalities in the basal Sensorimotor disruption ganglia, or reflects compensatory mechanisms, is still Environmental factors a matter of debate. Some arguments support the fact that there is a In an important review on the abnormal link between stereotyped, skilled repetitive move- structure–function relationship in hereditary dys- ments and the vulnerability to develop task- specific tonia[43], the metabolic patterns and anatomical dystonia. In a large case-control study [33], the risk connectivity relative to penetrance and genotype of being affected by writer’s cramp increased pro- (DYT1 and DYT6) were extensively described: gressively with the time spent writing each day and an increased activity pattern distinguished the was also associated with an abrupt increase in the dystonia-manifesting carriers, across genotypes. writing time during the year before onset, but this A recent study on DYT11 myoclonus-dystonia finding must be interpreted cautiously because of demonstrated disorganized sensorimotor integra- the strong possibility of a retrospective recall bias. tion [44]. Measurements of the basal ganglia volumes may have an importance for the phenotypic Imaging studies expression of dystonia (asymptomatic DYT1 carri- Although brain MRI was previously thought to be ers and larger than those of symptomatic DYT1 normal in dystonia, structural (VBM, DTI) [34] and patients [41]) and for the detection of endopheno- functional [35] abnormalities were recently dem- type (unaffected relatives of patients with sporadic onstrated within the sensorimotor network (includ- cervical dystonia, who had abnormal sensori- ing the putamen, the thalamus, and the cortical determination, had reduced putaminal gray matter representation of the hand) and the cerebellum in volume bilaterally compared with those with nor- various types of dystonia [34, 36]. Additional com- mal SDT [45]. Overall, these findings point toward monalities between different types of dystonia was a pathophysiological core common to several types supported by the finding of alterations of the fibers of genetic or sporadic dystonia. connecting: (i) the primary sensorimotor areas with subcortical structures in writer’s cramp [37, Electrotrophysiological studies 38]; (ii) the thalamic prefrontal connections in a Abnormal modulation of cortical excitability in small group of various focal dystonia [39]; and (iii) sporadic and DYT1 dystonia [46], and abnormal the pontine brainstem in the vicinity of the supe- plasticity [47, 48] in DYT1 and sporadic dystonia, rior cerebellar peduncle and the sensorimotor are hallmarks of the disease. Other abnormalities region in DYT1 and DYT6 patients [40]. appear to be common to sporadic and DYT1 Sequence learning abnormalities were related to dystonia, such as alterations in sensory processing the genotype as reduced performance was observed [49], inner representation of the body (including a in DYT1 individuals, regardless of the phenotype non-manifesting carriers) [50], and per- operative

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GPi recordings [51]. In contrast, DYT11 more than 3 months; the onset of tics must be myoclonus-dystonia appears different since corti- before the age of 18 (DSM-IV-TR) or 21 (Tourette cal excitability is normal (hypothetically related to Syndrome Classification Study Group) depending neuron membrane properties) [52]. on the diagnostic criteria applied. TS is in many cases accompanied by comorbid psychiatric An integrative model of the features such as obsessive-compulsive symp- pathophysiology of dystonia toms (OCS), attention deficit hyperactivity Despite the multiple phenotypes and genotypes of disorder (ADHD), self-injurious behavior, and dystonia, imaging and experimental data points to a other behavioral problems. No single cause of TS disorder of the basal ganglia and the sensorimotor has been identified so far. However, genetic, circuits, including, more recently, the cerbello- anatomical, neuroradiologic, and animal model thalamo-cortical pathways [53, 54]. Aberrant plas- studies have shed light on possible pathogenic ticity (either maladaptative or developmental) is the mechanisms of TS. hallmark of dystonia at the striatal (with impaired synaptic plasticity – with a role of cholinergic fast- Genetic aspects spiking interneurons and of dopamine imbalance) There is strong evidence in favor of a genetic base and cortical levels [48]. In monogenic forms of dys- of TS. Concordance rates for tic disorders are tonia (e.g. DYT1, DYT6, DYT3), imbrications of pro- 77–100% in monozygotic twins but only 23% in teins and genes functions suggest the existence of dizygotic twins. Family studies show a 10- to 100- some common (although poorly understood) path- fold increased risk of having TS in first-degree rela- ways. Functional imaging may help to disentangle tives of TS patients and that chronic tics are more the mechanisms underlying the phenotypic expres- common among first-degree relatives of TS patients sion of the disease as activated networks are differ- than in the general population (for a review see ent in symptomatic and asymptomatic carriers of O’Rourke et al. [57]. TS and chronic tic disorders DYT1 and DYT6 subjects. Neuro-imaging may also are therefore likely to represent manifestations of open some insight in the compensatory mecha- different severity that belong to the same disease nisms (activation studies, striatal volume measures). entity. However, familial aggregation of TS does not Finally, animal models may be more useful for stud- prove a genetic cause as family members share a ying the pathogenesis of dystonia at the molecular common environment. Comorbid psychiatric con- and cellular levels than for mimicking; the pheno- ditions are common among patients with TS, and typic expressions of the human disease. only 12% show a pure movement disorder [58]. OCS and ADHD affect more than 50% of patients with TS [58, 59] – a significantly higher proportion Gilles de la Tourette syndrome than in the general population. Linkage analyses showed an association of TS Tics are sudden, brief, intermittent, repetitive, with various markers, including chromosome non-rhythmic stereotyped movements (simple or 2p23.2, 5p, 6p, and 14q [57]. The Slit and Trk-like complex motor tics) or vocalizations (phonic tics, family member 1 (SLITRK1) was selected as a can- coprolalia, echolalia) that can be voluntarily didate gene [60]. However, the association suppressed (for at least one minute) at the price between this gene and TS has not been confirmed of an increasing discomfort that is transiently in several subsequent studies [57, 61]. Other can- relieved by the execution of the tic [55]. Gilles de didate gene studies focused on genes involved la Tourette syndrome (TS) has been arbitrarily with the dopaminergic neurotransmission but defined [56] by the occurrence of multiple motor failed to identify a causative susceptibility gene plus one or more vocal tics that are present not for TS. Multiple rare copy number variants (CNVs) necessarily concurrently, but on most days over including genomic deletions and duplications at least one year, and without a tic-free period of were associated in a subset of patients with

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TS [62]. Recently, a genome wide linkage analysis and cholinergic striatal interneurons points to an in a large family with autosomal dominant trans- alteration of the cortico-striato-pallido-thalamic mission of TS revealed a mutation in the HDC circuitry in TS with impaired corticothalamic gene encoding L-histidine decarboxylase, the control of striatal neuronal activity [66]. rate-limiting enzyme in histamine synthesis [63], supporting a role for histamine in the pathogene- Imaging studies sis of TS. The relatively disappointing results of Structural imaging studies genetic research in this highly inheritable condi- Neuroimaging studies have provided contradictory tion could be due to the involvement of several findings [67]. Increased proportion of white matter genes and complex genetic interactions in the in the right frontal lobe,[68]. increased cortical vol- pathogenesis of TS. Moreover, the phenotypic umes in the dorsal prefrontal and parieto-occipital definition of “cases” for linkage studies is difficult regions, reduced inferior occipital cortical volumes because TS is only the extreme manifestation at and frontal and parietal cortical thinning has been one end of the broad spectrum of tic disorders, described [69, 70]. Reduced gray matter resulting and it is unclear whether mild simple tics, or in smaller hemispheric volumes has recently also psychiatric conditions such as OCS and ADHD been demonstrated in the cerebellum of TS patients without tics, represent an attenuated expression [71]. Smaller volumes of the basal ganglia (caudate of the same genetic condition as TS. and lenticular nuclei) were observed. The severity of tics in early adulthood correlated with the childhood caudate volumes in a prospective long-term Histological studies study [72]. Bilateral fractional anisotropy increase Few brains from patients with TS have been was observed in the corpus callosum [73] in the histologically examined, but an increased density of white matter underlying the post- and precentral small striatal neurons has been observed. In another gyrus, below the left supplementary motor area, case, a decrease of dynorphin, especially in the and in the right ventro-postero-lateral part of the dorsal part of the external segment of the globus thalamus. The increase in regional underlying the pallidus and the ventral pallidum, pointed toward a left postcentral gyrus correlated with tic severity loss of dynorphin in the striatopallidal projections [74]. It was hypothesized that the morphological [64]. As compared to normal controls, 3 patients cortical and subcortical alterations in patients with with severe TS had a higher total number of TS could be cause as well as compensatory process neurons in the internal segment of the globus of the disease. pallidus and a lower number of neurons in the external pallidum and in the caudate. The number Functional imaging studies and proportion of neurons that were positive for Ligand studies with single photon emission the calcium-binding protein parvalbumin were computed tomography (SPECT) or positron emis- increased in the globus pallidus internus, whereas sion tomography (PET) have focused on the the density of parvalbumin-positive neurons was dopamine and serotonin systems because of the decreased in the putamen and caudate [65]. therapeutic implication of these systems in TS. The same group recently reported a 50–60% However, several studies did not reveal any differ- decrease of parvalbumin-positive and choline ences between patients with TS and healthy con- acetyltransferase-positive cholinergic interneurons trols. Moreover, neuroleptic medication could have in the caudate and the putamen in 5 patients with altered the results in some patients. An increased TS as compared to normal controls. Interestingly, dopamine activity has been found mainly in the left the sensorimotor and associative regions, but not striatum, possibly more pronounced in the ventral the limbic parts of the striatum, were affected. The area [75] and amphetamine challenge has shown a imbalance in striatal and pallidal neuron distribu- relatively overactive striatal [76] and extrastriatal tion with a selective deficit of parvalbumin-positive [77] dopaminergic system.

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Studies using fMRI found decreased pallidal and connected with prefrontal cortical areas implicated putaminal activity and an increase of activity in the in TS. More recently, bicuculline injections in the ventral head of the right caudate nucleus [78] and ventral striatum of monkeys resulted in either hypo- frontostriatal activation [79] during tic suppression. activity without motor slowing, sexual behavior, or The largest fMRI study in TS [80] used the Stroop stereotypy, whereas injections in the sensorimotor test (a test involving mainly the frontostriatal and associative regions of the striatum led to hyper- circuits) as a paradigm in a cross-sectional sample kinetic manifestations, attention-deficit and of TS patients. There were age-related differences impulsivity [22]. between patients with TS and controls, especially an absence of the relative deactivation of the An integrative model of the posterior cingulate cortex with age in TS patients. pathophysiology of TS Moreover, frontostriatal activity increased with age Even though the cause of TS remains elusive, the in controls but not in TS patients [80]. A study anatomical, imaging, and experimental data point to addressing resting-state functional connectivity in a disorder of the basal ganglia and the frontocortical adolescent TS patients [81] suggest abnormal mat- circuits. Mink [84] proposed a model of TS with uration of cingulate and frontostriatal circuits. selective facilitation and surround-inhibition of Increased activity was observed in the paralimbic specific motor and non-motor programs of the basal (anterior cingulate and insula), sensory association ganglia and frontocortical circuitry. The execution of (parietal operculum), and premotor (supplemen- unwanted motor programs results in motor or vocal tary motor area) cortex during the premonitory tics; the execution of unwanted associative programs phase. At the onset of the tic, the superior parietal may be related to attention-deficit and hyperactivity; lobule, cerebellum, and motor cortex became and the execution of unwanted limbic programs activated and the activity in the paralimbic cortex may be related to obsessive-compulsive symptoms and supplementary motor area was reduced [82]. [85]. The genetic contribution to the disease is Overall, varied and sometimes contradictory complex and may in most cases concern susceptibility findings of functional imaging in TS point to a to develop the clinical disorder. The therapeutic complex and dynamic involvement of different response to dopamine blocking drugs (or in some cerebral systems, including areas outside the cases dopamine agonists) illustrates that the cortico-striato-thalamo-cortical circuitry. Basal gan- dopaminergic system is pivotal in the pathogenesis glia are hypoactive with (possibly compensatory) of TS although the exact mechanisms remain to be hyperactivity of the cortical motor and premotor elucidated. The therapeutic response to deep brain regions. The striatum, mainly its ventral part, is the stimulation [86–88] in different target in the basal most commonly involved brain area, and changes ganglia circuitry (including pallidum and thalamus), are more commonly observed on the left side. as well as the results of functional imaging studies, Animal models underline the basal ganglia dysfunction in TS. The Since the pathogenesis of TS is incompletely anatomical data point to a developmental cause (e.g. understood, it is difficult to develop an animal model altered tangential neuronal migration affecting the with high construct validity. However, in monkeys, neuronal distribution in the basal ganglia) and to injections of the GABA antagonist bicuculline into additional compensatory consequences (altered the associative part of the external pallidum produced cortical volumes and fractional anisotropy). attention deficit and hyperactivity, and injections into the limbic part induced stereotypy [23]. These References results suggested the involvement of the associative and limbic parts of the basal ganglia in TS. Moreover, 1 Muller U. The monogenic primary dystonias. Brain anatomical tracing confirmed the segregated parallel 2009; 132: 2005–25. organization of the distinct sensorimotor, associative, 2 Granata A, Watson R, Collinson LM, Schiavo G, Warner and limbic circuits [83] that are topographically TT. The dystonia-associated protein torsinA modulates

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synaptic vesicle recycling. J Biol Chem 2008; 17 Zhao Y, DeCuypere M, LeDoux MS. Abnormal motor 283:7568–79. function and dopamine neurotransmission in DYT1 3 Zhao Y, Xiao J, Ueda M, et al. Glial elements DeltaGAG transgenic mice. Exp Neurol 2008; contribute to stress-induced torsinA expression in the 210:719–30. CNS and peripheral nervous system. Neurosci 2008; 18 Balcioglu A, Kim MO, Sharma N, Cha JH, Breakefield 155:439–53. XO, Standaert DG. Dopamine release is impaired in a 4 Herzfeld T, Nolte D, Muller U. Structural and functional mouse model of DYT1 dystonia. J Neurochem 2007; analysis of the human TAF1/DYT3 multiple transcript 102:783–8. system. Mamm Genome 2007; 18:787–95. 19 Hewett J, Johanson P, Sharma N, Standaert D, 5 Nolte D, Niemann S, Muller U. Specific sequence Balcioglu A. Function of dopamine transporter is changes in multiple transcript system DYT3 are compromised in DYT1 transgenic animal model in associated with X-linked dystonia parkinsonism. Proc vivo. J Neurochem 2010; 113:228–35. Natl Acad Sci USA 2003; 100:10347–52. 20 Beukers RJ, Booij J, Weisscher N, Zijlstra F, van 6 Djarmati A, Schneider SA, Lohmann K, et al. Amelsvoort TA, Tijssen MA. Reduced striatal D2 Mutations in THAP1 (DYT6]. and generalised dystonia receptor binding in myoclonus-dystonia. Eur J Nucl with prominent spasmodic dysphonia:a genetic Med Mol Imaging 2009; 36:269–74. screening study. Lancet Neurol 2009; 8:447–52. 21 Guehl D, Cuny E, Ghorayeb I, Michelet T, Bioulac 7 Fuchs T, Gavarini S, Saunders-Pullman R, et al. B, Burbaud P. Primate models of dystonia. Prog Mutations in the THAP1 gene are responsible for DYT6 Neurobiol 2009; 87:118–31. primary torsion dystonia. Nat Genet 2009; 41:286–8. 22 Worbe Y, Baup N, Grabli D, et al. Behavioral and 8 Roussigne M, Cayrol C, Clouaire T, Amalric F, Girard movement disorders induced by local inhibitory JP. THAP1 is a nuclear proapoptotic factor that links dysfunction in primate striatum. Cereb Cortex 2009; prostate-apoptosis-response–4 (Par–4]. to PML 19:1844–56. nuclear bodies. Oncogene 2003; 22:2432–42. 23 Grabli D, McCairn K, Hirsch EC, et al. Behavioural 9 Mazars R, Gonzalez-de-Peredo A, Cayrol C, et al. disorders induced by external globus pallidus The THAP-zinc finger protein THAP1 associates with dysfunction in primates: I. Behavioural study. Brain coactivator HCF–1 and O-GlcNAc transferase: a link 2004; 127:2039–54. between DYT6 and DYT3 dystonias. J Biol Chem 24 Martella G, Tassone A, Sciamanna G, et al. Impairment 2010; 285:13364–71. of bidirectional synaptic plasticity in the striatum of a 10 Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli D, mouse model of DYT1 dystonia: role of endogenous Roze E. Myoclonus-dystonia: an update. Mov Disord acetylcholine. Brain 2009; 132:2336–49. 2009; 24:479–89. 25 Pisani A, Bernardi G, Ding J, Surmeier DJ. Re-emergence 11 Roze E, Apartis E, Clot F, et al. Myoclonus-dystonia: of striatal cholinergic interneurons in movement clinical and electrophysiologic pattern related to SGCE disorders. Trends Neurosci 2007; 30:545–53. mutations. Neurol 2008; 70:1010–16. 26 Akopian G, Crawford C, Beal MF, et al. Decreased 12 Saugier-Veber P, Doummar D, Barthez MA, et al. striatal dopamine release underlies increased expres- Myoclonus dystonia plus syndrome due to a novel sion of long-term synaptic potentiation at corticostria- 7q21 microdeletion. Am J Med Genet A 2010; tal synapses 24 h after 3-nitropropionic-acid-induced 152A:1244–9. chemical hypoxia. J Neurosci 2008; 28:9585–97. 13 Gavarini S, Cayrol C, Fuchs T, et al. Direct interaction 27 Pong M, Horn KM, Gibson AR. Pathways for control between causative genes of DYT1 and DYT6 primary of face and neck musculature by the basal ganglia and dystonia. Ann Neurol 2010; 68:549–53. cerebellum. Brain Res Rev 2008; 58:249–64. 14 Tamiya G. Transcriptional dysregulation: a cause of 28 Jinnah HA, Hess EJ. A new twist on the anatomy of dystonia? Lancet Neurol 2009; 8:416–18. dystonia: the basal ganglia and the cerebellum? Neurol 15 Luciano MS, Ozelius L, Sims K, Raymond D, Liu L, 2006; 67:1740–1. Saunders-Pullman R. Responsiveness to levodopa in 29 Chen G, Popa LS, Wang X, et al. Low-frequency epsilon-sarcoglycan deletions. Mov Disord 2009; oscillations in the cerebellar cortex of the tottering 24:425–8. mouse. J Neurophysiol 2009; 101:234–45. 16 Sciamanna G, Bonsi P, Tassone A, et al. Impaired 30 Neychev VK, Fan X, Mitev VI, Hess EJ, Jinnah HA. striatal D2 receptor function leads to enhanced GABA The basal ganglia and cerebellum interact in the transmission in a mouse model of DYT1 dystonia. expression of dystonic movement. Brain 2008; Neurobiol Dis 2009; 34:133–45. 131:2499–2509.

Albanese_c02.indd 23 12/24/2011 6:02:53 AM 24 Chapter 2

31 Hoshi E, Tremblay L, Feger J, Carras PL, Strick PL. endophenotype in adult onset primary torsion The cerebellum communicates with the basal ganglia. dystonia. Brain 2009; 132:2327–35. Nat Neurosci 2005; 8:1491–3. 46 Quartarone A, Rizzo V, Terranova C, et al. Abnormal 32 Bostan AC, Dum RP, Strick PL. The basal ganglia sensorimotor plasticity in organic but not in communicate with the cerebellum. Proc Natl Acad Sci psychogenic dystonia. Brain 2009; 132:2871–7. USA 2010; 107:8452–6. 47 Tamura Y, Ueki Y, Lin P, et al. Disordered plasticity in 33 Roze E, Soumare A, Pironneau I, et al. Case-control the primary somatosensory cortex in focal hand study of writer’s cramp. Brain 2009; 132:756–64. dystonia. Brain 2009; 132:749–55. 34 Delmaire C, Vidailhet M, Elbaz A, et al. Structural 48 Quartarone A, Morgante F, Sant’angelo A, et al. abnormalities in the cerebellum and sensorimotor Abnormal plasticity of sensorimotor circuits extends circuit in writer’s cramp. Neurol 2007; 69:376–80. beyond the affected body part in focal dystonia. 35 Carbon M, Argyelan M, Habeck C, et al. Increased J Neurol Neurosurg Psychiat 2008; 79:985–90. sensorimotor network activity in DYT1 dystonia: a 49 Tinazzi M, Fiorio M, Fiaschi A, Rothwell JC, Bhatia functional imaging study. Brain 2010; 133:690–700. KP. Sensory functions in dystonia: insights from 36 Egger K, Mueller J, Schocke M, et al. Voxel based behavioral studies. Mov Disord 2009; 24:1427–36. morphometry reveals specific gray matter changes in 50 Fiorio M, Gambarin M, Defazio G, et al. Impaired body primary dystonia. Mov Disord 2007; 22:1538–42. movement representation in DYT1 mutation carriers. 37 Fabbrini G, Pantano P, Totaro P, et al. Diffusion tensor Clin Neurophysiol 2008; 119:1864–9. imaging in patients with primary cervical dystonia and 51 Zittel S, Moll CK, Hamel W, et al. Successful GPi deep in patients with blepharospasm. Eur J Neurol 2008; brain stimulation in a patient with adult onset primary 15:185–9. axial dystonia. J Neurol Neurosurg Psychiat 2009; 38 Delmaire C, Vidailhet M, Wassermann D, et al. 80:811–12. Diffusion abnormalities in the primary sensorimotor 52 Meunier S, Lourenco G, Roze E, Apartis E, Trocello pathways in writer’s cramp. Arch Neurol 2009; JM. Cortical excitability in DYT–11 positive myoclonus 66:502–8. dystonia. Mov Disord 2008; 23:761–4. 39 Bonilha L, de Vries PM, Hurd MW, et al. Disrupted 53 Hallett M. Pathophysiology of dystonia. J Neural thalamic prefrontal pathways in patients with Transm Suppl 2006:485–8. idiopathic dystonia. Parkinsonism Relat Disord 2009; 54 Vidailhet M, Grabli D, Roze E. Pathophysiology of 15:64–7. dystonia. Curr Opin Neurol 2009; 22:406–13. 40 Carbon M, Kingsley PB, Tang C, Bressman S, Eidelberg 55 Leckman JF BM, King RA, Scahill L. Phenomenology D. Microstructural white matter changes in primary of tics and natural history of tic disorders. Adv Neurol torsion dystonia. Mov Disord 2008; 23:234–9. 2006; 99:1–16. 41 Draganski B, Schneider SA, Fiorio M, et al. Genotype- 56 Freeman RD, Fast DK, Kent M. DSM-IV criteria for phenotype interactions in primary dystonias revealed Tourette’s. J Am Acad Child Adolesc Psychiat 1995; by differential changes in brain structure. Neuroimage 34:400–1. 2009; 47:1141–7. 57 O’Rourke JA, Scharf JM, Yu D, Pauls DL. The genetics 42 Carbon M, Ghilardi MF, Argyelan M, Dhawan V, of Tourette syndrome: a review. J Psychosom Res Bressman SB, Eidelberg D. Increased cerebellar 2009; 67:533–45. activation during sequence learning in DYT1 58 Freeman RD, Fast DK, Burd L, et al. An international carriers: an equiperformance study. Brain 2008; perspective on Tourette syndrome: selected findings 131:146–54. from 3,500 individuals in 22 countries. Dev Med Child 43 Argyelan M, Carbon M, Niethammer M, et al. Neurol 2000; 42:436–47. Cerebellothalamocortical connectivity regulates pene- 59 Saccomani L, Fabiana V, Manuela B, Giambattista trance in dystonia. J Neurosci 2009; 29:9740–7. R. Tourette syndrome and chronic tics in a sample 44 Beukers RJ, Foncke EM, van der Meer JN, et al. of children and adolescents. Brain Dev 2005; Disorganized sensorimotor integration in mutation- 27:349–52. positive myoclonus-dystonia: a functional magnetic 60 Miranda DM, Wigg K, Kabia EM, et al. Association of resonance imaging study. Arch Neurol 2010; SLITRK1 to Gilles de la Tourette Syndrome. Am J Med 67:469–74. Genet B Neuropsychiatr Genet 2009; 150B:483–6. 45 Bradley D, Whelan R, Walsh R, et al. Temporal 61 Scharf JM, Moorjani P, Fagerness J, et al. Lack of discrimination threshold: VBM evidence for an association between SLITRK1var321 and Tourette

Albanese_c02.indd 24 12/24/2011 6:02:53 AM Pathophysiology and Molecular Pathology of Dystonia and Tics 25

syndrome in a large family-based sample. Neurol 75 Rickards H. Functional neuroimaging in Tourette 2008; 70:1495–6. syndrome. J Psychosom Res 2009; 67:575–84. 62 Sundaram SK, Huq AM, Wilson BJ, Chugani HT. 76 Wong DF, Brasic JR, Singer HS, et al. Mechanisms Tourette syndrome is associated with recurrent exonic of dopaminergic and serotonergic neurotransmission copy number variants. Neurol 2010; 74:1583–90. in Tourette syndrome: clues from an in vivo 63 Ercan-Sencicek AG, Stillman AA, Ghosh AK, et al. neurochemistry study with PET. Neuropsychopharmacol L-Histidine Decarboxylase and Tourette’s Syndrome. 2008; 33:1239–51. N Engl J Med. 2010; 362:1901–8. 77 Steeves TD, Ko JH, Kideckel DM, et al. Extrastriatal 64 Haber SN, Kowall NW, Vonsattel JP, Bird ED, Richardson dopaminergic dysfunction in tourette syndrome. Ann EP, Jr. Gilles de la Tourette’s syndrome. A postmortem Neurol 2010; 67:170–81. neuropathological and immunohistochemical study. 78 Peterson BS, Skudlarski P, Anderson AW, et al. J Neurol Sci 1986; 75:225–41. A functional magnetic resonance imaging study of tic 65 Kalanithi PS, Zheng W, Kataoka Y, et al. Altered suppression in Tourette syndrome. Arch Gen Psychiat parvalbumin-positive neuron distribution in basal 1998; 55:326–33. ganglia of individuals with Tourette syndrome. Proc 79 Mazzone L, Yu S, Blair C, et al. An FMRI study of Natl Acad Sci USA 2005; 102:13307–12. frontostriatal circuits during the inhibition of eye 66 Kataoka Y, Kalanithi PS, Grantz H, et al. Decreased blinking in persons with Tourette syndrome. Am number of parvalbumin and cholinergic interneurons J Psychiat 2010; 167:341–9. in the striatum of individuals with Tourette syndrome. 80 Marsh R, Zhu H, Wang Z, Skudlarski P, Peterson BS. J Comp Neurol 2010; 518:277–91. A developmental fMRI study of self-regulatory control 67 Plessen KJ, Bansal R, Peterson BS. Imaging evidence in Tourette’s syndrome. Am J Psychiat 2007; for anatomical disturbances and neuroplastic 164:955–66. compensation in persons with Tourette syndrome. 81 Church JA, Fair DA, Dosenbach NU, et al. Control J Psychosom Res 2009; 67:559–73. networks in paediatric Tourette syndrome show 68 Fredericksen KA, Cutting LE, Kates WR, et al. immature and anomalous patterns of functional Disproportionate increases of white matter in right connectivity. Brain 2009; 132:225–38. frontal lobe in Tourette syndrome. Neurol 2002; 82 Bohlhalter S, Goldfine A, Matteson S, et al. Neural 58:85–9. correlates of tic generation in Tourette syndrome: an 69 Sowell ER, Kan E, Yoshii J, et al. Thinning of event-related functional MRI study. Brain 2006; sensorimotor cortices in children with Tourette 129:2029–37. syndrome. Nat Neurosci 2008; 11:637–9. 83 Francois C, Grabli D, McCairn K, et al. Behavioural 70 Fahim C, Yoon U, Das S, et al. Somatosensory-motor disorders induced by external globus pallidus bodily representation cortical thinning in Tourette: dysfunction in primates II. Anatomical study. Brain effects of tic severity, age and gender. Cortex 2010; 2004; 127:2055–70. 46:750–60. 84 Mink JW. Basal ganglia dysfunction in Tourette’s 71 Tobe RH, Bansal R, Xu D, et al. Cerebellar morphology syndrome: a new hypothesis. Pediatr Neurol 2001; in Tourette syndrome and obsessive-compulsive 25:190–8. disorder. Ann Neurol 2010; 67:479–87. 85 Worbe Y, Mallet L, Golmard JL, et al. Repetitive 72 Bloch MH, Leckman JF, Zhu H, Peterson BS. Caudate behaviours in patients with Gilles de la Tourette volumes in childhood predict symptom severity in adults syndrome: tics, compulsions, or both? PLoS One 2010; with Tourette syndrome. Neurol 2005; 65:1253–8. 5:e12959. 73 Neuner I, Kupriyanova Y, Stocker T, et al. White- 86 Welter ML, Mallet L, Houeto JL, et al. Internal pallidal matter abnormalities in Tourette syndrome extend and thalamic stimulation in patients with Tourette beyond motor pathways. Neuroimage 2010; syndrome. Arch Neurol 2008; 65:952–7. 51:1184–93. 87 Mink JW. Clinical review of DBS for Tourette 74 Thomalla G, Siebner HR, Jonas M, et al. Structural Syndrome. Front Biosci (Elite Edn) 2009; 1:72–6. changes in the somatosensory system correlate with 88 Welter ML, Grabli D, Vidailhet M. DBS for hyperki- tic severity in Gilles de la Tourette syndrome. Brain netic disorders: dystonia, tardive dyskinesia and tics 2009; 132:765–77. Curr Opin Neurol 2010; 23:420–5.

Albanese_c02.indd 25 12/24/2011 6:02:53 AM CHAPTER 3 Pathophysiology and Molecular Pathology of Tremor, Myoclonus, and Chorea Johannes D. Speelman,1 Elisabeth M. Foncke,2 Anne-Fleur van Rootselaar,1 and Marina A. Tijssen1 1 Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 2 Department of Neurology, Free University Medical Center (VUmc), Amsterdam, the Netherlands

Tremor contraction for keeping an antigravity position or weight bearing of the body part. The resonance Tremor is a rhythmical, involuntary, oscillatory frequency is determined by inertial, viscous, and movement of a body part [1], sometimes redefined elastic properties [2, 3]. The reflex oscillations are as an approximately rhythmic, roughly sinusoidal elicited by combinations of various peripheral involuntary movement [2]. Commonly used reflex loops: afferents from the spindles to the clinical classifications relate to the frequency and spinal alphamotor neurons (spinal loop), afferents conditions under which the tremor is activated. from peripheral sensors to the motor cortex However, with progression of the disease, tremulous (transcortical loop), and stretch reflexes [4, 5]. disorders may often have a combination of various In tremors involving peripheral mechanisms, tremor types (Table 3.1). the tremor frequency can be reduced by adding weight to the appropriate body part [2].

Tremor mechanisms Central generator(s) The whole motor system is organized by Complex combinations of peripheral mechanical- reciprocally innervated circuits from cortical to reflex and central generator(s) oscillations are spinal level [2]. The main neuronal circuits considered responsible for tremor [3, 4]. controlling voluntary and involuntary motor movements are: loops between (a) the motor Peripheral mechanical-reflex cortex and the basal ganglia, (b) the cerebellum oscillations and the brainstem (cerebello-rubro-olivary tract), The mechanical oscillations occur in a body part in and (c) the cerebellum, the thalamic nuclei, and response to cardioballistic vibrations produced the motor cortex (cerebello-thalamo-cortical and by ejection and propagation of blood flow at cortico-ponto-cerebellar tracts). In addition, there the cardiac systole, and subtetanic motor unit are reciprocal connections with the motor

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Table 3.1 Characteristics of various tremor types.

Tremor type frequency Activation condition Peripheral Central mechanism generator rest postural kinetic Intention/cerebellar

Physiologic (enhanced) 3–30//8–12 Hz (+) ++ ++ ++ (+) Parkinsonian 4.5–7 Hz ++ + + ++ SWEDD 4.5–7 Hz ++ + + ? ? Essential 4–12 HZ ++ + (+) ++ ++ Neuropathic 3–6 Hz ++ ++ ++ ? Cerebellar 2–4 Hz + + ++ + ++ Holmes’ 2–4 Hz ++ + ++ ++ + ++ Palatal 1–3 Hz ++ ++ Orthostatic 13–18 Hz ++ ++ Dystonic 4–9 Hz + + + + + Task-specific 4–12 Hz ++ ?

++: characteristic for tremor type and mechanism; +: may be present, or may play a minor role as peripheral mechanism; (+): possible, hypothesized; ?: unknown, but considered as a possibility.

networks in the brainstem and at spinal levels Various types of tremor (Figure 3.1). It is hypothesized that GABAergic projections from the GPi modulates activity of the (Enhanced) physiologic tremor is a normal motor nuclei of the thalamus with subsequent phenomenon that can become evident during activation of excitatory glutamatergic projections precise, fine motor activities, anxiety, or alcohol to the premotor and supplementary motor areas withdrawal, but is in many persons invisible. Two which facilitate movement. Activity of the GPi is types of oscillation can be registered, one caused by modulated by the “direct” and “indirect” pathways. peripheral mechanical-reflex mechanisms and one The direct pathway is monosynaptic whereas the of possibly central origin. In certain conditions, like indirect pathway runs through the GPe and the fatigue, anxiety, hyperthyroidism, or use of certain subthalamic nucleus. The direct striatopallidal drugs, the tremor is more severe, due to an increase pathway leads to thalamocortical motor facilitation of the stretch reflex. This may be bothersome for through GPi inhibition, and the indirect pathway the patient, and is called “enhanced” physiologic leads to thala mocortical inhibition through GPi tremor [2]. Loading the body part with a weight stimulation [6]. will reduce the tremor frequency [5] and beta- These complex mechanisms can be disturbed by blockers may also reduce this peripheral tremor an increase in excitability of the reciprocally type [2]. In addition, an 8–12 Hz tremor is registered, innervated neurons by hyperpolarization of the cell and probably originates from the olivo-cerebello- membrane or alterations in the intracellular thalamo-cortical pathway [2, 5, 6]. modulators of ion channels [3, 4, 7]. The widespread complex motor networks consist of multiple Rest tremor independent oscillators that tend to couple and This occurs in a body part that is not voluntary contribute to tremor. The various pathological activated and is completely supported against grav- tremors differ by the topography and frequency ity. Mental stress and movements of another body components in these networks. The debate part may increase the amplitude. [1] Rest tremor is concerning single or multiple generator structures a characteristic symptom in patients with Parkinson in the different disorders is yet not finished [3, 8]. disease (PD), SWEDD, Holmes’ tremor, and palatal

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Pre-motor areas Central generator(s) Mechanically-induced Spinal reflexes Motor areas oscillations supra-spinal reflexes feedback loops UMN

TREMOR

Thalamus BG

CEREBELLUM stn sn CN mf RN BRAINSTEM cf IO

SPINAL ANTAGONIST AGONIST CORD

Golgi la MNg MN Pool – agonist MNa

MN Pool – antagonist

TREMOR BURSTS

Figure 3.1 Main anatomical pathways implicated in tremor. Abbreviations: UMN, upper motor neurons projecting to anterior horn in spinal cord; BG, basal ganglia; stn, subthalamic nucleus; sn, substantia nigra; RN, red nucleus; IO, inferior olivary complex; mf, mossy fibers; cf, climbing fibers;1a, spindle afferents; MNγ, gamma-motoneuron; MN pool, motoneuron pool. 9(Reproduced from Manto [3] with permission from Biomed Central Ltd.)

tremor: therefore, different mechanisms are potentials in the basal ganglia nuclei, demonstrate assumed to be responsible. coherent rhythmic activity with a frequency of In PD, with implanted DBS electrodes and animal 4.5–7 Hz between the basal ganglia nuclei, cortical models, coherence studies with EEG, MEG, cortical areas, and limb muscles [9, 10]. A number of inde- electrodes, microrecordings, and local field pendent oscillating circuits are assumed within a

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widespread tremor-generating network, including which re-enhances the olivary oscillations [4, 5]. cortical, subcortical, spinal centers and the oscillat- Only strong external stimuli in test situations ing peripheral limbs [3] (Figure 3.1). can influence the rhythmicity and reset the Dopamine deficiency is responsible for rest tremor [16–18]. tremor in PD and, Holmes tremor, supported by 1MPTP studies on primates [5, 9, 10]. In PD, tremor Action tremor is related to specific loss of dopaminergic This is defined as any tremor present during volun- neurons located in the mesencephalic A8 area, tary contractions of muscles [1]. the retrorubral area, and a loss of other neuro- Postural tremor may occur when maintaining a transmitters, such as serotonin [2, 11]. In Holmes voluntary position against gravity. When it appears tremor a lesion of the nigrostriatal connection will or exacerbates in specific postures it is called be responsible for a striatal dopamine deficiency. In ‘ position-specific’ tremor [1]. the case of dopamine deficiency, the subthalamic In PD, during sustained action after a short nucleus (STN) with its dopaminergic afferents from delay of several seconds, (called a re-emergent the substantia nigra is probably responsible for the tremor), often a postural tremor or an action rest tremor due to disruption of these motor neural tremor, may develop with an increase in the rest networks [9–11]. This is in agreement with the tremor. This re-emergent tremor has about the favourable results of STN–DBS for parkinsonian same frequency as the rest tremor [20]. A combi- tremor [34, 12], and case reports of Holmes tremor nation of rest and action tremors can be produced patients with favorable outcome of combined DBS in MTPT monkeys and therefore the same in the Vim and STN [13]. Although, on a PET scan, pathophysiology is assumed for both tremor types the cerebellum is abnormally active in PD patients [2]. In some PD patients an action tremor develops with tremor, it appears that the cerebellum is with a higher frequency of 5–10 Hz and without a not necessary for producing a parkinsonian rest delay at the beginning of the limb action as in tremor [7]. essential tremor (ET). A combination of PD and ET SWEDD (Subject Without Evidence of is assumed [21]. Dopaminergic Deficit) The tremors may be Kinetic tremor phenomenologically indistinguishable from those Essential tremor (ET) is the most common of PD patients [14]. The pathophysiology is still movement disorder; it is characterized by a kinetic unknown, but indicates that a rest tremor can tremor, and is often accompanied by a postural develop without dopaminergic cell loss in the tremor. The kinetic tremor, as in ET, is probably nigrostriatal system. SWEDD is considered to be a caused by a functional disturbance of the olivocer- form of dystonia [15]. ebellar circuit with the inferior olive (IO) as the Palatal tremor consists of a rhythmic movement of central oscillator. This is supported by the disap- the soft palate with a frequency of 1–3 Hz (see pearance of the tremor after lesions in parts of the Chapter 7). The pathophysiology of the essential cerebro-cerebello-cerebral loop, and the finding in palatal tremor is unknown [16–18]. The secondary the “harmaline animal model” of synchronization form is always accompanied by the olivary hypertro- of inferior olive cells into rhythmic activity which is phy, caused by damage of the dentate nucleus, or the transferred through the cerebellum and the reticu- fiber tracts forming the Guillain–Mollaret triangle, lospinal projections to the spinal motor neurons the crossing dentate-rubro-olivary and olivo-dentate [22]. Although, the thalamus (VIM) as a central pathways [16–19] (Figure 3.1). The inferior olive oscillator for the kinetic tremor is still in discussion (IO) is assumed to be an autonomous central oscilla- (based on a patient who developed classical ET with tor. The slow rhythmic palatal tremor is the inherent a long delay after hemicerebellectomy [23]), the activity of cells within the IO, probably due to loss of development of an intention tremor in about 50% dentate-olivary GABA-ergic inhibition of the elec- of the ET patients during the progression of the tronic coupling of the IO neurons. This possibly disease indicates a cerebellar involvement in at results in a state of hyperexcitability of Purkinje cells, least part of the patients (see below) [5, 22, 24].

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Intention tremor is an action tremor with an onset with an interval of weeks to years after the increase of the amplitude when coming close to the origin of the causal lesion [1], probably caused target. A position-specific postural tremor should by a secondary degeneration with functional be excluded [1]. The cerebellar and Holmes tremor, changes [2, 27]. Only if Holmes tremor is typical representatives of the intention tremor, will accompanied by symptomatic palatal tremor can be discussed. ahypertrophic degeneration of the inferior Cerebellar tremor is characterized by a low- olive be detected [2]. frequency intention tremor, mostly below 5 Hz, and Neuropathic tremor This may be assumed in a an absence of rest tremor. A postural tremor may patient with a tremor in a limb with a peripheral be present. In all disorders with an intention tremor neuropathy, and without other neurological a disturbance of the cerebellum and its afferent or disorders associated with tremors. Demyelinating efferent pathways can be assumed on the bases neuropathies are particularly frequent causes of of experiments with primates and from the studies this condition [22]. A disturbed peripheral reflex of patients [1, 22]. mechanism due to the abnormal sensory input In primate experiments lesions in the globose- seems to be the major pathophysiologic mecha- emboliform nucleus cause a low-frequency inten- nism, supported by the effects of external stimuli tion tremor by altering the function of peripheral on the tremor frequency. An abnormal cerebellar somatosensory reflex pathways [25]. Tremor- processing of the disturbed sensory input may also related activity can be registered in the motor and be involved – the so-called feedback control [22]. somatosensory cortex, and the cerebellar glo- Because only a minority of patients with peripheral bose-embiliform nucleus. This indicates involve- neuropathies develop a central tremor, another ment of transcerebellar and transcortical loops mechanism, may also be involved. participating in the cerebellar feedback function Orthostatic tremor is a tremor syndrome character- [22, 25]. Based on the persistence of the inten- ized by a typical high-frequency postural weight- tion tremor after deafferentiation, it is argued bearing limbs tremor of 13–18 Hz, predominantly that a major cause of the intention tremor is of the trunk and legs, but upper limbs, neck, and caused by a disturbed timing and grading of con- cranium muscles may also be involved [2, 5, 8]. tractions of antagonistic muscles, called the cere- Physiological, neuroimaging (PET, FP-Spect), and bellar feed-forward control dysfunction, due to transcranial magnetic stimulation (TMS) studies lesions in the cerebello-thalamo-cortical pathway indicate a central generator of the oscillating activ- at the level of the dentate nucleus, the cerebello- ity, most likely in the brainstem. The cerebellothalamic fibers, or the cerebellar afferences thalamo-cortical and the dopaminergic nigrostriatal nucleus in the thalamus (VIM) [2, 22, 26, 27]. loops appear to be involved without parkinsonism. This mechanism is supported by registrations of However, dopaminergic medications do not enhanced long-latency reflexes in cerebellar dis- improve the tremor, but it can be suppressed by orders [24]. It is not yet clear if a central oscillator VIM DBS ( [29], own experience). is involved [18]. Holmes tremor is a condition with a combination Conclusions of rest and intention tremors. A postural tremor Various types of tremor can be observed in the may be present. The tremor has a low frequency same patient in the different kinds of tremor disor- (2–4 Hz), and is often irregular. [27]. It is a symp- der. Besides peripheral mechanisms, especially a tomatic tremor due to lesions involving the dysfunctioning of neuronal circuits involved in dopaminergic nigrostriatal system (rest tremor) motor organization are assumed to be responsible and the cerebello-thalamo-cortical system (inten- for the generation of the various types of tremor. tion tremor). This may happen at multiple sites Hyperexcitability of cell membranes due to vari- and even multiple cortical lesions have been ous conditions is assumed to be an important mentioned [22, 28]. There is typically a delayed mechanism. [For dystonic tremor, SWEDD, and

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task-specific tremor, see dystonia syndromes Table 3.2 Classification of myolonus. (Chapters 7 and 8).] Clinical Clinical Spontaneous presentation Reflex myoclonus Action-induced Myoclonus Distribution Synchronous in different parts Myoclonus is a hyperkinetic movement disorder of the body consisting of brief, quick, and involuntary jerks Generalized caused by muscle contractions (positive myo- Segmental (Multi)focal clonus) or interruptions of tonic muscle activity Temporal pattern Irregular (negative myoclonus). The clinical characteristics Rythmic and etiology of myoclonic jerks are related to the Anatomical Cortical anatomical origin, classified as cortical, subcortical, Subcortical Basal ganglia or brainstem, spinal cord, and peripheral nerve Brainstem myoclonus (Table 3.2) [30]. Spinal Segmental or In this section we will discuss the pathophysiology Peripheral Propriospinal of myoclonus based on the anatomical classification Aetiology Physiological with a focus on functional aspects. The, individual Essential diseases causing myoclonus will not be discussed in Epileptic detail. The genetic background of different types of Symptomatic myoclonus will be discussed in Chapter 14 [31].

Cortical myoclonus Cortical myoclonus is believed to result from cortical myoclonus, EEG spikes preceding EMG abnormal firing of the sensorimotor cortex resulting bursts representing the myclonic jerk may be in activity that travels through the fast corticospinal seen in multichannel EEG–EMG recordings. Also, pathways to the muscles [31, 32]. EMG-registrations EEG–EMG back-averaging may reveal a “time- typically show irregular short-lasting bursts locked” biphasic potential on the contralateral (<50 ms) [33]. Diseases known to be associated sensory cortex, typically preceding EMG bursts with cortical myoclonus are focal lesions of the with 15–25 ms when recorded from the upper limb, sensorimotor cortex, post-hypoxic encephalopathy and with 40 ms when recorded from the lower limb or as part of syndromes such as progressive [38, 39]. When the myoclonic jerks are continuous myoclonic ataxia or epilepsy. Cortical myoclonus and back-averaging is not possible, coherence can also be a relatively minor symptom of different analysis can reveal the correlation between cortical degenerative disorders such as multisystem atro- and muscle activity and between muscles [40]. phy (MSA) and Alzheimer disease [34]. Clinically, In cortical myoclonus patients, an exaggerated cortical myoclonus manifests as spontaneous or corticomuscular and intermuscular coherence in reflex myoclonus, and is mainly induced by volun- the alpha and beta band can be detected with a tary movements. The jerks can be focal or multi- phase difference consistent with a cortical drive focal [34, 35]. Parts of the body with a large cortical [41–44]. With a magnetoencephalogram (MEG) representation, like the mouth, the hands, and the study, the generator has been localized to the face, are most frequently involved [34, 36]. primary motor cortex [45]. Pathophysiologically, cortical myoclonus is related Electrophysiologically, cortical myoclonus is to epilepsy and is often associated with generalized characterized by signs of increased cortical excita- convulsions. Continuous isolated muscle jerks of bility, including a giant somatosensory-evoked focal cortical origin are described as epilepsia potential (g-SSEP) and the presence of a cortical partialis continua (EPC) [37]. In patients with reflex (C-reflex). The SSEP N20 component can be

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FCMTE patient N35 C4´

N20 P14 C3´ N18 Control C4´

N20 N35 N18 P1 N20 C3´

0.5 uV 0.5 uV 5 ms P25 5 ms P25

Figure 3.2 After stimulation of the right median nerve at the wrist of a patient with “familial cortical myoclonic tremor with epilepsy” (FCMTE), a giant potential (P25–N35) is seen after the normal N20 potential over the left hemisphere (C3′). Insert: normal recording in healthy control. Stimulation at 1.1 Hz; 2 averages of 300 recordings, reference A1; C3′, and C4′: left and right sensorimotor hand areas.

normal, but the P25/P30 and N35 peaks have role in the generation of cortical myoclonus, as enlarged amplitudes [45] (Figure 3.2). The C-reflex suggested by the stimulus sensitivity and the elec- response can be seen in cortical myoclonus patients trophysiological signs of cortical hyperexcitability, in the ipsilateral thenar muscle with a latency of including giant SSEPs. An EMG–fMRI study in around 45 ms, and sometimes contralaterally with patients with FCMTE showed parietal (sensory a delay of 10–15 ms pointing to interhemispheric area) brain activations coupled to involuntary spread [46]. muscle activity [48]. The precise mechanisms that give rise to cortical Neuropathological studies in patients with hyperexcitability, and their localization in the cortical myoclonus show involvement of cerebel- brain, remain unknown and may range from lum, frontotemporal cortex, hippocampus, thala- intrinsic cortical changes to more isolated cerebel- mus and other areas in various combinations lar changes resulting in decreased cortical inhibi- [49, 50]. Interestingly, primary cerebellar changes tion. A generator in the primary motor cortex is were observed in cortical myoclonus patients suggested by cortical lesions giving rise to myo- (already described by Hunt [51]), and more recently clonus and supported by MEG studies [45]. It has in patients with celiac disease [52] and FCMTE been suggested that cortical motor neurons [50]. In the absence of structural changes, func- become partly deafferented in neurodegenerative tional cortical changes may exist, for instance as a diseases and therefore subtle sensory stimulation result of a channelopathy. Channelopathies are may produce paroxysmal activity [47]. In fact, recognized in the inherited epilepsy syndromes. changes in sensory input may play an important It has, however, been suggested that cerebellar

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disease, leading to decreased cortical inhibition via diaphragm myoclonus can originate from the the cerebello-thalamo-cortical loop, is the principal rostral medulla [62]. In reticular reflex myoclonus, cause of cortical myoclonus. intervals between bursts are shorter as compared to Imaging studies of cortical myoclonus are limited spread of bursts in startle syndromes indicating and usually focused on the underlying disorder involvement of different neuronal circuits and rather than the origin of the myoclonus. pathways. The jerks in reticular reflex myoclonus are thought to originate from the reticular Subcortical myoclonus formation. The brainstem motor systems are closely In subcortical myoclonus the source of myoclonus related to subcortical reflex centers, possibly is localized between the cortex and the spinal cord explaining the stimulus sensitivity [30, 34, 36]. and includes myoclonus-dystonia (M-D), brain- Excessive startle reflexes can be part of stem reticular reflex myoclonus, and orthostatic hyperekplexia, an inheritable mainly autosomal myoclonus. In contrast to cortical myoclonus, dominant disorder with mutations in the glycine electrophysiological signs of cortical hyperexcita- receptor [36, 63–66]. bility are not typical and EMG bursts are more Orthostatic myoclonus is myoclonus induced or variable, ranging from 25 to 300 ms [34, 53]. increased by the assumption of an upright posture Myoclonus-dystonia (M-D, essential myoclonus) is (see also orthostatic tremor). This type of myo- characterized by alcohol-responsive jerks in the clonus has not been formally anatomically classi- upper body, mild to moderate dystonia, and com- fied yet, but is most likely from a subcortical origin. monly autosomal dominant inheritance with often It has been described in elderly patients and usually a mutation in the epsilon-sarcoglycan gene (SGCE, presents as slowly progressive unsteadiness of gait chromosome 7q21, DYT11). Myoclonic bursts are and stance. It is often associated with an underlying variable but mainly short (25–750 ms) [54, 55]. neurodegenerative disease, particularly Parkinson Myoclonus in M-D is supposed to originate from disease. EMG shows non-rhythmic short burst the basal ganglia. Local field potential recordings durations (20 to 99 ms) [67, 68]. from the globus pallidus internus (GPi) in M-D patients showed significant coherence between dystonic muscle activity and GPi [56]. Reduced Spinal myoclonus striatal D2 receptor binding was also detected in Spinal myoclonus is the result of abnormal MD [ [57]. Electrophysiological studies, including discharges generated in the spinal cord and can be (EMG-)EEG, SSEP, and TMS reveal no changes in subdivided in spinal segmental myoclonus and cortical excitability [58, 59]. Cortical functional propriospinal myoclonus. changes have been described in a TMS study, Segmental myoclonus is a rare disorder mostly showing polyphasic MEPs possibly reflecting cen- caused by a lesion in the spinal cord, such as a tral neuron membrane instability. A functional tumour, syringomyelia, myelitis, or ischemia. It is MRI study revealed disorganized sensorimotor thought that spinal segmental systems become integration consistent with other types of (heredi- hyperexcitable, evoking jerks in muscles inner- tary) dystonia [58, 60, 61]. These cortical func- vated by this particular segment and one or two tional changes are possibly secondary to basal contiguous spinal segments. The jerks are con- ganglia pathology. tinuous, unaffected by voluntary movement and Brainstem reticular reflex myoclonus, mainly seen in sensory stimulation, and often persist during post-hypoxic encephalopathy and startle syndromes sleep [69]. The jerks are usually rhythmic with a are stimulus sensitive and characterized by frequency varying from 1 to 200 per minute. The abnormal activity that begins in the brainstem and duration of the EMG-bursts can be up to 1,000 ms. spreads in both rostral and caudal directions, EMG discharges after nerve stimulation were found producing generalized jerks due to the bilateral with different latencies, possibly reflecting involve- pathways involved. Focal forms are rare, although ment of polysynaptic pathways.

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Propriospinal myoclonus (PSM) is characterized by aggravated during action. EMG burst duration both spontaneous and stimulus-sensitive jerks of ranges from 25 to 240 ms. Coherence studies the trunk and abdominal muscles, often induced showed increased intermuscular coherence in 4 out by lying down, and without involvement of the of 8 patients in the 6–12 Hz band. Significant facial musculature [70, 71]. PSM is presumed to coherence entrainment was detected in 5 out of 8 originate from a spinal generator that elicits activ- patients. The characteristics of myoclonus in ity spreading up and down the spinal cord, sup- CRPS appear to be different from other forms posedly via intrinsic propriospinal pathways [71]. of myoclonus [81]. Electrophysiological features include a fixed pattern of muscle activation, slow spinal cord conduction velocity (5–15 m/s), EMG burst dura- Chorea tion of less than 1,000 ms, synchronous activation of agonist and antagonist muscles, and no involve- Chorea is defined as a syndrome characterized by ment of facial muscles [72]. In some patients the continuous flow of random, involuntary, lesions in the spinal cord have been reported, but muscle contractions [82]. Chorea can be associated PSM is usually idiopathic [73]. MRI of patients with a variety of different causes but the most well- with idiopathic PSM is normal. Diffusion tensor known disorder is Huntington disease (HD) imaging detected associated microstructural (see also Chapters 10 and 11). abnormalities of the spinal cord [74]. In idiopathic PSM a psychogenic origin might be considered. Pathophysiology Recently, in 20 patients diagnosed with idiopathic The pathophysiological mechanisms of chorea is spinal myoclonus, a bereitschaftspotential (BP) considered to be due to the dysfunction of a was shown in 15 patients [75]. In another study, complex neuronal network consisting of the basal axial jerking closely resembling PSM had a psy- ganglia and different motor cortical areas [82] The chogenic origin in 34 out of 35 patients [61]. basal ganglia comprise the caudate nucleus, puta- Further prospective studies toward the origin of men, the internal and external globus pallidus PSM are required. (GPe and GPi), as well as associated structures such as the subthalamic nucleus and the substantia Peripheral myoclonus nigra. These corticosubcortical motor circuits are Peripheral myoclonus driven from the peripheral essential to facilitate voluntary movements and nervous system includes hemifacial spasm [32] stop unwanted movements through parallel path- and, described in case reports, myoclonus after ways that modulate thalamocortical motor projec- lesions of the brachial plexus [76], spinal root, [77], tions. Their role has been proposed to be a braking the long thoracic nerve [78], and after amputation mechanism which facilitates or inhibits motor pat- (“jumping stump”) [79, 80]. Peripheral myoclonus tern generators. The model of these motor loops is limited to one segment of the body, usually the stem from animal studies [6]. According to this proximal part of a limb or the trunk. Bursts can be model, GABAenergic projections from the GPi triggered by voluntary movement and burst dura- modulates activity of the motor nuclei of the thala- tion varies. In hemifacial spasm, electrical stimula- mus with subsequent activation of excitatory glu- tion of one branch of the facial nerve on the affected tamatergic projections to the premotor and side in patients elicits a response from muscles supplementary motor areas which facilitate move- that are innervated by another branch (ephaptic ment. Activity of the GPi is modulated by the transmission). “direct” and “indirect” pathways. The direct path- The origin of myoclonus in patients with complex way is monosynaptic whereas the indirect path- regional pain syndrome (CRPS) is unknown but is way runs through the GPe and the subthalamic likely to be induced by peripheral trauma. CRPS- nucleus. The direct striatopallidal pathway leads to related myoclonic jerks are observed at rest, and thalamocortical motor facilitation through GPi

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inhibition and the indirect pathway leads to thalam- against the hypothesis that TD is the result ocortical inhibition through GPi stimulation [6]. of striatal D2 hypersensitivity after prolonged According to this model, chorea is considered to be exposure to neuroleptics. the result from deficient GPi inhibition to the thal- Hyperglycemic choreathetosis is often associated amus resulting in excessive thalamocortical activa- with hyperintensity of the putamen on T1 MRI. tion. However, several inconsistencies within this HMPAO SPECT scan shows hypometabolism of model have been reported leading to the assump- the striatum [91], hence, striatal dysfunction is tion that more complex changes in this motor net- commonly involved in different causes of chorea. work – i.e. temporal and spatial firing pattern Hypo- but also hyperfunction of the striatum may alterations – are involved in the pathophysiology lead to chorea. of chorea [83]. An important characteristic of HD is the particular vulnerability of the caudate–putamen region, Molecular pathology despite similar expression of the mutated protein in HD is an inherited neurodegenerative disorder, other brain areas. Several mechanisms have been characterized by progressively worsening chorea, identified that mediate cell death in HD, including cognitive and psychiatric disturbances involving excitotoxicity, transcriptional dysregulation, altered the basal ganglia and cerebral cortex. HD is an energy metabolism, impaired axonal transport, and autosomal dominantly inherited disorder caused altered synaptic transmission [91, 92]. by CAG trinucleotide expansion from 36 to 121 at the Huntingtin (HTT ) gene [83]. Until now, the Excitotoxicity precise role of HTT in HD is unknown, but the Excitotoxicity involves an enormous increase in pathology of HD targets medium spiny neurons in intracellular Ca2+ concentration in response to the the striatum [84]. A number of other disorders can effects of excitatory amino acids (EAA), including also cause chorea, including neuroacanthocytosis glutamate. In particular, the NMDA receptor – a (NA), benign familial chorea (BFC), systemic lupus receptor-channel complex permeable to Ca2+ – plays erythematosus (SLE), Sydenham chorea, and tar- an important role in neurotoxicity. Stimulation of dive dyskinesia (TD) (see Chapters 10 and 11). All this glutamate receptor induces an influx of Ca2+ these different types of chorea may be explained which increases the formation of reactive oxygen by deficient GPi inhibitory output to the motor and nitrogen by means of proteases and endo- thalamus as previously mentioned. However, nucleases, leading to cell damage and cell death. inconsistencies has been demonstrated by several Stimulation of the NMDA receptor is probably the imaging studies. Clinically affected HD patients result of an increase of glutamate and glutamate show severely reduced glucose and oxygen metab- agonist release from the cortex, the decrease of olism of the caudate and lentiform nuclei [84]. glutamate uptake by glia cells, and hypersensitivity Caudate hypometabolism is also seen in NA and of the postsynaptic NMDA receptors [93, 94]. BFC [85]. In contrast, striatal glucose metabolism Recent evidence has shown that excitotoxic has been reported to be normal or elevated in degeneration in HD is not only related to corticos- Sydenham chorea, chorea secondary to SLE and triatal glutamergic input but also to nigrostriatal TD [86–88]. The medium spiny striatal neurons dopaminergic stimulation. Dopamine is believed to that degenerate in HD express D1 and D2 recep- act synergistically with glutamate, making striatal tors. Striatal D2 binding is severely reduced in neurons highly sensitive to mutant HTT [95]. symptomatic HD patients as demonstrated with IBZM SPECT or C-raclopride PET [89, 90]. Similar Transcriptional dysregulation changes have been reported in other neurodegen- Transcriptional dysregulation of multiple genes erative choreas, including NA [89]. In contrast, encoding neurotransmitter receptors, enzymes, normal striatal D2 binding has been observed in and proteins involved in neuron structure, stress SLE chorea and TD [91]. This finding argues responses, and axonal transport has been described

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in transgenic mice but recently also in human HD Epilogue brains. Mutant HTT has been shown to interact with basal transcription factors, including TATA In this chapter the pathophysiology and molecular binding protein and transcription factor IIF. pathology of three different kinds of hyperkinetic Nowadays, the role of histones, highly basic pro- symptoms, tremor, myoclonus and chorea, are dis- teins, has been linked to transcriptional activity. In cussed. Dysregulations of cerebral networks due to particular, histone methylation and acetylating is many causes and in different diseases may lead to regulating transcription factor access to DNA pro- one of these symptoms. Most often abnormal moter regions [96]. functioning of the basal ganglia circuits is involved, reflected in the often successful application of Mitochondrial dysfunction and altered stereotactic functional neurosurgery. Progression of energy metabolism the knowledge of the molecular pathology will lead Biochemical studies in HD postmortem tissue have to an improvement of the pharmacotherapy. revealed selective dysfunction of components of the mitochondrial tricarboxylic acid cycle and electron transport chain in affected brain regions including complex II, complex IV and aconitase. References These changes may lead to reduced O consump- 2 1 Deuschl G, Bain P, Brin M. 1998. Consensus statement tion and ATP production rates. This may disrupt the of the Movement Disorder Society on Tremor. Ad Hoc maintenance of Na/K ATP-ase pumps that regulate Scientific Committee. Mov Disord 13(Suppl 3):2–23. ionic and voltage gradients across cell membranes, 2 Elble RJ. 2009. Tremor: clinical features, pathophysi- inducing nitric oxide synthase (NOS) activation ology, and treatment. Neurol Clin 27:679–6, vi. and free radical production with a progressive 3 Manto M. 2008. Tremorgenesis: a new conceptual increase of oxidative damage to the mitochondria scheme using reciprocally innervated circuit of which ultimately leads to cellular injury. This neurons. J Transl Med 6:71. process is a gradual build-up until a threshold is 4 Raethjen J, Deuschl G. 2009. Tremor. Curr Opin reached, which explains the slow progressive Neurol 22:400–5. nature of the disease [94]. 5 Deuschl G, Raethjen J, Lindemann M, et al. 2001. The pathophysiology of tremor. Muscle Nerve 24:716–35. 6 DeLong MR. 1990. Primate models of movement Changes in axonal transport disorders of basal ganglia origin. Trends Neurosci and synaptic dysfunction 13:281–5. Several studies have shown that HTT is impli- 7 Deuschl G, Wilms H, Krack P, et al. 1999. Function of cated in the control of intracellular processes, the cerebellum in Parkinsonian rest tremor and including trafficking of vesicles and synaptic Holmes’ tremor. Ann Neurol 46:126–8. transport. In HD the abnormal polyQ expansion 8 Piboolnurak P, Yu QP, Pullman SL. 2005. Clinical and leads to a reduction in axonal transport due to neurophysiologic spectrum of orthostatic tremor: case the altered interactions between HTT and parts of series of 26 subjects. Mov Disord 20:1455–61. the motor complex. Of particular interest is the 9 Kerr G, Silburn P. 2009. Deciphering the tremor alteration of the brain derived nerve factor enigma. Clin Neurophysiol 120:1766–7. (BDNF), because BDNF is crucial for neuronal 10 Reck C, Florin E, Wojtecki L, et al. 2009. Characterisation of tremor-associated local field function and survival [92]. potentials in the subthalamic nucleus in Parkinson’s These new insights into the molecular pathology disease. Eur J Neurosci 29:599–612. of HD by means of several animal models has given 11 Carr J. 2002. Tremor in Parkinson’s disease. us the motivation to develop new therapeutic Parkinsonism Relat Disord 8:223–4. approaches which are likely to be a combination of 12 Benabid AL, Chabardes S, Torres N, et al. 2009. therapies due to the multiplicity of mechanisms Functional neurosurgery for movement disorders: a underlying HD. historical perspective. Prog Brain Res 175:379–91.

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13 Romanelli P, Bronte-Stewart H, Courtney T, et al. 28 Seidel S, Kasprian G, Leutmezer F, et al. 2009. 2003. Possible necessity for deep brain stimulation of Disruption of nigrostriatal and cerebellothalamic both the ventralis intermedius and subthalamic nuclei pathways in dopamine responsive Holmes’ tremor. to resolve Holmes tremor. Case report. J Neurosurg J Neurol Neurosurg Psychiat 80:921–3. 99:566–71. 29 Guridi J, Rodriguez-Oroz MC, Arbizu J, et al. 2008. 14 Schneider SA, Edwards MJ, Mir P, et al. 2007. Patients Successful thalamic deep brain stimulation for with adult-onset dystonic tremor resembling parkin- orthostatic tremor. Mov Disord 23:1808–11. sonian tremor have scans without evidence of dopa- 30 Caviness JN, Brown P. 2004. Myoclonus: current con- minergic deficit (SWEDDs). Mov Disord 22:2210–15. cepts and recent advances. Lancet Neurol 3:598–607. 15 Schwingenschuh P, Ruge D, Edwards MJ, et al. 2010. 31 Hallett M, Chadwick D, Marsden CD. 1979. Cortical Distinguishing SWEDDs patients with asymmetric reflex myoclonus. Neurol 29:1107–25. resting tremor from Parkinson’s disease: a clinical and 32 Tassinari CA, Rubboli G, Shibasaki H. 1998. electrophysiological study. Mov Disord 25:560–9. Neurophysiology of positive and negative myoclonus. 16 Deuschl G, Wilms H. 2002. Clinical spectrum and Electroencephalogr Clin Neurophysiol 107:181–95. physiology of palatal tremor. Mov Disord 17(Suppl 33 Shibasaki H, Hallett M. 2005. Electrophysiological 2):S63–S66. studies of myoclonus. Muscle Nerve 31:157–74. 17 Pearce JM. 2008. Palatal Myoclonus (syn. Palatal 34 Caviness JN. 2009. Pathophysiology and treatment of Tremor). Eur Neurol 60:312–15. myoclonus. Neurol Clin 27:757–77, vii. 18 Zadikoff C, Lang AE, Klein C. 2006. The ‘essentials’ of 35 Obeso JA. 1995. Therapy of myoclonus. Clin Neurosci essential palatal tremor: a reappraisal of the nosology. 3:253–7. Brain 129:832–40. 36 Tijssen MAJ, Tijssen CC. 2007. Myoclonus. In: Wolters 19 Hornyak M, Osborn AG, Couldwell WT. 2008. ECh, van Laar T, Berendse HW, editors. Parkinsonism Hypertrophic olivary degeneration after surgical and Related Disorders.Amsterdam: VU University removal of cavernous malformations of the brain Press. stem: report of four cases and review of the literature. 37 Cockerell OC, Rothwell J, Thompson PD, et al. 1996. Acta Neurochir (Wien ) 150:149–56. Clinical and physiological features of epilepsia partialis 20 Jankovic J, Schwartz KS, Ondo W. 1999. Re-emergent continua. Cases ascertained in the UK. Brain 119 tremor of Parkinson’s disease. J Neurol Neurosurg (Pt 2):393–407. Psychiat 67:646–50. 38 Shibasaki H, Yamashita Y, Kuroiwa Y. 1978. 21 Minen MT, Louis ED. 2008. Emergence of Parkinson’s Electroencephalographic studies myoclonus. Brain disease in essential tremor: a study of the clinical 101:447–60. correlates in 53 patients. Mov Disord 23:1602–5. 39 Hallett M, Aminoff MJ. 2010. Electrophysiologic 22 Deuschl G, Bergman H. 2002. Pathophysiology evaluation or movement disorders. In: Hallett, of nonparkinsonian tremors. Mov Disord Aminoff MJ, editors. Electrodiagnosis in Clinical 17(Suppl 3):S41–S48. Neurology, 1992 edn. New York: Churchill Livingstone; 23 Chahine LM, Ghosh D. 2009. Essential tremor after pp 403–19. ipsilateral cerebellar hemispherectomy: support for 40 Grosse P, Cassidy MJ, Brown P. 2002. EEG-EMG, the thalamus as the central oscillator. J Child Neurol MEG-EMG and EMG-EMG frequency analysis: 24:861–4. physiological principles and clinical applications. Clin 24 Louis ED. 2010. Essential tremor: evolving Neurophysiol 113:1523–31. clinicopathological concepts in an era of intensive 41 Brown P, Farmer SF, Halliday DM, et al. 1999. post-mortem enquiry. Lancet Neurol 9:613–22. Coherent cortical and muscle discharge in cortical 25 Elble RJ, Schieber MH, Thach WT, Jr. 1984. Activity of myoclonus. Brain 122( Pt 3):461–72. muscle spindles, motor cortex and cerebellar nuclei 42 Grosse P, Cassidy MJ, Brown P. 2002. EEG-EMG, during action tremor. Brain Res 323:330–334. MEG-EMG and EMG-EMG frequency analysis: 26 Qureshi F, Morales A, Elble RJ. 1996. Tremor due to physiological principles and clinical applications. Clin infarction in the ventrolateral thalamus. Mov Disord Neurophysiol 113:1523–31. 11:440–4. 43 Grosse P, Guerrini R, Parmeggiani L, et al. 2003. 27 Vidailhet M, Jedynak CP, Pollak P, et al. 1998. Abnormal corticomuscular and intermuscular Pathology of symptomatic tremors. Mov Disord coupling in high-frequency rhythmic myoclonus. 13(Suppl 3):49–54. Brain 126:326–42.

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44 van Rootselaar AF, Maurits NM, Koelman JH, et al. 59 Li JY, Cunic DI, Paradiso G, et al. 2008. 2006. Coherence analysis differentiates between Electrophysiological features of myoclonus-dystonia. cortical myoclonic tremor and essential tremor. Mov Mov Disord 23:2055–61. Disord 21:215–22. 60 Beukers RJ, Foncke EM, van der Meer JN, et al. 45 Mima T, Nagamine T, Ikeda A, et al. 1998. Pathogenesis 2010. Disorganized sensorimotor integration in of cortical myoclonus studied by magnetoencephalog- mutation-positive myoclonus-dystonia: a functional raphy. Ann Neurol 43:598–607. magnetic resonance imaging study. Arch Neurol 46 Shibasaki H, Yamashita Y, Neshige R, et al. 1985. 67:469–74. Pathogenesis of giant somatosensory evoked poten- 61 van der Salm SM, van Rootselaar AF, Foncke EM, tials in progressive myoclonic epilepsy. Brain et al. 2009. Normal cortical excitability in Myoclonus- 108(Pt 1):225–40. Dystonia – a TMS study. Exp Neurol 216:300–5. 47 Myoclonus and epilepsy in childhood. Commission on 62 Chen R, Remtulla H, Bolton CF. 1995. Pediatric Epilepsy of the International League Against Electrophysiological study of diaphragmatic myo- Epilepsy. 1997. Epilepsia 38:1251–4. clonus. J Neurol Neurosurg Psychiat 58:480–3. 48 van Rootselaar AF, Maurits NM, Renken R, et al. 2008. 63 Brown P, Rothwell JC, Thompson PD, et al. 1991. New Simultaneous EMG-functional MRI recordings can observations on the normal auditory startle reflex in directly relate hyperkinetic movements to brain man. Brain 114(Pt 4):1891–1902. activity. Hum Brain Mapp 29:1430–1441. 64 Brown P, Rothwell JC, Thompson PD, et al. 1991. The 49 Cohen NR, Hammans SR, Macpherson J, et al. 2011. hyperekplexias and their relationship to the normal New neuropathological findings in Unverricht– startle reflex. Brain 114(Pt 4):1903–28. Lundborg disease: neuronal intranuclear and cyto- 65 Hallett M, Chadwick D, Adam J, et al. 1977. Reticular plasmic inclusions. Acta Neuropathol 131:421–7. reflex myoclonus: a physiological type of human post- 50 van Rootselaar AF, van der Salm SM, Bour LJ, et al. hypoxic myoclonus. J Neurol Neurosurg Psychiat 2007. Decreased cortical inhibition and yet cerebellar 40:253–64. pathology in ‘familial cortical myoclonic tremor with 66 Tijssen MA, Voorkamp LM, Padberg GW, et al. 1997. epilepsy’. Mov Disord 22:2378–2385. Startle responses in hereditary hyperekplexia. Arch 51 Hunt JR. 1921. Dyssynergia cerebellaris myoclonica, Neurol 54:388–93. primary atrophy of the dentate system. Brain 67 Leu-Semenescu S, Roze E, Vidailhet M, et al. 2007. 44:490–538. Myoclonus or tremor in orthostatism: an under- 52 Tijssen MA, Thom M, Ellison DW, et al. 2000. Cortical recognized cause of unsteadiness in Parkinson’s myoclonus and cerebellar pathology. Neurol 54:1350–6. disease. Mov Disord 22:2063–69. 53 Christe W, Jacob R, Janz D. 1995. Juvenile myoclonic 68 Glass GA, Ahlskog JE, Matsumoto JY. 2007. Orthostatic epilepsy: response to valproate monotherapy in 27 myoclonus: a contributor to gait decline in selected previously untreated patients. Epilepsia Suppl. 3:S65. elderly. Neurol 68:1826–30. 54 Foncke EM, Cath D, Zwinderman K, et al. 2009. Is 69 Esposito M, Edwards MJ, Bhatia KP, et al. 2009. psychopathology part of the phenotypic spectrum of Idiopathic spinal myoclonus: a clinical and neuro- myoclonus-dystonia?: a study of a large Dutch M-D physiological assessment of a movement disorder of family. Cogn Behav Neurol 22:127–33. uncertain origin. Mov Disord 24:2344–9. 55 Roze E, Apartis E, Clot F, et al. 2008. Myoclonus- 70 Brown P, Thompson PD, Rothwell JC, et al. 1991. dystonia: clinical and electrophysiologic pattern Axial myoclonus of propriospinal origin. Brain related to SGCE mutations. Neurol 70:1010–16. 114(Pt 1A):197–214. 56 Foncke EM, Bour LJ, Speelman JD, et al. 2007. Local 71 Brown P, Rothwell JC, Thompson PD, et al. 1994. field potentials and oscillatory activity of the internal Propriospinal myoclonus: evidence for spinal “pattern” globus pallidus in myoclonus-dystonia. Mov Disord generators in humans. Mov Disord 9:571–6. 22:369–76. 72 Chokroverty S, Walters A, Zimmerman T, et al. 1992. 57 Beukers RJ, Booij J, Weisscher N, et al. 2009. Reduced Propriospinal myoclonus: a neurophysiologic analysis. striatal D2 receptor binding in myoclonus-dystonia. Neurol 42:1591–5. Eur J Nucl Med Mol Imaging 36:269–74. 73 Roze E, Bounolleau P, Ducreux D, et al. 2009. 58 Kinugawa K, Vidailhet M, Clot F, et al. 2009. Propriospinal myoclonus revisited: Clinical, neuro- Myoclonus-dystonia: an update. Mov Disord physiologic, and neuroradiologic findings. Neurol 24:479–89. 72:1301–9.

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74 Roze E, Apartis E, Vidailhet M, et al. 2007. 86 Guttman M, Lang AE, Garnett ES, et al. 1987. Regional Propriospinal myoclonus: utility of magnetic reso- cerebral glucose metabolism in SLE chorea: further nance diffusion tensor imaging and fiber tracking. evidence that striatal hypometabolism is not a Mov Disord 22:1506–9. correlate of chorea. Mov Disord 2:201–210. 75 Esposito M, Edwards MJ, Bhatia KP, et al. 2009. 87 Weindl A, Kuwert T, Leenders KL, et al. 1993. Idiopathic spinal myoclonus: A clinical and neuro- Increased striatal glucose consumption in Sydenham’s physiological assessment of a movement disorder of chorea. Mov Disord 8:437–444. uncertain origin. Mov Disord 24:2344–9. 88 Pahl JJ, Mazziota JC, Cummings J, et al. 1987. Positron 76 Banks G, Nielsen VK, Short MP, et al. 1985. Brachial emission tomography in tardive dyskinesias and plexus myoclonus. J Neurol Neurosurg Psychiat Huntington’s disease. J Cerebral Blood Flow Metab 48:582–4. 7:1253–5. 77 Seidel G, Vieregge P, Wessel K, et al. 1997. Peripheral 89 Turjanski N, Weeks R, Dolan R, et al. 1995. Striatal D1 myoclonus due to spinal root lesion. Muscle Nerve and D2 receptor binding in patients with Huntington’s 20:1602–3. disease and other choreas. A PET study. Brain 78 Camerota F, Celletti C, Paoloni M, et al. 2006. 118(Pt 3):689–96. Myoclonus of the scapula after acute long thoracic 90 Ichise M, Toyama H, Fornazzari L, et al. 1993.) nerve lesion: a case report. Mov Disord 21:71–3. Iodine–123-IBZM dopamine D2 receptor and techne- 79 Jankovic J. 2009. Peripherally induced movement tium–99m-HMPAO brain perfusion SPECT in the disorders. Neurol Clin 27:821–32, vii. evaluation of patients with and subjects at risk for 80 Tyvaert L, Krystkowiak P, Cassim F, et al. 2009. Huntington’s disease. J Nucl Med 34:1274–81. Myoclonus of peripheral origin: two case reports. Mov 91 Blin J, Baron JC, Cambon H, et al. 1989. Striatal Disord 24:274–7. dopamine D2 receptors in tardive dyskinesia: PET 81 Munts AG, van Rootselaar AF, van der Meer JN, et al. study. J Neurol Neurosurg Psychiat 52:1248–52. 2008. Clinical and neurophysiological characteriza- 92 Roze E:Saudou F, Caboche J. 2008. Pathophysiology tion of myoclonus in complex regional pain syndrome. of Huntington’s disease: from huntingtin functions Mov Disord 23:581–7. to potential treatments. Curr Opin Neurol 82 Cardoso F, Seppi K, Mair KJ, et al. 2006. Seminar on 21:497–503. choreas. Lancet Neurol 5:589–602. 93 Cepeda C, Hurst RS, Calvert CR, et al. 2003. Transient 83 A novel gene containing a trinucleotide repeat that is and progressive electrophysiological alterations in the expanded and unstable on Huntington’s disease corticostriatal pathway in a mouse model of chromosomes. The Huntington’s Disease Collaborative Huntington’s disease. J Neurosci 23:961–9. Research Group. 1993 Cell 72:971–83. 94 Imarisio S, Carmichael J, Korolchuk V, et al. 2008. 84 Antonini A, Leenders KL, Spiegel R, et al. 1996. Huntington’s disease: from pathology and genetics to Striatal glucose metabolism and dopamine D2 recep- potential therapies. Biochem J 412:191–209. tor binding in asymptomatic gene carriers and patients 95 Tang TS, Chen X, Liu J, et al. 2007. Dopaminergic with Huntington’s disease. Brain 119(Pt 6):2085–95. signaling and striatal neurodegeneration in 85 Hosawaka S, Ichiya Y, Kuwabara Y, et al. 1987. Huntington’s disease. J Neurosci 27:7899–910. Positron emission tomography in case of chorea with 96 Anderson AN, Roncaroli F, Hodges A, et al. 2008. different underlying disease. J Neurol Neurosurg Chromosomal profiles of gene expression in Psychiat 50:1284–7. Huntington’s disease. Brain 131:381–8.

Albanese_c03.indd 39 12/24/2011 6:24:53 AM CHAPTER 4 Overview of the Medical Treatments of Hyperkinetic Disorders William Ondo Department of Neurology, Baylor College of Medicine, Houston, Texas, USA

Introduction additional information is often required for a correct classification. For example, simple demographics are Hyperkinetic movement disorders encompass a important. Tics almost always start in childhood and broad spectrum of diseases and neurophysiologies. lessen with age. Generalized dystonia and chorea/ In the majority of cases they originate in the central athetosis may begin in childhood but focal dystonias nervous system and involve the basal ganglia, usually appear in midlife. Tremor can occur early but although a complete understanding of physiology usually presents later and worsens with age. is lacking in any of these conditions. Hyperkinetic The degree of suppressibility can differentiate hyper- disorders are associated with dysfunction in multi- kinetic movements. Tics and stereotypies are usually ple neurotransmitter systems that cause abnormal partially suppressible whereas dystonia, action data handling within the basal ganglia. In some tremor, and chorea usually are not. Clinical history is instances these abnormalities can be mitigated or also important in many cases. Tardive syndromes corrected by medical intervention. only occur in the setting of exposure to dopamine Recognizing the phenotype is the first critical step receptor-blocking drugs, also referred to as neurolep- to diagnosing the underlying condition and eventually tics of dopamine antagonists. Hemichorea/ballismus choosing the most appropriate treatment (Table 4.1). almost always follows a CNS lesion. Many systemic The detailed phenomenology of each hyperkinetic diseases can cause relatively specific movement movement type will be analyzed in the forthcoming disorders, i.e. paraneoplastic chorea or ataxia, cere- chapters. In this chapter, we will present an overview bellar outflow tremors with appropriate CNS lesion, of hyperkinetic disorders and briefly discuss clinical, autoimmune chorea, and tics. In some cases specific diagnostic, and physiologic features. We will then serologies or imaging is diagnostic. Genetics tests are discuss treatments used for these disorders. especially helpful for chorea diseases. The degree to which hyperkinetic disorders affect quality of life depends upon their severity. Some Motor phenotypes conditions, such as hemiballismus from a stroke almost always cause severe disability. Most condi- Hyperkinetic basal ganglia disorders are character- tions, however, range from mild to severe and affect ized by the onset of an involuntary movement that quality of life accordingly. The best example is can be controlled to varying degrees. On simple essential tremor, which may be barely noticed or observation there can be phenotypic overlap, so result in a complete inability to use the hands.

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Table 4.1 Hyperkinetic movement Tremor Rhythmic oscillation around a joint disorder phenotypes. Tics Intermittent, patterned, partially suppressible movements out of a normal background, often preceded by premonitory sensation Dystonia Patterned, usually sustained involuntary muscle contractions Chorea Involuntary unpredictable and random, jerk-like or fluid, movements Ballismus Chorea that is more proximal and larger in amplitude Athetosis Slow unpredictable writhing movements Stereotypies Repetitive, often constant, patterned, coordinated, movements

Pathophysiology of hyperkinetic most commonly treat parkinsonism, a hypokinetic disorders disorder. That said they usually also improve the rest tremor of Parkinson disease (PD), which may be con- Many hyperkinetic disorders are associated with sidered a hyperkinetic component of parkinsonism. a biochemical rearrangement of neural circuits Restless legs syndrome (RLS) is the other common flowing through the basal ganglia. Some neuro- condition that is treated successfully with dopamin- transmitter systems are affected more than others, ergic drugs. The main pathology of RLS is reduced namely dopaminergic, adrenergic, noradrenergic, CNS iron. The mechanism by which dopaminergics GABAergic, and glutamatergic systems. In most improve symptoms is unknown, as there is almost no cases, it is not simply an absence or overabundance evidence of dopamine deficiency [1, 2]. Nevertheless, of a single neurotransmitter, but rather neuro- initial improvement of RLS with dopaminergics is degeneration and cell loss that results in altered immediate and among the most dramatic in all rhythmic output from the basal ganglia. Many of medicine. Long-term complications, including hyperkinetic disorders also show physiological augmentation of symptoms, are common, but abnormalities outside the basal ganglia, such as dopamine agonists, when appropriately dosed and increased cerebellar activity in essential tremor and administered, almost always initially improve increased cortical representation in dystonia. The idiopathic RLS. main exceptions to neurodegenerative physiology Dopamine-responsive dystonia also dramatically are several metabolic diseases that result in reduced improves with dopaminergics, often for life, without dopamine production. These often present as dys- tolerance or complications. This condition usually tonia and, as would be expected, improve with results from mutations in enzymes that produce dopamine supplementation. Other hyperkinetic dopamine (most commonly GTP cyclohydrolase I) disorders result form neurotransmitter receptor so improvement with dopamine replacement is abnormalities and do not respond well to intuitive. Since testing for these mutations is diffi- supplemental neurotransmitters. cult, it is usually recommended that all cases of generalized dystonia be tried on levodopa or dopamine agonists to assess their effect. Medical treatments of Apomorphine, a short acting DA, is also reported hyperkinetic disorders to improve chorea associated with Huntington disease [3], although levodopa was traditionally used to Dopamine agonists provoke chorea to diagnose chorea in undiagnosed Dopamine agonist (DA) drugs include pergolide, bro- Huntington disease. This apparent anomaly under- mocriptine, lisuride, pramipexole, ropinirole, caber- scores the complexity of specific neurotransmitter goline, rotigotine, and apomorphine; and levodopa interactions in hyperkinetic disorders.

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Table 4.2 Dopamine receptor blockers1. High potency Medium potency Low potency

Haloperidol Promazine Quetiapine Fluphenazine Olanzapine Clozapine Metoclopramide Ziprasidone Promethazine Prochlorperazine Trimethobenzamide Risperidone Domperidone2 Pimozide Droperidol Thioridazine Trifluperazine

1 Higher potency drugs result in greater improvement in hyperkinetic movement disorders but a higher risk of drug-induced movement disorders. 2 Does not cross blood–brain barrier.

DAs possess a number of side effects, almost all of as effective for tics. Dopamine antagonists can also which are thought to result from the stimulation of be used to treat chorea, ballismus, and possibly dopamine receptors in different parts of the central stereotypies. and peripheral nervous system. Nausea, hypoten- Dopamine antagonists possess a number of sion, sedation, and peripheral edema are probably potentially serious side effects. Most result from the most common. Nasal congestion, constipation, the direct blockade of dopamine receptors but headache are also reported. DAs can cause impul- others result from effects on other neurotransmitter sivity, usually manifested by increased spending, receptors, especially serotonin. Fatigue, sedation, gambling, and increased sexual activity. DA-induced apathy, and depression are common. The so-called visual hallucinations and choreatic-like dyskinesia extra-pyramidal side effects include parkinsonism, are usually seen when used for the treatment of akathisia, tardive dyskinesia (TD), and neuroleptic PD. In contrast, nasal congestion related to DAs malignant syndrome (NMS). TD is particularly seems to be more common in RLS. problematic as drug withdrawal does not help initially. One advantage of tetrabenazine (a mono- Dopamine antagonists amine depleting drug) over other antidopaminergic Dopamine antagonists (neuroleptics) block D2/D3 drugs is that it does not cause TD [4]. Weight gain receptors and, to varying degrees, other dopamine and the development of type II diabetes is a major receptors and serotonin, cholinergic, and histamin- concern with some, but is probably related to ergic receptors. In general, newer or “atypical” serotonin and histamine receptor stimulation. neuroleptics have less dopaminergic and greater Some of these drugs also prolong cardiac QT serotonergic and histaminergic affinities. These interval, possibly increasing the risk of cardiac differences result in different efficacy and side effect arrhythmias (Table 4.2). profiles among the drugs. Dopamine antagonists remain the mainstay of Tetrabenazine pharmacotherapy for tics. We prefer fluphenazine Tetrabenazine (TBZ), the best studied and probably and tetrabenazine (TBZ), but pimozide, haloperidol, most effective antichorea treatment, is most com- and other neuroleptics are also used [4]. Dopamine monly used for chorea associated with Huntington antagonists typically reduce tics by 50–75% from disease [5], but is probably equally effective for baseline in a dose-dependent manner. Formal data choreas of other etiologies. It seems particularly is lacking but newer “atypical” antipsychotics, with beneficial for chorea with hyperglycemia, an inter- less dopamine antagonist affinities, are probably not esting condition associated with very characteristic

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MRI changes [6]. We have had excellent results blood–brain barrier, namely propranolol and with TBZ for stereotypies associated with fronto- nadolol. These often reduce tremor amplitude by temporal dementia. It is also commonly used for 50% in a dose-dependent manner, and are most hemiballismus and tics. Perhaps the greatest utility useful in mild to moderate cases. Side effects of beta of TBZ, however, is the treatment of TD [7]. In antagonists include hypotension, bradycardia, short, TBZ probably has good utility for more fatigue, and erectile dysfunction. hyperkinetic disorders than any other single agent. Clonidine and guanfacine are alpha-2 agonists that TBZ is a vesicular monoamine transmitter-2 reduce adrenergic tone by inhibiting norepinephrine (VAMT-2) inhibitor. It most closely resembles reser- release. Although the drugs are commonly used to pine, except reserpine is also a VMAT-1 inhibitor, treat tics, they rarely exert potent anti-tic effects, but which seems to cause greater hypotensive and may be useful in the treatment of comorbid impul- sedation adverse events. Our anecdotal experience sivity. Side effects include hypotension, sedation and suggests that compared to TBZ, reserpine confers fatigue. less benefit and increased side effects. VMAT-2 controls the influx and efflux of mon- Anticholinergic drugs oamines (dopamine, histamine, norepinephrine, Anticholinergics, including trihexyphenidyl and serotonin) to intracytoplasmic vesicles. These (Artane), benztropine (Cogentin), orphenadrine neurotransmitters, when free, can be very toxic (Norflex), and ethopropazine (Parsidol) are proba- to cells so a considerable amount of energy is bly the most effective oral medications for dystonia. dedicated to compartmentalizing them into the These drugs block the release of acetylcholine at the presynaptic vesicles. This is especially true for neuromuscular junction, resulting in muscle relax- dopamine which has a vesicle to cytoplasmic ation. Unfortunately they block acetylcholine and ratio of more than 50,000:1. VMAT-2 is also histamine in the central nervous system resulting involved with shepherding these vesicles to the in a robust side effect profile, including sedation, nerve junction for release. The end result of TBZ cognitive slowing, including psychosis and delir- is a reduction of dopamine and histamine > nor- ium, dry mouth, constipation, and heat intoler- epinephrine > serotonin release. The improve- ance. Children tolerate these medicines better than ment in hyperkinetic disorders likely results from adults so they have their greatest overall utility in reduced dopamine release. young patients with generalized dystonia. They are The dose of TBZ ranges from 25 to 150 mg/day. sometimes used to prevent acute dystonic reactions Metabolism of some metabolytes, mediated by and treat parkinsonian tremor. Anticholinergics are CYP2D6 enzymes, is highly individualized so the occasionally prescribed for the “treatment” of cho- drug is titrated to effect versus side effects rather rea and TD, but these drugs can actually exacerbate than a dose. The most common side effects include these hyperkinetic movement disorders. There are sedation, fatigue, depression, and insomnia. Like no comparative studies among the drugs. dopamine antagonists, TBZ can cause parkinsonism and akathisia, but these and other side-effects GABA receptor agonists are dose related. TBZ does not cause TD but par- Benzodiazepines, such as baclofen and tizanidine, kinsonism may occur, particularly when TBZ is stimulate gamma-aminobutyric acid (GABA) recep- used in the treatment of TD. tors. The GABA-A receptor is a heterogeneous subunit transmembrane chloride gated ion channel Antiadrenergic drugs usually composed of 2G, 2H, and 1F units in varying Non-cardiac selective beta-adrenergic antagonists combinations [9]. They possess several distinct are the most commonly used medications for binding sites for neurotransmitters and drugs. The essential tremor (ET) [8]. There is little comparative actual GABA site straddles the G and H subunits, data among these drugs but expert consensus whereas the benzodiazepine (BZD) site straddles G favors the non-cardiac selective drugs that cross the and F subunits. Benzodiazepine affinity is largely

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predicted by the G subtype. Stimulation of the Both effect and adverse events are dose dependent benzodiazepine with agonists facilitates the effect of with a range from 25 mg to 400 mg/day, usually in GABA on the GABA receptors, resulting in chloride two divided doses. Adverse events are common, ion influx, which usually inhibits synaptic firing. and include word-finding difficulties and other cog- Benzodiazepines are non-specific muscle relax- nitive slowing, paresthesia, altered taste, especially ants that have been used to treat dystonia, tremor, with carbonated beverages, weight loss, and renal myoclonus, chorea, and tics. They are generally lithiasis. only moderately effective and formal trials for Gabapentin, gabapentin enacarbil, and hyperkinetic disorders or comparisons among pregabalin both demonstrate good efficacy for drugs are rare. Nevertheless physician familiarity, RLS in controlled trials. They may improve ET but low cost and a well-described side effect profile results of trials are mixed. Gabapentin and make them convenient options for a number of pregabalin are occasionally reported to improve conditions. The main side effect is sedation and most other hyperkinetic movement disorders mental slowing. They also increase the risk of falls but data is mostly anecdotal and inconsistent. in the elderly. Primidone and, to a lesser extent, its metabolite Baclofen and tizanidine are most commonly used phenobarbital often help ET. Other seizure for dystonia but may occasionally help tics. medications occasionally help some hyperkinetic disorders (Table 4.3). Ethanol Arguably, the most consistent tremorlytic agent is Amantadine ethanol. Tremor suppression usually occurs within Amantadine is an old antiviral medication with mul- 20 minutes and lasts for 3–5 hours. This is often fol- tiple mechanisms of action. In the early 1970s, it was lowed by a rebound tremor augmentation. The reported to help PD. Later, amantadine showed ben- equivalent of one drink appears adequate for this efit against the chorea and stereotypic movements of clinical effect but the mechanism by which ethanol L-dopa-induced dyskinesia in PD [13]. Subsequently, improves tremor is not known. The use and abuse of amantadine also improved HD-associated chorea in alcohol is probably not increased in ET patients, controlled trials [14]. Memantine (Namenda), although this is debated. Other less intoxicating which is marketed for dementia, has also shown alcohols are currently being studied for ET [10]. some benefit for HD chorea [15]. The antichorea Ethanol can also improve a group of overlapping properties of amantadine probably result from conditions variably named “alcohol responsive myo- its antagonism of N-methyl-aspartate receptors. clonus,” dystonia with lightning jerks, “and myo- Amantadine has modest anti-cholinergic properties clonus-dystonia syndrome,” sometimes associated and side effects (dry mouth, constipation, and cogni- with abnormalities in the epsilon-sarcoglycan gene. tive slowing, including psychosis). It also consistently results in livido reticularis, typically after Topiramate and other seizure several months of use. This may be associated with medications problematic peripheral edema. Topiramate was first developed as an antidiabetes drug and later approved as a medication for sei- Botulinum toxins zures. There is good data that this drug is useful for Botulinum toxins (BoNTs) inhibit the release of tremor [11] and tics [12]. It is also commonly used acetylcholine from the nerve terminal by cleaving for migraine headache and for weight loss. The one of the required SNARE proteins necessary for drug has multiple mechanisms of action including the release of acetylcholine into the neuro- sodium, calcium, and potassium channels; at muscular junction, thus preventing contraction GABA-A and α-amino-3-hydroxy-5-methyl-isoxa- of the muscle. Without functioning neuro- zole-4-propionate (AMPA)/kainate-type glutamate transmitters, the nerve terminal and muscle receptors; and as a carbonic anhydrase inhibitor. atrophy. The duration of benefit averages between

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Table 4.3 Efficacy of selected epilepsy ET RLS Tics Dystonia Chorea Myoclonus medications in hyperkinetic movement disorders. Topiramate +++ + +++ + + + Primidone +++ + + Gabapentin ++ +++ + + + + / W Pregabalin ++ +++ Phenobarbital ++ + Phenytoin W + / W Depakote W +++ ++ Carbamazepine ++++ / W ++++ / W Levetiracetam ++ / N ++ + ++ Lacosamide N Vigabatrin W N Zonisamide ++ + / W W

+++ = Placebo control trials consistently demonstrate efficacy. ++ = Mixed placebo trials or positive large series. + = Anecdotal benefit or small series. N = Controlled trials or reports negative. W = May worsen the condition or side effect of drug.

12 and 16 weeks, followed by recrudescence as consistent results seen in head tremor. We have the original nerve bouton regenerates. found great utility of BoNT for arm tremor that Clinical results depend upon injection tech- primarily involves the wrists, for task-specific niques, including dosing, dilutions, and localization tremors such as writing tremor, for head tremor, techniques. Four different BoNT preparations are and for jaw tremor. BoNT can effectively treat tics currently available: onabotulinumtoxin-A (Botox), in certain anatomies, mostly the upper face (eye abobotulinumtoxin-A (Dysport), rimabotulinum- blinking, forehead contractions, paranasal move- toxin-B (Myobloc, Neurobloc), and incobotuli- ments) and neck (head pulling and rotation, and numtoxin-A (Xeomin). The type-A toxins differ in shoulder shrugging). Therefore, the treatment is the complexing proteins that stabilize the actual reserved for patients with problematic tics in these 150 Kd protein. Other toxins have been developed areas. Interestingly, the treatment usually improves but are not commercially available. Potency is the premonitory sensation, not just the move- based on biological activity rather than mass, and is ment. It often results in complete cessation of the not interchangeable among the toxins. Gross ratios injected tic, but some patients subsequently mani- of potency are also commonly employed by practi- fest tics in different areas after the injections. BoNT tioners: uno = 1: inco = 1, abo = 2–5, rima = 40–60. can treat myoclonus, chorea, and stereotypie but BoNT injections are first-line therapy for most efficacy depends upon the involved anatomy. In focal dystonias. Multiple trials have demonstrated general, smaller muscles and a focal distribution efficacy for cervical dystonia and blepharospasm. will respond best. Hand dystonia, such as writer’s cramp and hemifa- The treatment has minimal systemic adverse cial spasm, consistently improve but are less well events, but can cause focal weakness. Therefore the studied. There are also more than 200 other pub- side effect profile depends on the injected anatomy. lished uses for BoNT, including a number of hyper- Potential non-motor side effects include dry mouth kinetic movements disorders. Multiple trials of (more common with rimabotulinum toxin-B), flu both arm tremor and head tremor have variably like symptoms, and consequences of any injection demonstrated the efficacy of BoNT, with more (bleeding, bruise, site irritation).

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Phenol, alcohol, and other destructive agents i.e. using a wide or Y pen for writer’s cramp. Not are occasionally used for dystonia, but more com- performing the dystonia-provoking task, some- monly for spasticity. As these agents permanently times facilitated by casting, often transiently destroy muscle and nerve, they are reserved for improves the dystonia. This is most commonly only very refractory hyperkinetic disorders. employed in musician task-specific dystonia.

Surgical treatments and physical Miscellaneous treatments for specific treatments for hyperkinetic disorders movement disorders Surgical treatments for hyperkinetic disorders will be Although desirable, behavioral treatments for tics discussed in detail in subsequent chapters. These can have only occasionally demonstrated consistent be roughly segregated in ablation/stimulation in the efficacy in trials [17]. The most common is habit central nervous syndrome or ablation/stimulation in reversal training, where patients try to replace the the peripheral nervous system. tic with an unnoticed movement such as clinching Lesioning or deep brain stimulation (DBS) into their fist. Anxiety relieving techniques, such as bio- the VIM thalamus is the most robust treatment for feedback, cognitive therapy, and exposure desensi- refractory tremor. This is most effective for distal tization are also tried. Immunomodulation with aspects of the appendages, and is less effective for plasmapheresis has been advocated for the treat- midline tremor. Lesions and DBS of the globus ment of tics, but controlled trials were negative. pallidus internus can be very effective for idiopathic Treatment of tardive dyskinesia may be difficult if generalized dystonia, and some focal dystonias. In tetrabenazine is ineffective or not available. There general the best efficacy is seen in the appendages, is clear data to suggest that TD becomes more as opposed to midline features, and when the refractory if the culpable medication is not with- dystonia has a pronounced kinetic (action-induced) drawn, therefore discontinuation is recommended component, as opposed to fixed dystonias, which whenever possible. TD often acutely worsens with are usually secondary (cerebral palsy and other the offending drug’s discontinuation. Vitamin B6 brain injuries). Targeting the VIM thalamus may be (pyridoxine 300 mg), branched chain amino acids relatively more beneficial in these fixed dystonias. (Leucine, Isoleucine, Valine), and vitamin E (alpha- DBS is also used for severe cases of tics. Various tocopherol) have controlled trials showing efficacy targets are used, including the globus pallidus in TD. However, trials for B6 and amino acids have internus, the anterior limb of internal capsule, and not been replicated and most vitamin E studies are several areas of the thalamus [16]. Results in open negative. Other drug-induced movement disorders label series have ranged from modest to dramatic are variably treated (Table 4.4). and life changing. This is of course reserved for the most severe and refractory cases. Peripheral surgical procedures for dystonia Summary include rhizotomy, ramisectomy, peripheral nerve lesioning, and myectomy. These are most commonly A number of oral, injectable, and surgical treat- performed for cervical dystonia although myectomy ments exist for hyperkinetic disorders. There is is also used for blepharospasm. good scientific data supporting several treatments Physical measures for dystonia include forceful for ET, RLS, for TBZ in chorea, and for BoNT in focal bracing against the dystonic movement, and braces dystonias. There are very few other well-designed designed to facilitate the sensory trick (geste antag- trials for dystonia, chorea, myoclonus, ballismus/ oniste) seen in many focal/segmental dystonias. For athetosis, or stereotypies. With few exceptions, example, a brace that just touches the back of the these treatments are only symptomatic in nature. head may help cervical dystonia. Talking or singing Medications are only effective while actively taken often improves blepharospasm. Various adaptive and none of the injections or surgeries treats the changes can also lessen task specific dystonia, underlying etiology. As many of these therapeutic

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Table 4.4 Phenotypes and treatments of hyperkinetic dopaminergic drug-induced syndromes.

Phenotype Prognosis Treatment

Rabbit syndrome 4–6 Hz large amplitude Variable Anticholinergics, mouth tremor amantadine Acute dystonic Upward eye deviation Neck Resolves in several Antihistamines; reaction extension days anticholinergics; benzodiazepines (usually only one dose required); diphenhydramine 50 mg most commonly used Tardive dyskinesia Variable Usually mouth, Persistent but may Tetrabenazine; B6; tongue, jaw repetitive gradually lessen over Vit E; Botulinum toxin; smooth movements that years. Withdrawal TD Benzodiazepines; GPi deep lessen with volitional action has a better prognosis brain stimulation Acute akathisia Inner body need to move, Improves with drug Drug withdrawal pacing, rocking withdrawal Tardive akathisia Inner body need to move, Variable, may persist Benzodiazepines; pacing, rocking for years B blockers; anticholinergics Neuroleptic malignant Rigidity, autonomic instability 25% mortality; Dopamine agonists; syndrome (fever), altered mental status Improves over months dantrolene; supportive care

options have serious potential side effects, the 7 Ondo WG, Hanna PA, Jankovic J. Tetrabenazine symptomatic benefit must in all cases be weighed treatment for tardive dyskinesia: assessment by against side effects and cost. randomized videotape protocol. Am J Psychiat 1999; 156(8):1279–81. 8 Zesiewicz TA, Elble R, Louis ED, et al. Practice param- References eter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American 1 Connor JR, Boyer PJ, Menzies SL, et al. Neuro- Academy of Neurology. Neurol 2005; 64(12): pathological examination suggests impaired brain iron 2008–20. acquisition in restless legs syndrome. Neurol 2003; 9 Dawson GR, Collinson N, Atack JR. Development of 61(3):304–9. subtype selective GABAA modulators. CNS Spectr 2 Connor JR, Wang XS, Allen RP, et al. Altered dopamin- 2005; 10(1):21–7. ergic profile in the and substantia nigra in restless leg 10 Mostile G, Jankovic J. Alcohol in essential tremor and syndrome. Brain 2009; 132(Pt 9):2403–12. other movement disorders. Mov Disord 2010; 3 Vitale C, Marconi S, Di Maio L, et al. Short-term 25:2274–84. continuous infusion of apomorphine hydrochloride for 11 Ondo WG, Jankovic J, Connor GS, et al. Topiramate in treatment of Huntington’s chorea: a double blind, essential tremor: a double-blind, placebo-controlled randomized cross-over trial. Mov Disord 2007; trial. Neurol 2006; 66(5):672–7. 22(16):2359–64. 12 Jankovic J, Jimenez-Shahed J, Brown LW. A ran- 4 Jankovic J. Treatment of hyperkinetic movement domised, double-blind, placebo-controlled study of disorders. Lancet Neurol 2009; 8:844–56. topiramate in the treatment of Tourette syndrome. 5 Tetrabenazine as antichorea therapy in Huntington J Neurol Neurosurg Psychiat 2009; 81(1):70–3. disease: a randomized controlled trial. Neurol 2006; 13 Snow BJ, Macdonald L, McAuley D, Wallis W. The 66(3):366–72. effect of amantadine on levodopa-induced dyskinesias 6 Sitburana O, Ondo WG. Tetrabenazine for hyperglyce- in Parkinson’s disease: a double-blind, placebo- mic-induced hemichorea-hemiballismus. Mov Disord controlled study. Clinical Neuropharmacology 2000; 2006; 21(11):2023–5. 23(2):82–5.

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14 O’Suilleabhain P, Dewey RB, Jr. A randomized trial of 16 Mink JW. Clinical review of DBS for Tourette syn- amantadine in Huntington disease. Arch Neurol 2003; drome. Front Biosci (Elite edn) 2009; 1:72–6. 60(7):996–8. 17 Piacentini J, Woods DW, Scahill L, et al. Behavior 15 Ondo WG, Mejia NI, Hunter CB. A pilot study of the therapy for children with Tourette disorder: a rand- clinical efficacy and safety of memantine for Huntington’s omized controlled trial. JAMA 303(19):1929–37. disease. Parkin Rel Disord 2007; 13(7):453–4.

Albanese_c04.indd 48 12/24/2011 6:26:08 AM CHAPTER 5 Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders Vinata Vedam-Mai,1 Oscar Bernal,2,3 and Michael S. Okun1,2,3 1 Department of Neurological Surgery, University of Florida, Gainesville, FL, USA 2 Movement Disorders Center, University of Florida, Gainesville, FL, USA 3 Department of Neurology, University of Florida, Gainesville, FL, USA

Introduction refinements in these procedures were introduced in the second half of the 20th century when Spiegel Movement disorders have been grossly categorized and Wycis utilized the stereotactic head frame into either hypokinetic (e.g. PD, and related disorders) technology. This approach was subsequently fine- where there is a paucity of movement, or hyperkinetic tuned by clinician-scientists such as Hassler, Cooper, (dystonia, tremor, choreas, etc.) where there is Laitenen, and others [5, 6]. The addition of stero- excessive movement [1–3]. In many cases there is taxis has allowed surgeons to target subcortical a complexity in the classification as hyperkinetic structures on the basis of a relatively simple 3D and hypokinetic components may exist. In this Cartesian coordinate system [7]. The accuracy of chapter we will provide an overview of, and surgical targeting has significantly improved over time, treatment for, hyperkinetic movement disorders however the pathophysiological basis underlying with an emphasis on brain stimulation therapy. most basal ganglia disorders remains incompletely understood. Surgical therapy was largely abandoned with the advent of levodopa therapy in 1967 [8]. Historical background Surgical therapies re-emerged, however, as dyskinesias and motor fluctuations were recognized Dating back as far as Victor Horsley [4], neuro- as being drug associated, and potentially disabling surgeons have attempted to address HKDs by a disease manifestations. Several studies have dem- variety of destructive, or ablative approaches. The onstrated the effectiveness of brain lesion therapy, actual process involves unilateral lesioning in the including thalamotomy for tremor, and pallidot- sensorimotor territory of the GPi. This process is omy for the treatment of idiopathic PD [7, 9]. called pallidotomy. Generally, it is believed that the During pallidotomies and thalamotomies it was success of pallidotomy in reducing the effects of observed that high-frequency test stimulation often movement disorders is due to an interruption of the produced clinically similar effects to the ablative pro- abnormal neuronal activity in the GPi. This ablation cedure itself [10, 11]. Following Benabid’s successful technique is similar to the removal of a broken part implantation of a chronic deep brain stimulation in an electrical circuit. Hence, when the damaged [DBS) lead in the thalamus in 1987, the DBS piece is removed, the healthy/remainder of the procedure, which was both reversible and program- circuit can continue to function normally. Important mable, established itself as a potentially safer and

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more attractive alternative to ablative approaches. It likely a result of changes in the neuronal outputs should mentioned, however, that ablative lesions are arising from the thalamocortical circuitry. There are still excellent treatments for many HKDs and are uti- several theories about the mechanisms of HKD and lized in many of the same targets also used for DBS. their related syndromes. Recordings from the GPi Currently, thalamic DBS is FDA approved in the in patients with HD, dystonia, and in levodopa- United States for the treatment of PD, ET, and induced dyskinesia patients, have revealed that the dystonia. DBS therapy (Medtronic) for essential neuronal discharges may be at a lower frequency, tremor has been approved in Canada, Europe, and and perhaps may be more irregular when compared Australia since 1993. DBS therapy for Parkinson to PD [17–19]. These changes are, however, per- disease has been approved in Canada, Europe, and haps different from patient to patient but a good Australia since 1998. In 2009, Medtronic achieved generalization is that there are significant changes a landmark by receiving the world’s first DBS CE in firing rates and patterns. We will discuss briefly mark approval for a psychiatric condition. Even the known pathophysiology of a few of the most though there is a lack of understanding of the common HKDs. mechanism of action of DBS, there is reasonable evidence that it is effective in the treatment of many movement disorder symptoms. Specialized Stereotactic central nervous centers for the treatment of movement disorders system surgery have been established in almost every industrial- ized nation, and also in some third world countries. Patients evaluation Specific symptoms treated by DBS should be Initial evaluation tailored to the patient (brain target and symptom) Practical principles applied for PD surgical [12]. Neuropsychiatric diseases also have been candidates can be generally applied for HKDs recently targeted by DBS and the efficacy data is [20–22], perhaps with the exception of the on/off still relatively new and emerging [13–16]. levodopa challenge test (utilized in PD surgical evaluations). A complete clinical workup of the Phenomenology and clinical patient should include a review of the evolution of features symptoms, family history, physical and neurological examination and appropriate laboratories (e.g. Wilson disease, rare choreas, workup of mito- HKDs have a wide array of motor and non-motor chondrial disease, tics, ataxia plus syndromes, etc.). manifestations. Common features usually include The initial assessment should include careful an excess of movement, which may be characterized documentation of contractures and limitations in by involuntary/voluntary, automatic/non-automatic, range of motion of any joint as this may impact the and purposeful/purposeless intention, but the outcome (fixed contracture usually do not respond manifestations can be widely variable. to DBS). Also, neuroimaging can be helpful in the Although many motor and non-motor features preoperative process to establish diagnosis, and also may be addressed by DBS, we will focus this chapter for evaluating the integrity of potential DBS targets on primary HKDs, or HKDs which have manifest- (e.g. some secondary diseases or syndromes may ations addressable by DBS (tremor, dystonia, have produced structural changes such as black chorea, and tics). holes, making targeting a challenge). After the initial neurological assessment and diagnosis, the Physiology, pathophysiology, patient must be evaluated by an interdisciplinary and neuropathology team that usually includes an experienced movement disorders specialist, an experienced neurosur- In general, HKDs are thought to arise from geon, a neuropsychologist (to evaluate cognitive pathophysiological changes within the basal function), and a psychiatrist (to evaluate for ganglia. The main symptoms of HKDs are most affective disorders). In select cases, social workers,

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physical therapists, and speech therapists may be cognition, and quality of life scales as appropriate utilized and their roles should be tailored to the to the population. patient’s individual need. Cognitive dysfunction and active untreated affective disorders may preclude DBS [12]. The patient and family should Surgical procedures be well informed about the possible side effects and realistic expectations of surgery as this may be Surgical treatment of HKDs may include ablative widely variable in HKDs when compared to other lesions and also DBS. Lesioning, however, is less disorders, for example PD. The most frequent frequently used as it is irreversible. Lesioning may postoperative DBS complications as reported from be performed unilaterally in the globus pallidus and a recent series: headache (15%), confusion (5%), bilaterally in the STN. Bilateral lesion of GPi can hallucinations (2.8%), nausea and vomiting induce a high risk of side effects and it is used or (1.6%), seizures (1.2%), and these are usually alternatively recommended when the patient has resolved a few weeks following the surgery. immunological susceptibility, or if there is an issue Infection (4.4%), cognitive dysfunction (4%), with access to other treatment options (due to dysarthria (4%), worsening of gait (3.8%), agitation availability, travel, and/or economics). In some (1.6%), bleeding (1.6–3%), displacement and cases, patients may prefer lesions (as no wires or migration of the lead (2.2%), and suicide (0.1–0.3%) hardware issues are involved). were the most serious and disabling complications, DBS, unlike lesion therapy, is a reversible surgical potentially limiting the therapeutic benefits. How- technique where a quadropolar lead is implanted in ever, it should be stressed that this is one series and one or more brain targets. The lead is powered by a each group may have more or less of a specific com- pulse generator which, at a later point, is implanted plication depending on patient selection/level of (usually subclavicularly in special static cases or in difficult cases and experience [23–25]. patients with risk of chest trauma can placed in the abdominal wall). Subsequently, the patients Scales undergo multiple programming adjustments over When a physician recommends surgery for a many visits within the office setting. MRI, CT, MRI/ patient with a HKD, the first and perhaps most CT fusion and ventriculography have all been important issue is confirmation of diagnosis. The utilized to aid in targeting with or without the use appropriate scale for pre- and postoperative of microelectrode mapping and macrostimulation patient assessment should be tailored to the dis- [27] (Plate 5.1). Techniques for DBS implantation ease and to the patient. The Fahn—Tolosa–Marin vary from center to center. In most cases it is prefer- Tremor Rating Scale has been widely used for able to perform the surgical procedure with the evaluation of tremor, the Unified Huntington patient awake, in a nearly supine position, and off Disease Rating Scale (UHDRS) has been used to their specific antimovement disorder medication. evaluate the severity and symptoms of HD, This procedure will help to evaluate responsiveness the Burke—Fahn–Marsden Dystonia Rating Scale to movement in the neuronal population during (BFMDRS) and the Unified Dystonia Rating Scale the microelectrode mapping and stimulation (UDRS) are commonly utilized to evaluate the testing. Local anesthesia and light sedation can be severity of dystonia (both scales show an equal administered during application of the frame and reliability as pre and post DBS tools) [26]. The this may also serve to relieve severe anxiety [26]. Yale Global Tic Severity Scale (YSGSS) and the Leads can be implanted unilaterally, or bilaterally, Modified Rush Tic Rating Scale are both useful depending on the recommendation of the neuro- for evaluation of tic disorders such as TS. The surgeon and the individual patient’s needs. The Unified Myoclonus Rating Scale (UMRS) is help- four common HKDs currently being treated with ful to evaluate symptoms in myoclonus cohorts. DBS are tremors, chorea, dystonia, and tics, but It is also common practice to follow patients even more HKDs have been used for treatment both pre- and postoperatively with motor, mood, with DBS including chorea secondary to cerebral

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Table 5.1 Summary of DBS outcomes for tremor.

Author Cases HKD Target Max. ben. Range Stimulation

Graff-Radford, et al. [59] 31 ET VIM Unilateral: 53%, Unilateral 2.7 151 102 Bilateral: 78% Bilateral L 2.7 153 78 Bilateral R 2.9 149 93 Morishita T, et al. [60] 19 ET VIM Zhang K, et al. [61] 34 ET VIM 80% A: 2.5–3, F: 130–180 Hz, PW: 60–120 μsec. Pilitsis JG, et al. [62] 27 ET VIM 42–58% A: 1.5–3.6, F: 135–180 Hz, PW: 45–90 μsec. Lyons KE, et al. [55] 2 ET C. S. A: 3, F: 310 Hz, PW 250 μsec. Pahwa R, et al. [63] 26 ET VIM 75% A: 3.6, F: 158 Hz, PW: 111 μsec. Lee YJ, et al. [64] 18 ET VIM 75% A: 0–3, F: 170–185 Hz, PW: 90 μsec. Stover NP, et al. [65] 1 ET STN 50% A: 2.6, F: 130 Hz, PW: 90 μsec. Chou KL, et al. [66] 1 ET STN 80% A: 2–3.2, F: 185 Hz, PW 90 μsec. Putzke JD, et al. [67] 24 ET VIM 81% A: 2.6–2.8, F: 140–180 Hz, PW: 60–90 μsec. Yamamoto T, et al. [68] 15 ET VIM major improvement A: 1.3–2.6, F: 120–180 Hz, PW: 90–210 μsec. Plaha P, et al. [69] 4 ET STN 80% A: 1.6–2, F: 160–180 Hz, PW: 100–120 μsec. Papavassiliou E, et al. [70] 37 ET VIM 53 ± 36% A: 1–5.4, F: 130–185 Hz, PW: 60–180 Rehncrona S, et al. [71] 19 ET VIM 50% A: 1–3.4, F: 120–190 Hz, PW: 60–90 μsec. Kumar R, et al. [72] 5 ET VIM 50% NA Fields JE, et al. [73] 40 ET VIM 56% A: 2.6–4, F: 120–180 Hz, PW: 60–130 μsec. Hariz GM, et al. [74] 27 ET VIM 47% NA Krauss JK, et al. [75] 42 ET VIM 57% A: 1–4, F: 130 Hz, PW: 210 μsec. Limousin, et al. [76] 37 ET VIM 50% A: 1.4–3.2, F: 130–180 Hz, PW: 60–130 μsec.

ET: Essential tremor, VIM: Ventral intermeio nucleus, STN: Subthalamic nucleus, CS: Cortical stimulation, NA: Not available, CD: Cervical dystonia.

palsy, stroke, trauma, myoclonus-dystonia, focal although other targets including STN have recently dystonia, Lesch Nyhan syndrome, paroxysmal been utilized. VIM DBS may address refractory non-kinesiogenic dystonia, Cockayne syndrome tremors other than ET, but inclusive of PD tremors, [28, 29]. DBS devices allow for a vast array of MS tremors, mid-brain tremors, orthostatic trem- configurations for stimulation including potential ors, and essential tremors previously treated with combinations of pulse width, frequency, and ampli- DBS in another target. Ventralis oralis anterior and tude. Adjustments are usually made by expert posterior (VOA/VOP) thalamic nuclei, STN or other teams, and are patient and symptom specific. targets including ZI may be used [30]. Double leading (VIM plus VOA/VOP) [31] has become Essential tremor more popular and studies are under way to look at Candidates must have a documented medication efficacy and whether it helps proximal tremor refractory tremor at maximum doses of tremor (Plate 5.2). Contraindications to tremor surgery medication including a beta-blocker (propanolol is may include moderate to severe dementia, active usually the first choice), primidone (or phenobarbi- alcohol and drug use, and severe untreated affec- tal in some countries where primidone is unavail- tive disorders [12]. A review of tremor outcomes able) and/or benzodiazepines. Medications such across available studies and targets is provided in as Topiramate, Trazodone, Gabapentin, Pregabalin, Tables 5.1 and 5.2. Clozapine, Carbamazepine, Trihexyphenidyl, Sine- met, and Levetiracetam can be used but in general Chorea have not proven highly efficacious for severe In HD and other hereditary choreas, as well as tremor. The usual target for DBS is the ventralis secondary choreas, there is a wide variation in the intermedius nucleus of the thalamus (VIM), response to the usual pharmacological options, in

Albanese_c05.indd 52 12/24/2011 6:40:02 AM Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders 53

Table 5.2 Summary of hyperkinetic disorders with stimulation of the Zona Incerta.

Author Cases HKD Target Max. ben. Range Stimulation Comments

Plaha P, et al. [130] 4 MST cZI 57.2% A: 1.9, Good response, requires high PW: 210 μsec. F (>60 Hz) Hyam JA, et al. 5 MST ZI, VIM-VOP 40% A: 1.5–5, With Bittar RG in 2005 [131] F: 135–180 Hz, compare DBS 10 patients vs PW: 90–210 μsec. thalamotomy 10 patients, better response in lesion but more long-term side effects Nandi D, Tipu ZA. 15 MST ZI, VIM-VOP 36–63% NA Benefit in tremor, disability [132] and central neuropathic pain Plaha P, et al. [69] 6 ET cZI 76% A: 2.48 [1], Includes also 7 patients with F: 147 [25] Hz, Holmes, Cerebellar, MS and PW: 120 [42] dystonic tremor with distal, proximal and axial component

MST: Tremor secondary to multiple sclerosis. ZI: Zona incerta; Vlt: Ventrolateral thalamus; VIM: Ventral intermedio nucleus; VOP: Ventral oralis posterior nucleus; VOA: Ventral oralis anterior nucleus. Thal: Thalamus. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width.

Table 5.3 Summary of DBS outcomes for chorea.

Author Cases HKD Target Max. ben. Range stimulation

Biolsi B, et al. [77] 1 HD GPi 50% A: 1.9, F: 130 Hz, PW: 450 μsec. Fasano A, [78] 1 HD GPi Dramatic A: 2.0–2.7, F: 40–130 Hz, PW: 90 μsec. improvement Hebb MO, et al. [32] 1 HD GPi A: 2.8, F: 180 Hz, PW: 120 μsec. Moro E, et al. [79] 1 HD GPi A; 2.5–3.5 F: 40–130 Hz, Pw: 90–120 μsec. Yianni J, et al. [33] 1 Chorea GPi, VOM almost 100% A: 2.5, F: 185 Hz, PW: 90 μsec. Hebb MO, et al. [32] 1 Chorea GPi NA A: 1–3. F: 180 Hz, PW: 60–90 μsec. Krauss JK, et al. [80] 4 Chorea GPi 29% A: 3.3, F: 135 Hz, PW: 210 μsec. Thompson TP, et al. [81] 2 Chorea VIM A: 1.5–3.2, F: 170–185 Hz, PW: 120–150 μsec. Guehl D [82] 2 Neuro GPi 50% F: 40 Hz. acanthocytosis Ruiz PJ, et al. [83] 1 Chorea GPi 50% A: 4.2–4.4, F: 130 Hz, PW: 180 μsec. acanthoc-ytosis Hasegawa H, et al. [84] 1 Hemibal-lism GPi Control of A: 4.5, F: 130 Hz, PW: 60 μsec. movement

HD: Huntington disease, CP: Cerebral palsy, GPi: Globus pallidus interna.

addition to side effects. This variability in response A better control of movement has been observed has opened the door for DBS in a very select group with higher frequencies; however, an exacerbation of patients. GPi DBS has shown benefit for chorea of bradykinesia may be observed (remains to be con- and dystonia with lower frequencies (40 Hz), but firmed). Outcomes and long-term efficacy data are also with higher frequencies [32, 33] (Plate 5.3). scarce; however, new cases are emerging (Table 5.3).

Albanese_c05.indd 53 12/24/2011 6:40:02 AM 54 Chapter 5

Dystonia who do not have fixed contractures [37]. The dura- The best candidates for DBS are usually those that tion of dystonia has been raised as an important have been diagnosed with primary dystonia factor in outcome, with longer durations being (generalized or cervical), however this is only based associated with less benefit in a recent small surgical on limited available information [28, 34]. Secondary series [38]; however, this data, though interesting, dystonia (e.g. post-traumatic, infectious, hypoxic, remains to be replicated across diverse populations. toxic) has been observed to respond less well to A review of all dystonia outcome studies in the DBS, although even this response rate is variable literature is provided in Table 5.4 [22]. Interestingly, from patient to patient. Prior to undergoing the tardive dystonia/ dyskinesia [39], segmental, focal, DBS procedure, dystonia patients should be and task-specific dystonias have all been addressed subjected to medication trials including all potential by DBS of various targets [40]. However, recently combinations of anticholinergics, carbidopa-levodopa, the STN as well as thalamic targets have been muscle relaxants, benzodiazepines, baclofen, tizani- emerging for different disease presentations [41] dine, and botulinum toxin [35, 36]. Better surgical (Plate 5.4). Currently, the optimal target-symptom outcomes in general seem to be achieved in patients selection criteria are unknown in dystonia [42].

Table 5.4 Summary of DBS outcomes for dystonia.

Author Cases HKD Target Max. ben. Range stimulation

Altermann RL, et al. [133] 15 PD GPi 76% A: 2.5, F: 60 Hz, PW: 120 μsec. Mueller J, 2008 [85] 40 PD GPi 42–53% NA Susatia F, et al. [26] 25 PD, SD GPi 20–43% A: 1.8–5.4, F: 60–210 Hz, PW: 120–420 μsec. Parr J, et al. [134] 4 PD GPi 27–85% NA Katsakiori P, et al. [86] 8 SD GPi [7] 41,4% A: 2.5–4.5, F: 185 Hz, PW: 219–450 μsec. VOA[1] Cif L, et al. [87] 26 PD GPi 76% aprox. A: 0.3–2.1, F: 130 Hz, PW: 450 μsec. Vidailhet M, et al. [88] 13 SD GPi 24.4% A: 3–3.5, F: 130, PW 60 μsec. Jeong SG, et al. [89] 6 PD GPi 76% A: 1–4, F: 130 Hz, PW: 60–200 μsec. Blomstedt P, et al. [90] 4 PD GPi 79% NA Isaias IU, et al. [37] 30 PD GPi 79% A: 4, F: 60 and 130 Hz, PW 210 μsec. Woehrle JC, et al. [28] 12 PD GPi 57% Woehrle JC, et al. [28] 2 SD VIM 57% Sensi M, et al. [91] 11 Seg. D. GPi 61% A: 3.2, F: 130 Hz, PW: 150 μsec. Magariños-Ascone CM, 10 PD GPi 65% A: 2–3, F: 120–150 Hz, PW: 100–120 μsec. et al. [92] Cersosimo M [93] 10 PD GPi 32–62% NA Kiss ZH, et al. [94] 10 PD GPi 43% A: 3–3.3, F: 170–180 Hz, PW: 180–204 μsec. Loher TJ, et al. [95] 7 PD GPi 61–82% A: 2–5, F: 130 Hz, PW 210 μsec. Loher TJ, et al. [95] 1 Hemidys. GPi 61–82% A: 2–5, F: 130 Hz, PW 210 μsec. Loher TJ, et al. [95] 1 Parox. D. VIM, GPi 61–82% A: 2–5, F: 130 Hz, PW 210 μsec. Kleiner-Fishman G [96] 4 PD STN 30–50% A: 1–2.5, F: 100–185 Hz, PW: 90 μsec. Hung SW [97] 10 PD GPi 54.8% A: 3.1 ± 0.7, F: 135 ± 21 Hz, PW: 71 ± 17 μsec. Moro E [98] 8 PD GPi 56.7% A: 2–4, F: 130 Hz, PW: 60–120 μsec. Krauss JK, et al. [80] 2 PD GPi 78% A: 3.3, F: 135 Hz, PW: 210 μsec. Martinez-Torres I, et al. [99] 1 PD GPi 70% A: 3.3, F: 130, PW: 60 μsec. Gruber D, et al. [100] 9 TD. GPi 83% A: 0.6–3, F: 130–180 Hz, PW: 70–96 μsec. Blomstedt P, et al. [101] 1 MS. GPi 71% A: 4.6–5.2, F: 145 Hz, PW: 120 μsec. Markaki E, et al. [102] 1 MS. GPi 70% A: 2, F: 185 Hz, PW: 210 μsec. Ostrem JL [103] 6 MS. GPi 66% A: 2.9–5, F: 145–185 Hz, PW: 210 μsec. Cho CB, et al. [42] 1 WC Vo. 75% A: 2.3, F: 130 Hz, PW: 60 μsec.

Albanese_c05.indd 54 12/24/2011 6:40:02 AM Table 5.4 (cont’d).

Author Cases HKD Target Max. ben. Range stimulation

Fukaya C [104] 1 WC Vo, VIM Coubes P [105] 7 PD GPi NA A: 1.6, F: 130 Hz Bittar G, et al. [135] 12 PD GPi 59% A: 2.5–7, F: 100–200 Hz, PW: 90–210 μsec.

PD: Primary dystonia; SD: Secondary dystonia; Seg. D: Segmental dystonia; MS: Meige syndrome; WC: Writer Cramp; CP: Cerebral Palsy; GPi: Globus pallidus Internus; VIM: Ventral Intermedio Nucleus; Vo: Ventralis oralis anterior complex; STN: Subthalamic Nucleus.

Table 5.5 Summary of DBS outcomes for TS.

Author Cases HKD Target Max. ben. Range stimulation

Houeto JP, et al. [106] 1 TS Thal, GPi Flaherty AW, et al. [107] 1 TS AIC. 25% A: 4.1, F: 185 Hz, PW: 210 μsec. Diederich N, et al. [108] 1 TS GPi 73% A: 2, F: 185 Hz, PW: 120–150 μsec. Shahed J, et al. [109] 1 TS GPi 84% A: 5, F: 145–160 Hz, PW 90 μsec. Ackermans L, et al. [44] 2 TS Cm-Pf, VOA [1], A: 3.1–6.4, F: 130–170 Hz, PW: 120–210 μsec. Cm-Pf, GPi [1] Servello D, et al. [110] 4 TS Cm-Pf, VOA. 50–80% A: 4.5–5, F: 130–160 Hz, PW: 150–180 μsec. Dehning S, et al. [111] 1 TS GPi A: 3–4.2, F: 130–145 Hz, PW: 120–210 μsec. Shields DC, et al. [112] 1 TS Cm-Pf. Welter ML [113] 3 TS GPi, CM-Pf. 65% A: 1.5–3.5, F: 130 Hz, PW: 60 μsec. Zabek M, et al. [114] 1 TS NA 74% A: 3, F: 130 Hz, PW: 210 μsec. Servello D, et al. [110] 18 TS Cm-Pf, VOA. A: 2.5–4, F: 130 Hz, PW: 90–120 μsec. Porta M [115] 15 TS Cm-Pf, VOA. 65% NA Martinez-Torres I, et al. [116] 1 TS STN 97% A: 3–3.2, F: 130 Hz, PW: 60 μsec.

Table 5.6 Summary of hyperkinetic disorders with stimulation of the centro medial parafascicular complex.

Author Cases HKD Target Max. ben. Range stimulation Comments

Porta M [115] 15 TS Cm-Pf, VOA. 65% NA Benefit in Tics and Psychiatric scales after 2 years. Servello D, et al. [110] 18 TS Cm-Pf, VOA. 50–80% A: 2.5–4, F: 130 Hz, Followed, published by Porta PW: 90–120 μsec. M 2009. Shields DC, et al. [112] 1 TS Cm-Pf. Significant Patient had previous AIC. without improvement. Welter ML [113] 3 TS CM-Pf+Bilateral 65% A: 1.5–3.5, F: 130 Hz, Better control of tics with GPi PW: 60 μsec. stimulation in GPi, no benefit adde combined. Bajwa RJ, et al. [136] 1 TS CM Pf- VOA-VIM 66% A: 2, F: 130 Hz, Substancial reduction of tics PW: 60–120 μsec. Ackermans L, et al. [44] 2 TS Cm-Pf, VOA [1], >90% A: 3.1–6.4, Two targets in every patient. Cm-Pf, GPi [1] F: 130–170 Hz, Follow at 1 year, bennefit in PW: 120–210 μsec. Tics and OC. Houeto JL, et al. [106] 3 TS CM-Pf, GPi 96% NA unilateral or bilateral stimulation.

TS: Tourette syndrome; Thal: Thalamus, GPi: Globus pallidus internal; Cm-Pf: Centro medial para fascicular complex; VOA: Ventro oralis anterior complex. Max. ben. in the YGTSS total score. OC: Obsessive compulsive symptoms. QoL: Quality of life. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width.

Albanese_c05.indd 55 12/24/2011 6:40:02 AM Table 5.7 Summary of DBS outcomes for “other HKD syndromes”.

Author Cases HKD Target Maximal benefit Range stimulation

Guridi J, et al. [117] 1 OT VIM NA A: 2 F: 130–160 Hz, PW: 60 μsec. Espay A, et al. [118] 2 OT VIM A: 1.5-4, F: 160–185 Hz, 60–90 μsec. Krauss JK, et al. [119] 2 OT SC. S. NA A: 1–3.2, F: 100–110 Hz, PW: 210 μsec. Breit S, et al. [120] 1 Tremor Demiel. VIM 30% A: 4.5, F: 130 Hz, PW: 210 μsec. Neurop. McMaster J [137] 1 T. Anti-MAG VIM dramatically A: 3, F: 90 Hz, PW: 130 μsec. neuropathy improved Bayreuther C, et al. [121] 1 T. Anti-MAG VIM NA A: 3, F: 60–90 Hz, PW: 130 μsec. neuropathy Foote KD, et al. [31] 1 Holmes tremor VIM, VOA, 80% A: 4-4: 1, F: 130–185 Hz, VOP PW: 90 μsec. Yamamoto T, et al. [68] 12 Poststroke tremor VIM major improvement Bandt K, et al. [122] 1 Midbrain tremor VIM 1/4 A: 3, F: 170 Hz. PW: 120 μsec. Pahwa R, et al. [123] 1 Midbrain tremor VIM NA A: 3.7, F: 170 Hz, PW: 90 μsec. Sato K, et al. [124] 1 Multiple HKD GPi Control of A: 3, F: 130 Hz, PW: 60 μsec. movements Kaufman CB, et al. [125] 1 PNKD GPi 90% A: 3–3.7, F: 150 Hz, PW: 120 μsec. Yamada K, et al. [126] 1 PNKD GPi 100% A: 2.8, F: 130 Hz, PW: 90 μsec. Oropilla JQL, et al. [127] 1 Myoclonus-Dystonia GPi, VIM 81% A: 2.1, F: 140Hz, PW: 90 μsec. Kurtis MM, et al. [128] 1 Myoclonus-dystonia GPi Kuncel AM, et al. [129] 1 Myoclonus-dystonia VIM 90% A: 1.5–4.5, F: 90–185 Hz, PW: 90 μsec.

Table 5.8 Summary of hyperkinetic disorders with stimulation of other nucleus ans structures.

Author Cases HKD Target Maximal Benefit Range Stimulation Comments

Lyons KE, 2 ET C. S. NA A: 3, F: 310 Hz, PW 250 μsec. No Benefit et al. [55] Cho CB, 1 WC VOA. 75% A: 2.3 F: 130 Hz, PW: 60 μsec. Unilateral implantation. et al. 42 Evaluation with BFMDRS 1/4 Loher TJ, 1 PNKD Thal. Dramatic A: 5.4, F: 65 Hz, PW: 180 μsec. sustained benefit after et al. [95] 4 years follow-up Berk C, 12 MST Thal. 63% NA Control of tremor but no et al. [138] benefit in QoL (SPF36]. Maciunas RJ, 5 TS Thal. 44% A: 3.5–3.6, F: 130–185 Hz, Benefit in Tics, OC, and QoL. et al. [139] PW: 90–210 μsec. Flaherty AW, 1 TS AIC. 25% A: 4.1, F: 185 Hz, PW: 210 μsec. Benefit in tics, may et al. [107] influence mood disorders due to position in AIC Zabek M, 1 TS Nuc. 74% A: 3, F: 130 Hz, PW: 210 μsec. Control of tics and OC et al. [114] Acumbens

ET: Essential tremor; TS: Tourette syndrome; PNKD: Paroxismal non-kinesigenic dystonia; GM: Gammapathy monoclonal; Vo: Ventro oralis complex; CM-Pf: Centro-medial para fascicular complex; Thal: Thalamus; AIC: Anterior limb internal capsule; Vlm: Ventrolateral thalamus; GPi: Globus pallidus internal; STN: subthalamic nucleus. CS: Cortical stimulation. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width.

Albanese_c05.indd 56 12/24/2011 6:40:02 AM Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders 57

Table 5.9 Summary of hyperkinetic disorders with stimulation subthalamic nucleus.

Author Cases HKD Target Max. ben. Range stimulation Comments

Stover NP, et al. [65] 1 ET STN 50% A: 2.6 F: 130 Hz, Also with PD, unilateral left VIM PW: 90 μsec. benefit 40% in UPDRS. Previous left pallidotomy didn`t help tremors Chou KL, et al. [66] 1 ET STN 80% A: 2–3.2 F: 185 Hz, In this case with CD, bilateral approx. PW 90 μsec. implantation also shows benefit. Plaha P, et al. [69] 4 ET STN 80% A: 1.6–2, No tolerance after one year, benefit F: 160–180 Hz, also in Global Disability Assessment. PW: 100–120 μsec. Kleiner-Fisman G [96] 4 PD STN 30–50% A: 1–2.5 With CD, benefit in QoL, disability F: 100–185 Hz, and motor acording to TWSTRS and PW: 90 μsec. BFMDRS evaluation Martinez-Torres I, 1 TS Bilateral 97% A: 3–3.2, F: 130 Hz, Patient also had PD with 57% et al. [116] STN PW: 60 μsec. benefit.

ET: Essential tremor; PD: Parkinson disease; TS: Tourette syndrome. STN: Subthalamic nucleus. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width.

Tourette syndrome and leg from medial to lateral). VIM is surrounded The Tourette Syndrome Association has recently by the ventral oralis anterior and posterior subnu- published guidelines for TS surgery [43] and, cleus (VOA/VOP); this subnucleus receives afferents currently, target and patient selection remain from the posterior and lateral GPi and projects to largely unknown. The field has however been the supplementary motor cortex area. Tremor cells enlightened by recent studies. The centromedian are located in the VIM and VOP areas, discharging parafascicular complex of thalamus (Cm-Pf) has equal to the patient’s tremor, and respond to passive been the most utilized target; however, motor and or active movement of the contralateral somato- non-motor GPi may also be promising [44, 45]. The topic joint when is recording with microelectrode, Anterior limb of Internal Capsule has been overall specifically in the hand area which is the most less successful in TS [46, 47], but more data will be favorable target for tremors. Stimulation of VIM, needed to understand this approach. A summary of particularly in ET, shows good outcomes and DBS outcomes for TS is provided in Tables 5.5 control of tremor varies between 41 and 81%, also and 5.6, and the targets and outcomes of “other” with good outcomes in quality of life and global HKDs and hyperkinetic symptoms addressed by disability. And although some authors report DBS are summarized in Tables 5.7 and 5.8. Further, tolerance after 2 years of implantation, VIM is the a summary of DBS outcomes in the STN for HKDs best target for ET (Table 5.10). Parkinsonian resting is provided in Table 5.9. Sample trajectories from tremor can be addressed by stimulation of the VIM, anatomical targeting of DBS brain targets using however bradykinesia, rigidity, dyskinesia, and MRI scanning are provided in Plates 5.1 to 5.4. dystonia are not alleviated by DBS in this subnucleus. Other tremors such as tremor secondary to Ventralis intermedius nucleus multiple sclerosis, post-traumatic tremor, orthos- of the thalamus tatic tremor, Holmes tremor, tremor secondary to VIM is a deep subnucleus of the thalamus that neuropathy, and even dystonic tremor have been receives fibers from the deep cerebellar nuclei and treated with stimulation of the VIM, showing projects to the cerebral cortex. Like other nuclei, it benefit. Chorea, secondary to cerebral palsy, and is arranged in somatotopic areas (face, jaw, arm, secondary to Cockayne syndrome, have been

Albanese_c05.indd 57 12/24/2011 6:40:03 AM laeec5id 58 Albanese_c05.indd 58

Table 5.10 Summary of hyperkinetic disorders (essential tremor) with stimulation of the ventral intermedius nucleus.

Author Cases HKD Target Max. ben. Range stimulation Comments

Graff-Radford, et al. [59] 31 ET VIM 53–78% A: 2.7–2.9, F: 150, PW: 60–120 μsec. Benefit in motor and mood scales (VAMS and BDI) Morishita T, et al. [24] 19 ET VIM 64% NA Using mTRS. Immediate improvement in postural and intention tremors may predict successful at 6 months. Zhang K, et al. [61] 34 ET VIM 80% A: 2.5–3, F: 130–180 Hz, Adjustment in stimulation parameters may help to control PW: 60–120 μsec. tolerance, good response in long term Pilitsis JG, et al. [62] 27 ET VIM 42–58% A: 1.5–3.6, F: 135–180 Hz, Suboptimal placement of the lead, waning of the effect of the PW: 45–90 μsec. device or disease progression may explain tolerance Hamel W, et al. [140] 11 ET Vlt 68–73% A: 2–3.6, F: 130–145 Hz, PW: 60 μsec. Report of 8 ET, 1 SCA. and 2 MST Pahwa R, et al. [123] 26 ET VIM 75% A: 3.6, F: 158 Hz, PW: 111 μsec. 18 unilateral, 8 bilateral implantation. Persistent benefit after 5 years follow-up. Lee JY, et al. [64] 18 ET VIM 75% A: 0–3, F: 170–185 Hz, PW: 90 μsec. Median follow-up 27 months. Some patients require adjustments in programming setting after 6 months Putzke JD, et al. [67] 24 ET VIM 81% A: 2.6–2.8, F: 140–180 Hz, Unilateral implant produce benefit in axial involvement of tremor, PW: 60–90 μsec. bilateral stimulation produce adding benefit. Yamamoto T, et al. [68] 15 ET VIM Major A: 1.3–2.6, F: 120–180 Hz, In this series also reports 12 patients with poststroke tremor, VIM PW: 90–210 μsec. stimulation with good response Papavassiliou, et al. [70] 37 ET VIM 53 ± 36% A: 1–5.4, F: 130–185 Hz, PW: 60–180 Suboptimal placement of the lead is associated to tolerance Rehncrona S, et al. [71] 19 ET VIM 50% A: 1–3.4, F: 120–190 Hz, Optimal response after 6 and 7 years of follow-up. Response is PW: 60–90 μsec. better with high F (>130 Hz) Kumar R, et al. [72] 5 ET VIM 68–62% NA Two patients developed tolerance. Fields JA, et al. [73] 40 ET VIM 56% A: 2.6–4, F: 120–180 Hz, Good response in long term without impair cognition and with PW: 60–130 μsec. benefit in anxiety and QoL. Hariz GM, et al. [23] 27 ET VIM 47% NA Posterior article in 2008 with 19 patients after 1–7 years implanted report decreased effect over time Koller W, et al. [141] 49 ET VIM Variable NA Good response in long term [40.2 ± 14.7 months) in 25 patients, some patients without response. Krauss JK, et al. [75] 42 ET VIM 57% A: 1–4, F: 130 Hz, PW: 210 μsec. In this series also reports 7 patients with MS, trauma or post-stroke tremor with less effective response. Limousin, et al. [76] 37 ET VIM 83% A: 1.4–3.2, F: 130–180 Hz, Multicentre study, good benefit after one year, low rate of side PW: 60–130 μsec. effects.

ET: Essential tremor; SCA: Spino cerebellar ataxia; MST: Multiple sclerosis tremor. VIM: Ventral intermedio nucleus; Vlt: Ventrolateral thalamus. mTRS: Modified Tremor Rating Scale. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width. VAMS: Visual Analog Mood Scale; BDI: Beck Depression Inventory; QoL: Quality of life. 22/0164:3AM 6:40:03 12/24/2011 6:40:03AM laeec5id 59 Albanese_c05.indd 59

Table 5.11 Summary of hyperkinetic disorders with stimulation of the ventral intermedius nucleus.

Author Cases HKD Target Max. ben. Range stimulation Comments

Hamel W, et al. [140] 2 MST VIM 68–73% A: 2–3.6, F: 130–145 Hz, PW: 60 μsec. In a series, report benefit Lim DA, et al. [142] 1 MST VIM+VOA NA NA No benefit with dual electrode stimulation Foote KD, et al. [31] 1 MST VIM+VOA/VOP 23–66% A: 2.9–5.8, F: 135–185 Hz, PW: 60–120 μsec. Benefit with dual electrode stimulation Wishart HA, et al. [143] 4 MST VIM, VOP. NA A: 1.5–4.8, F: 90–160 Hz, PW: 60–120 μsec. This is also a review of 12 authors. Significant improvement in tremor and disability Hebb MO, et al. [32] 1 Chorea UnilVIM Major A: 1–3. F: 180 Hz, PW: 60–90 μsec. benefit also in tremor, myoclonus, ataxia in Cockayne syndrome. Thompson TP, et al. [81] 2 Chorea VIM Major A: 1.5–3.2 F: 170–185 Hz, PW: 120–150 μsec. CP, “major” improvement. Fukaya C [104] 5 WC VOA, VIM 75% A: 1–3, F: 90–185 Hz, PW: 160–260 μsec. 1 Patient also GPi DBS. Espay A, et al. [30] 2 OT VIM Significantly A: 1.5-4, F: 160–185 Hz, 60–90 μsec. Good outcome after 3 years in 1 patient. in SF–36. Guridi J, et al. [117] 1 OT VIM Control of A: 2, F: 130–160 Hz, PW: 60 μsec. complete control with bilateral stimulation. tremor Krauss JK, et al. [49] 2 OT SCS NA A: 1–3.2, F: 100–110 Hz, PW: 210 μsec. Marked improvement in long term [3 years and 1 year). Breit S, et al. [120] 1 Tremor Demiel. VIM 30% A: 4–5, F: 130 Hz, PW: 210 μsec. Roussy-Levy syndrome. Benefit in functional and Neurop. tremor scales McMaster J, et al. [144] 1 T. Anti-MAG VIM almost 100% A: 1, F: 130 Hz, PW: 60 μsec. Sustained benefit. neuropathy Bayreuther C, et al. [121] 1 T. Anti-MAG VIM NA A: 3, F: 60–90 Hz, PW: 130 μsec. Tremor and QoL dramatically improved neuropathy Ruzicka E, et al. [145] 1 T. in neuropathy VIM 50% A: 1.1–1.5, F: 130–145 Hz, PW: 60–90 μsec. Good outcome in a Patient GM 72 years old Foote KD, Okun MS [31] 1 Holmes tremor VIM/ VOA, VOP 80% A: 4–4: 1, F: 130–185 Hz, PW: 90 μsec. Posttraumatic tremor. Two leads produce better and sustained response Yamamoto T, et al. [68] 12 Poststroke VIM major A: 1.2–2.9 F: 120–180 Hz, PW: 90–210 μsec. In a series of 27 patients, respond varies according tremor, ET, PD improvement to place of stimulation. Hamel W, et al. [140] 1 Tremor SCA VIM vs STN 68–73% A: 2–3.6, F: 130–145 Hz, PW: 60 μsec. In a series of 11 patients, 8 ET, 2 MST Better response in STN contact. Bandt SK, et al. [122] 1 Midbrain tremor VIM, LF. 0.25 A: 3, F: 170 Hz, PW: 120 μsec. Post-stroke. Evaluated with WHIGET Rating Tremor Scale. Pahwa R, et al. [123] 1 Midbrain tremor VIM Control A: 3.7, F: 170 Hz, PW: 90 μsec. Secondary to hemangioma resection with left side tremor. Kuncel AM, et al. [129] 1 Myoclonus- VIM 90% A: 1.5–4.5, F: 90–185 Hz, PW: 90 μsec. Low F. induce myoclonus and tremor. dystonia 22/0164:3AM 6:40:03 12/24/2011 6:40:03AM

MST: Tremor secondary to multiple sclerosis; OT: Orthostatic tremor; CP: Cerebral palsy; WC: Writer’s cramp. VIM: Ventral intermedio nucleus; VOP: Ventral oralis posterior nucleus; VOA: ventral oralis anterior nucleus; STN: Subthalamic nucleus; LF: Lenticular fasciculus. SCS: Spinal cord Stimulation. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width. laeec5id 60 Albanese_c05.indd 60

Table 5.12 Summary of hyperkinetic disorders (dystonia) with stimulation of the globus pallidus internal segment.

Author Cases HKD Target Max. ben. Range stimulation Comments

Vandeoriolla F, et al. [146] 22 PD GPi 50% Cif L, et al. [87] 26 PD GPi 76% A: 0.3–2.1, F: 130 Hz, PW: 450 μsec. DYT1 patients. All initially single lead bilateral GPi 8 aprox. requires double lead bilateral GPi, 4 non responding. Follow-up 10 years. Blomstedt P, et al. [90] 4 PD GPi 79% NA Idiopathic dystonia. Excluded DYT 1, DYT 5-DYT 17. All members of a family Isaias IU, et al. [37] 30 PD GPi 79% A: 4, F: 60 and 130 Hz, PW 210 μsec. Evaluation at different points in 8 years with sustained benefit. Similar benefit at 60 and 130 Hz. Jeong SG, et al. [89] 6 PD GPi 76% A: 1–4, F: 130 Hz, PW: 60–200 μsec. CD TWSTRS evaluation. Minimal side effects. Katsakiori P, et al. [86] 8 SD GPi [7] 41.4% A: 2.5–4.5, F: 185 Hz, PW: 219–450 μsec. CP, Drug induced and Postencephalitis (GPi), postanoxic VOA[1] (VOA). Variable outcome, SPECT shows hyperperfusion in “off” state in FL. Martinez-Torres I, et al. [116] 1 PD GPi 70% A: 3.3, F: 130, PW: 60 μsec. DYT 3, rapidly progressive dystonia. Moro E [79] 8 PD GPi 54.5% A: 2–4, F: 130 Hz, PW: 60–120 μsec. CD TWSTR evaluation, improvement with high F (>40 Hz). Sensi M, et al. [91] 11 PD GPi 61% A: 3.2, F: 130 Hz, PW: 150 μsec. Segmental dystonia. Significant improvement at 6 months and even better after 3 years. Vidailhet M, et al. [88] 13 SD GPi 24.4% A: 3–3.5, F: 130, PW 60 μsec. Multicenter, dystonia-choreoathetosis secondary to CP. Benefit in function, pain, mental health and QoL. Woehrle JC, et al. [28] 14 PD GPi or 57% NA 12 patients with SegD. (GPi) 2 patients with dystonic VIM tremor (VIM). Sustained benefit. Cersosimo M [93] 10 PD GPi 32–62% NA 9 patients with DYT 1 gene mutation, 3 receive bilateral DBS GPi, 5 pallidotomy plus DBS with better response in this subsetting. Loher TJ, et al. [95] 9 PD GPi 61–82% A: 2–5, F: 130 Hz, PW 210 μsec. 1 patient with hemidystonia, 4 CD, 2 Generalized dystonia, 1 Meige, 1 PNKD. Good response in long term [9 years] Magariños-Ascone CM, 10 PD GPi 65% A: 2–3, F: 120–150 Hz, PW: 100–120 μsec. In this study authors register pairs of cells simultaneously et al. [92] and use surface EMG to evaluate response in programming settings. Altermann RL, et al. [133] 15 PD GPi 89% A: 2.5, F: 60 Hz, PW: 120 μsec. 12 with DYT1 dystonia, young onset. Sustained low frequency in every patient. Benefit 89% after 1 year. Kiss ZHT, et al. [94] 10 PD GPi 43% A: 3–3.3, F: 170–180 Hz, PW: 180–210 μsec. Also benefit in disability, pain, depression and QoL. Hung SW [97] 10 PD GPi 54.8% A: 3.1 ± 0.7, F: 135 ± 21 Hz, PW: 71 ± 17 μsec. CD TWSTRS evaluation 22/0164:3AM 6:40:03 12/24/2011 6:40:03AM laeec5id 61 Albanese_c05.indd 61

Parr J, et al. [134] 4 PD GPi 27–85% NA Children 8–15 years old, idiopathic dystonia. 42% benefit in disability Krauss JK, et al. [80] 2 PD GPi 78% A: 3.3, F: 135 Hz, PW: 210 μsec. Sustained benefit in non DYT–1 dystonia. In this report 2 patients with chore-atethosis with minimal improvement [23% after 2 years] Gruber D, et al. [100] 9 TD. GPi 83% A: 0,6–3, F: 130–180 Hz, PW: 70–96 μsec. Sustained benefit in long term [18–80 months]. Benefit in QoL, and mood. Nonblinded study. Markaki E, et al. [102] 1 MS. GPi 70% A: 2, F: 185 Hz, PW: 210 μsec. Functionally blind. Benefit in BFMDRS and Disability score [84%] Blomstedt P, et al. [101] 1 MS. GPi 71% A: 4.6–5.2, F: 145 Hz, PW: 120 μsec. Unilateral GPi without benefit, bilateral GPi with good outcome Ostrem JL [103] 6 MS. GPi 66% A: 2.9–5, F: 145–185 Hz, PW: 210 μsec. Evaluation with TWSTRS and BFMDRS with good outcome. No side effects. Capelle HH, et al. [147] 1 MS. GPi 66% A: 4.3, F: 130 Hz, PW: 210 μsec. Bilateral stimulation, good outcome.

PD: Primary dystonia; SD: Secondary dystonia; Seg. D: Segmental dystonia; TD: Tardive dystonia; CD: Cervical dystonia. MS: Meige syndrome; WC: Writer’s cramp; CP: Cerebral palsy. GPi: Globus pallidus internal; VIM: Ventral intermedio nucleus; VOA: Ventro oralis anterior complex; STN: Subthalamic nucleus; FL: Frontal lobe. TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale. EMG: Electromyography. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width. 22/0164:3AM 6:40:03 12/24/2011 6:40:03AM laeec5id 62 Albanese_c05.indd 62

Table 5.13 Summary of hyperkinetic disorders with stimulation of the globus pallidus internal segment.

Author Cases HKD Target Max. ben. Range stimulation Comments

Biolsi B, et al. [77] 1 HD. GPi aprox. 50% A: 1.9, F: 130 Hz, PW: 450 μsec. Sustained benefit in choreic movements after 4 years Fasano A, et al. [78] 1 HD. GPi Significant. A: 2.0–2.7, F: 40–130 Hz, PW: 90 μsec. Worsening bradykinesia at high freq. Hebb MO, et al. [32] 1 HD. GPi Dramatic imp. A: 2.8, F: 180 Hz, PW: 120 μsec. No response at low frequency [40 Hz]. Moro E, et al. [98] 1 HD. GPi Considerably. A: 2.5–3.5, F: 40–130 Hz, PW: 90–120 μsec. Worsening bradykinesia at high freq. [130 Hz] Yianni J, et al. [33] 1 Chorea GPi, almost 100% A: 2.5, F: 185 Hz, PW: 90 μsec. Senile chorea. VOP. Krauss JK, et al. [80] 4 Chorea GPi 29% A: 3.3, F: 135 Hz, PW: 210 μsec. Secondary to CP with generalized choreoathetosis. Guehl D, et al. [82] 2 Neuroacanthocytosis GPi aprox. 50% F: 40 Hz. F at 130 Hz worsened chorea, dysarthria and drooling Ruiz PJ, et al. [83] 1 Chorea-acanthosytosis GPi aprox. 50% A: 4.2–4.4, F: 130 Hz, PW: 180 μsec. Also with dystonia, better response with high F. Hasegawa H, et al. [84] 1 Hemiballism, GPi 100% A: 4.5, F: 130 Hz, PW: 60 μsec. Symptoms caused by bleeding in STN. hemidyst. Dehning S, et al. [111] 1 TS GPi Major A: 3–4.2, F: 130–145 Hz, PW: Did not show tics after one year. 120–210 μsec. Shahed J, et al. [109] 1 TS GPi 84% A: 5, F: 145–160 Hz, PW 90 μsec. Benefit in Tics, OC, and QoL. Diederich N, et al. [108] 1 TS GPi 73% A: 2, F: 185 Hz, PW: 120–150 μsec. Benefit in Tics, depression, anxiety and distress, but not in OC Okun MS, et al. [21] 1 RLS GPi Control NA Report of side effect, DBS implanted in a patient with dystonia Gill S, et al. [148] 1 Multiple HKD GPi sustained NA Dystonic-athetoid-startle movements improvement of idiopatic origin in a Child. Sato K, et al. [124] 1 Multiple HKD GPi Control of A: 3, F: 130 Hz, PW: 60 μsec. Violent choreoatetoid movements movements of idiopatic origin in a Child. Kaufman CB, et al. [125] 1 PNKD GPi 90% A: 3–3.7, F: 150 Hz, PW: 120 μsec. Chorea-dystonia episodes. Yamada K, et al. [126] 1 PNKD GPi 0/4 A: 2.8, F: 130 Hz, PW: 90 μsec. Secondary to peripheral trauma. Complete supression Oropilla JQ, et al. [127] 1 Myoclonus-dystonia GPi, 81% A: 2.1, F: 140Hz, PW: 90 μsec. Unilateral implantation, better response VIM with GPi Kurtis MM, et al. [128] 1 Myoclonus-dystonia GPi Excellent NA Sustained clinical and neurophysiological improvement benefit after 2 years

HD: Huntington disease; CP: Cerebral palsy; TS: Tourette syndrome; RLS: Restless legs syndrome; PNKD: Paroxismal Non-kinesigenic dystonia. GPi: Globus pallidus internal; VIM: Ventral intermedio nucleus; VOP: Ventro oralis posterior nucleus; Subthalamic nucleus. NA: Non-available; A: Amplitude; F: Frequency; PW: Pulse width. OC: Obsessions compulsions; QoL: Quality of life. 22/0164:3AM 6:40:03 12/24/2011 6:40:03AM Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders 63

treated with stimulation in this target, reporting prior to the introduction of botulinum therapy [49]. control of myoclonus and tremor. Case reports of However, this has been generally abandoned due to writer’s cramp and myoclonus-dystonia have been the fact that it is not very effective, and has numer- reported with improvement in the final outcome ous side effects. The original technique of selective (Table 5.11). peripheral denervation was first introduced by Bertrand [50], but has been modified considerably Globus Pallidus (GPi) since then. Two standard approaches include rhi- This nucleus receives fibers from the striatum zotomy and ramisectomy. Technical details include ( specifically spiny neurons expressing dynorphin extradural and intradural nerve sectioning trying and peptide P targeting D1 receptors), STN, and to reduce abnormal posture, without losing the reaches areas of the VOA/VOP and VIM nucleus of normal action of the muscle, and for this purpose the thalamus, pedunculo pontine nucleus (PPN), electromicrographic guidance is helpful [50, 51]. and lateral habenula among others. Somatotopy of GPi shows face/arm lateral and leg medial, while Cortical stimulation posterior and lateral areas are sensorimotor, and anteromedial have associated functions. According One approach for cortical stimulation is the implan- to microrecordings, the final target for stimulation tation of a quadripolar electrode in the extradural is the posteroventrolateral portion of the GPi, space above the motor cortex region of the brain, which is dorsal to the optic tract, where kinesthetic contralateral to the motor symptoms needing to be neurons are detected. controlled [52]. This option is proposed for patients Placement of the electrode in this nucleus has with contraindications for receiving a basal ganglia been indicated in patients with PD, primary, or stimulator. The Turin group has found that patients secondary dystonia, and some reports of chorea, show relief in the cardinal motor symptoms of PD, myoclonus-dystonia, and Tourette syndrome. In including gait, balance, and extra movements patients with dystonia, parameter settings are induced by medications such as dyskinesia – and variable in each case; however, there is a tendency also benefit in their quality of life. However, con- to stimulate with low frequencies those patients crete evidence is lacking [53–54]. with primary dystonia, showing consistent benefit Cortical stimulation of the motor cortex has been in the long term (Table 5.12). Patients with PD used for essential tremor, but the final results are have benefit in improving dyskinesia, dystonic disappointing [55]. Another procedure used in postures, and tremor. Patients with TS, chorea, clinical research is the cathodal direct current stim- and other hyperkinetic disorders have been ulation. This procedure consists of direct electrical treated with reported good outcomes; however, stimulation applied in the motor cortex, with a long-term studies are still being developed voltage of 2 mA in 20 minutes. In one study, 10 (Table 5.13). dystonia patients (Musician’s Focal dystonia) showed no benefit in the final task; however, 2 patients, one with focal dystonia of the arm and Peripheral nervous system surgery another with dystonia in the hand, showed benefit after the stimulation [56]. Peripheral nervous system surgery is vital in the treatment of abnormal postures such as focal dystonias, spasticity, and also pain syndromes. This Transmagnetic cranial stimulation procedure is approved for patients not responding to the best pharmacological options and usually Studies of transmagnetic cranial stimulation (TMS) those who develop inmunoresistance to botulinum in dystonia patients have been contradictory. toxin [48]. For cervical dystonia, anterior cervical A report published by Schneider et al. shows no rhizotomy was the standard procedure employed benefit with rTMS at 5 Hz in the somatosensory

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cortex in 5 patients with writer’s cramp, while 9 Hooper AK, Okun MS, Foote KD, et al. Clinical cases Havrankova et al. stimulated the same region at where lesion therapy was chosen over deep brain 1 Hz in 11 patients, and reported subjective and stimulation. Stereotact Funct Neurosurg 2008; objective benefits in final tasks, with the effects 86(3):147–52. remaining even after 2 weeks. Another study 10 Hassler R, Riechert T, Mundinger F, et al. Physiological observations in stereotaxic operations in extrapyrami- showed benefit in focal dystonia from stimulation dal motor disturbances. Brain 1960; 83:337–50. of the premotor cortex at 1 Hz for 10 minutes, with 11 Ohye C, Kubota K, Hongo T, et al. Ventrolateral and lasting benefit, of up to 10 days. Subventrolateral Thalamic Stimulation. Motor Effects. In patients with ET, TMS has not shown benefit Arch Neurol 1964; 11:427–34. [57]. However in PD patients, TMS seems to help in 12 Kluger BM, Klepitskaya O, Okun MS. Surgical motor and non-motor symptoms. One study treatment of movement disorders. Neurol Clin 2009; focuses on dyskinesia in patients with PD, showing 27(3):633–77, v. benefit even 3 days after the stimulation was 13 Skidmore FM, Rodriguez RL, Fernandez HH, et al. stopped [58]. Lessons learned in deep brain stimulation for movement and neuropsychiatric disorders. CNS Spectr 2006; 11(7):521–36. Conclusions 14 Kopell BH, Greenberg B, Rezai AR. Deep brain stimulation for psychiatric disorders. J Clin Neurophysiol There are many reasons to be optimistic about 2004; 21(1):51–67. the future of DBS to address HKDs in medication 15 Greenberg BD, Rezai AR. Mechanisms and the current resistant patients. As our understanding of the state of deep brain stimulation in neuropsychiatry. underlying basal ganglia circuitry expands, we CNS Spectr 2003; 8(7):522–6. will be in a better position to tailor targets and 16 Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal stimulation parameters for individual patients. cingulate gyrus deep brain stimulation for treatment- resistant depression. Biol Psychiat 2008; 64(6): 461–7. References 17 Lenz FA, Jaeger CJ, Seike MS, et al. Thalamic single neuron activity in patients with dystonia: dystonia- 1 Jankovic J. Parkinson’s disease: clinical features and related activity and somatic sensory reorganization. diagnosis. J Neurol Neurosurg Psychiat 2008; 79(4): J Neurophysiol 1999; 82(5):2372–92. 368–76. 18 Vitek JL, Chockkan V, Zhang JY, et al. Neuronal 2 Jankovic J. Parkinson’s disease and movement disor- activity in the basal ganglia in patients with general- ders: moving forward. Lancet Neurol 2008; 7(1):9–11. ized dystonia and hemiballismus. Ann Neurol 1999; 3 Fahn S. How do you treat motor complications in 46(1):22–35. Parkinson’s disease: Medicine, surgery, or both? Ann 19 Tang JK, Moro E, Mahant N, et al. Neuronal firing Neurol 2008; 64(Suppl 2):S56–64. rates and patterns in the globus pallidus internus of 4 Schurr PH, Merrington WR. The Horsley-Clarke patients with cervical dystonia differ from those with stereotaxic apparatus. Br J Surg 1978; 65(1):33–6. Parkinson’s disease. J Neurophysiol 2007; 98(2):720–9. 5 Hassler R, Riechert T. Effects of stimulations and 20 Rodriguez RL, Fernandez HH, Haq I, Okun MS. Pearls coagulations in the basal ganglia in stereotactic brain in patient selection for deep brain stimulation. surgery. Nervenarzt 1961; 32:97–109. Neurologist 2007; 13(5):253–60. 6 Upton AR, Cooper IS, Amin I. Quantitative assessment 21 Okun MS, Fernandez HH, Rodriguez RL, Foote KD. of stereotactic and functional neurosurgery. Appl Identifying candidates for deep brain stimulation in Neurophysiol 1982; 45(3):281–90. Parkinson’s disease: the role of the primary care 7 Okun MS, Vitek JL. Lesion therapy for Parkinson’s physician. Geriatrics 2007; 62(5):18–24. disease and other movement disorders: update and 22 Hamani C, Moro E. Surgery for other movement controversies. Mov Disord 2004; 19(4):375–89. disorders: dystonia, tics. Curr Opin Neurol 2007; 8 Fahn S. The history of dopamine and levodopa in the 20(4):470–6. treatment of Parkinson’s disease. Mov Disord 2008; 23 23 Hariz MI, Rehncrona S, Quinn NP, et al. Multicenter Suppl 3:S497–508. study on deep brain stimulation in Parkinson’s

Albanese_c05.indd 64 12/24/2011 6:40:03 AM Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders 65

disease: an independent assessment of reported 37 Isaias IU, Alterman RL, Tagliati M. Deep brain adverse events at 4 years. Mov Disord 2008; 23(3): stimulation for primary generalized dystonia: long- 416–21. term outcomes. Arch Neurol 2009; 66(4):465–70. 24 Morishita T, Foote KD, Burdick AP, et al. Identification 38 Tagliati M, Shils J, Sun C, Alterman R. Deep brain and management of deep brain stimulation intra- and stimulation for dystonia. Expert Rev Med Devices postoperative urgencies and emergencies. Parkinsonism 2004; 1(1):33–41. Relat Disord 2009 Nov 4. 39 Toda H, Hamani C, Lozano A. Deep brain stimulation 25 Morishita T, Foote KD, Burdick AP, et al. Identification in the treatment of dyskinesia and dystonia. Neurosurg and management of deep brain stimulation intra- and Focus 2004; 17(1):E2. postoperative urgencies and emergencies. Parkinsonism 40 Ostrem JL, Starr PA. Treatment of dystonia with deep Relat Disord 2010; 16(3):153–62. brain stimulation. Neurotherapeutics 2008; 26 Susatia F, Malaty IA, Foote KD, et al. An evaluation of 5(2):320–30. rating scales utilized for deep brain stimulation for 41 Awan NR, Lozano A, Hamani C. Deep brain stimula- dystonia. J Neurol 2010; 257(1):44–58. tion: current and future perspectives. Neurosurg 27 Gross RE, Krack P, Rodriguez-Oroz MC, et al. Focus 2009; 27(1):E2. Electrophysiological mapping for the implantation of 42 Cho CB, Park HK, Lee KJ, Rha HK. Thalamic Deep deep brain stimulators for Parkinson’s disease and Brain Stimulation for Writer’s Cramp. J Korean tremor. Mov Disord 2006; 21(Suppl 14):S259–83. Neurosurg Soc 2009; 46(1):52–5. 28 Woehrle JC, Blahak C, Kekelia K, et al. Chronic deep 43 Mink JW, Walkup J, Frey KA, et al. Patient selection brain stimulation for segmental dystonia. Stereotact and assessment recommendations for deep brain Funct Neurosurg 2009; 87(6):379–84. stimulation in Tourette syndrome. Mov Disord 2006; 29 Pralong E, Pollo C, Coubes P, et al. Electrophysiological 21(11):1831–8. characteristics of limbic and motor globus pallidus 44 Ackermans L, Temel Y, Cath D, et al. Deep brain internus (GPI) neurons in two cases of Lesch-Nyhan stimulation in Tourette’s syndrome: two targets? Mov syndrome. Neurophysiol Clin 2005; 35(5–6):168–73. Disord 2006; 21(5):709–13. 30 Espay AJ, Mandybur GT, Revilla FJ. Surgical treatment 45 Ackermans L, Temel Y, Visser-Vandewalle V. Deep of movement disorders. Clin Geriatr Med 2006; brain stimulation in Tourette’s Syndrome. 22(4):813–25, vi. Neurotherapeutics 2008; 5(2):339–44. 31 Foote KD, Okun MS. Ventralis intermedius plus 46 Mink JW. Clinical review of DBS for tourette ventralis oralis anterior and posterior deep brain syndrome. Front Biosci (Elite edn) 2009; 1:72–6. stimulation for posttraumatic Holmes tremor: two 47 Burdick A, Foote KD, Goodman W, et al. Lack of leads may be better than one: technical note. benefit of accumbens/capsular deep brain stimulation Neurosurgery 2005; 56(2 Suppl):E445; discussion E. in a patient with both tics and obsessive-compulsive 32 Hebb MO, Garcia R, Gaudet P, Mendez IM. Bilateral disorder. Neurocase 1960; 22:1–10. stimulation of the globus pallidus internus to treat 48 Braun V, Richter HP. Selective peripheral denervation choreathetosis in Huntington’s disease: technical case for spasmodic torticollis: 13-year experience with 155 report. Neurosurgery 2006; 58(2):E383; discussion E. patients. J Neurosurg 2002; 97(2 Suppl):207–12. 33 Yianni J, Nandi D, Bradley K, et al. Senile chorea 49 Krauss JK. Surgical treatment of dystonia. Eur treated by deep brain stimulation: a clinical, neuro- J Neurol. 2008; 17(Suppl 1):97–101. physiological and functional imaging study. Mov 50 Bertrand CM. Selective peripheral denervation for spas- Disord 2004; 19(5):597–602. modic torticollis: surgical technique, results, and observa- 34 Schrock LE, Ostrem JL, Turner RS, et al. The subtha- tions in 260 cases. Surg Neurol 1993; 40(2):96–103. lamic nucleus in primary dystonia: single-unit discharge 51 Taira T, Kobayashi T, Takahashi K, Hori T. A new characteristics. J Neurophysiol 2009; 102(6):3740–52. denervation procedure for idiopathic cervical dysto- 35 Hamani C, Neimat JS, Lozano AM. Deep brain nia. J Neurosurg 2002; 97(2 Suppl):201–6. stimulation and chemical neuromodulation: current 52 Cioni B. Motor cortex stimulation for Parkinson’s use and perspectives for the future. Acta Neurochir disease. Acta Neurochir Suppl 2007; 97(Pt 2):233–8. Suppl 2007; 97(Pt 2):127–33. 53 Pagni CA, Zeme S, Zenga F, Maina R. Extradural 36 Ferreira JJ, Costa J, Coelho M, Sampaio C. The motor cortex stimulation in advanced Parkinson’s management of cervical dystonia. Expert Opin disease: the Turin experience: technical case report. Pharmacother 2007; 8(2):129–40. Neurosurgery 2005; 57(4 Suppl):E402; discussion E.

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54 Pagni CA, Altibrandi MG, Bentivoglio A, et al. 68 Yamamoto T, Katayama Y, Kano T, et al. Deep brain Extradural motor cortex stimulation (EMCS) for stimulation for the treatment of parkinsonian, essen- Parkinson’s disease. History and first results by the tial, and poststroke tremor: a suitable stimulation study group of the Italian neurosurgical society. Acta method and changes in effective stimulation intensity. Neurochir Suppl 2005; 93:113–9. J Neurosurg 2004; 101(2):201–9. 55 Lyons KE, Wilkinson SB, Pahwa R. Stimulation of the 69 Plaha P, Khan S, Gill SS. Bilateral stimulation of the motor cortex for disabling essential tremor. Clin caudal zona incerta nucleus for tremor control. Neurol Neurosurg 2006; 108(6):564–7. J Neurol Neurosurg Psychiat 2008; 79(5):504–13. 56 Buttkus F, Weidenmuller M, Schneider S, et al. Failure 70 Papavassiliou E, Rau G, Heath S, et al. Thalamic deep of cathodal direct current stimulation to improve fine brain stimulation for essential tremor: relation of lead motor control in musician’s dystonia. Mov Disord. location to outcome. Neurosurgery 2004; 54(5):1120; 2009a; 25(3):389–94. discussion 9–30. 57 Pascual-Leone A, Valls-Sole J, Toro C, et al. Resetting 71 Rehncrona S, Johnels B, Widner H, et al. Long-term of essential tremor and postural tremor in Parkinson’s efficacy of thalamic deep brain stimulation for tremor: disease with transcranial magnetic stimulation. double-blind assessments. Mov Disord 2003; 18(2): Muscle Nerve 1994; 17(7):800–7. 163–70. 58 Filipovic SR, Rothwell JC, van de Warrenburg BP, 72 Kumar R, Lozano AM, Sime E, Lang AE. Long-term Bhatia K. Repetitive transcranial magnetic stimula- follow-up of thalamic deep brain stimulation for tion for levodopa-induced dyskinesias in Parkinson’s essential and parkinsonian tremor. Neurol 2003; disease. Mov Disord 2009; 24(2):246–53. 61(11):1601–4. 59 Graff-Radford J, Foote KD, Mikos AE, et al. Mood and 73 Fields JA, Troster AI, Woods SP, et al. Neuro- motor effects of thalamic deep brain stimulation surgery psychological and quality of life outcomes 12 months for essential tremor. Eur J Neurol 0000. Jan 25. after unilateral thalamic stimulation for essential 60 Mann JM, Foote KD, Garvan CW, et al. Brain tremor. J Neurol Neurosurg Psychiat 2003; 74(3): penetration effects of microelectrodes and DBS leads 305–11. in STN or GPi. J Neurol Neurosurg Psychiat 2009; 74 Hariz GM, Lindberg M, Bergenheim AT. Impact of 80(7):794–7. thalamic deep brain stimulation on disability and 61 Zhang K, Bhatia S, Oh MY, et al. Long-term results of health-related quality of life in patients with essential thalamic deep brain stimulation for essential tremor. tremor. J Neurol Neurosurg Psychiat 2002; 72(1): J Neurosurg 2009 Nov 13. 47–52. 62 Pilitsis JG, Metman LV, Toleikis JR, et al. Factors 75 Krauss JK, Simpson RK, Jr., Ondo WG, et al. Concepts involved in long-term efficacy of deep brain stimula- and methods in chronic thalamic stimulation for tion of the thalamus for essential tremor. J Neurosurg treatment of tremor: technique and application. 2008; 109(4):640–6. Neurosurgery 2001; 48(3):535–41; discussion 41–3. 63 Pahwa R, Lyons KE, Wilkinson SB, et al. Long-term 76 Limousin P, Speelman JD, Gielen F, Janssens M. evaluation of deep brain stimulation of the thalamus. Multicentre European study of thalamic stimulation J Neurosurg 2006; 104(4):506–12. in parkinsonian and essential tremor. J Neurol 64 Lee JY, Kondziolka D. Thalamic deep brain stimula- Neurosurg Psychiat 1999; 66(3):289–96. tion for management of essential tremor. J Neurosurg 77 Biolsi B, Cif L, Fertit HE, et al. Long-term follow-up of 2005; 103(3):400–3. Huntington disease treated by bilateral deep brain 65 Stover NP, Okun MS, Evatt ML, et al. Stimulation of stimulation of the internal globus pallidus. J Neurosurg the subthalamic nucleus in a patient with Parkinson 2008; 109(1):130–2. disease and essential tremor. Arch Neurol 2005; 78 Fasano A, Mazzone P, Piano C, et al. GPi-DBS in 62(1):141–3. Huntington’s disease: results on motor function and 66 Chou KL, Hurtig HI, Jaggi JL, Baltuch GH. Bilateral cognition in a 72-year-old case. Mov Disord 2008; subthalamic nucleus deep brain stimulation in a 23(9):1289–92. patient with cervical dystonia and essential tremor. 79 Moro E, Lang AE, Strafella AP, et al. Bilateral globus Mov Disord 2005; 20(3):377–80. pallidus stimulation for Huntington’s disease. Ann 67 Putzke JD, Wharen RE, Jr., Obwegeser AA, et al. Neurol 2004; 56(2):290–4. Thalamic deep brain stimulation for essential tremor: 80 Krauss JK, Loher TJ, Weigel R, et al. Chronic recommendations for long-term outcome analysis. stimulation of the globus pallidus internus for Can J Neurol Sci 2004; 31(3):333–42. treatment of non-dYT1 generalized dystonia and

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choreoathetosis: 2-year follow up. J Neurosurg 2003; dystonia: long-term follow-up. Clin Neurol Neurosurg 98(4):785–92. 2008; 110(2):145–50. 81 Thompson TP, Kondziolka D, Albright AL. Thalamic 94 Kiss ZH. Bilateral pallidal neurostimulation–long- stimulation for choreiform movement disorders in term motor and cognitive effects in primary children. Report of two cases. J Neurosurg 2000; generalized dystonia. Nat Clin Pract Neurol 2007; 92(4):718–21. 3(9):482–3. 82 Guehl D, Cuny E, Tison F, et al. Deep brain pallidal 95 Loher TJ, Capelle HH, Kaelin-Lang A, et al. Deep stimulation for movement disorders in neuroacantho- brain stimulation for dystonia: outcome at long-term cytosis. Neurol 2007; 68(2):160–1. follow-up. J Neurol 2008; 255(6):881–4. 83 Ruiz PJ, Ayerbe J, Bader B, et al. Deep brain stimula- 96 Kleiner-Fisman G, Liang GS, Moberg PJ, et al. tion in chorea acanthocytosis. Mov Disord 2009; Subthalamic nucleus deep brain stimulation for 24(10):1546–7. severe idiopathic dystonia: impact on severity, 84 Hasegawa H, Mundil N, Samuel M, et al. The treatment neuropsychological status, and quality of life. of persistent vascular hemidystonia-hemiballismus J Neurosurg 2007; 107(1):29–36. with unilateral GPi deep brain stimulation. Mov 97 Hung SW, Hamani C, Lozano AM, et al. Long-term Disord 2009; 24(11):1697–8. outcome of bilateral pallidal deep brain stimulation 85 Mueller J, Skogseid IM, Benecke R, et al. Pallidal deep for primary cervical dystonia. Neurol 2007; 68(6): brain stimulation improves quality of life in segmental 457–9. and generalized dystonia: results from a prospective, 98 Moro E, Piboolnurak P, Arenovich T, et al. Pallidal randomized sham-controlled trial. Mov Disord 2008; stimulation in cervical dystonia: clinical implications 23(1):131–4. of acute changes in stimulation parameters. Eur J 86 Katsakiori PF, Kefalopoulou Z, Markaki E, et al. Deep Neurol 2009; 16(4):506–12. brain stimulation for secondary dystonia: results in 8 99 Martinez-Torres I, Limousin P, Tisch S, et al. Early patients. Acta Neurochir (Wien) 2009; 151(5):473–8; and marked benefit with GPi DBS for Lubag discussion 8. syndrome presenting with rapidly progressive life- 87 Cif L, Vasques X, Gonzalez V, et al. Long-term follow- threatening dystonia. Mov Disord 2009; 24(11): up of DYT1 dystonia patients treated by deep brain 1710–2. stimulation: An open-label study. Mov Disord 0000; 100 Gruber D, Trottenberg T, Kivi A, et al. Long-term 25(3):289–99. effects of pallidal deep brain stimulation in tardive 88 Vidailhet M, Yelnik J, Lagrange C, et al. Bilateral palli- dystonia. Neurol 2009; 73(1):53–8. dal deep brain stimulation for the treatment of patients 101 Blomstedt P, Tisch S, Hariz MI. Pallidal deep brain with dystonia-choreoathetosis cerebral palsy: a pro- stimulation in the treatment of Meige syndrome. spective pilot study. Lancet Neurol 2009; 8(8):709–17. Acta Neurol Scand 2008; 118(3):198–202. 89 Jeong SG, Lee MK, Kang JY, et al. Pallidal deep brain 102 Markaki E, Kefalopoulou Z, Georgiopoulos M, et al. stimulation in primary cervical dystonia with phasic Meige’s syndrome: A cranial dystonia treated with type: clinical outcome and postoperative course. bilateral pallidal deep brain stimulation. Clin Neurol J Korean Neurosurg Soc 2009; 46(4):346–50. Neurosurg 2007 Jan 8. 90 Blomstedt P, Hariz MI, Tisch S, et al. A family with a 103 Ostrem JL, Marks WJ, Jr, Volz MM, et al. Pallidal hereditary form of torsion dystonia from northern deep brain stimulation in patients with cranial- Sweden treated with bilateral pallidal deep brain stim- cervical dystonia (Meige syndrome). Mov Disord ulation. Mov Disord 2009; 24(16):2415–9. 2007; 22(13):1885–91. 91 Sensi M, Cavallo MA, Quatrale R, et al. Pallidal 104 xFukaya C, Katayama Y, Kano T, et al. Thalamic deep stimulation for segmental dystonia: long term follow brain stimulation for writer’s cramp. J Neurosurg up of 11 consecutive patients. Mov Disord 2009; 2007; 107(5):977–82. 24(12):1829–35. 105 Coubes P, Roubertie A, Vayssiere N, et al. Treatment 92 Magarinos-Ascone CM, Regidor I, Gomez-Galan M, et of DYT1-generalised dystonia by stimulation of the al. Deep brain stimulation in the globus pallidus to internal globus pallidus. Lancet 2000; 355(9222): treat dystonia: electrophysiological characteristics and 2220–1. 2 years’ follow-up in 10 patients. Neuroscience 2008; 106 Houeto JL, Karachi C, Mallet L, Pillon B, Yelnik J, 152(2):558–71. Mesnage V, et al. Tourette’s syndrome and deep brain 93 Cersosimo MG, Raina GB, Piedimonte F, et al. Pallidal stimulation. J Neurol Neurosurg Psychiat 2005; surgery for the treatment of primary generalized 76(7):992–5.

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107 Flaherty AW, Williams ZM, Amirnovin R, et al. Deep tremor. J Neurol Neurosurg Psychiat 2006; 77(9): brain stimulation of the anterior internal capsule for 1013–6. the treatment of Tourette syndrome: technical case 120 Breit S, Wachter T, Schols L, et al. Effective thalamic report. Neurosurgery 2005; 57(4 Suppl):E403; deep brain stimulation for neuropathic tremor in a discussion E. patient with severe demyelinating neuropathy. 108 Diederich NJ, Kalteis K, Stamenkovic M, et al. J Neurol Neurosurg Psychiat 2009; 80(2):235–6. Efficient internal pallidal stimulation in Gilles de la 121 Bayreuther C, Delmont E, Borg M, et al. Deep brain Tourette syndrome: a case report. Mov Disord 2005; stimulation of the ventral intermediate thalamic 20(11):1496–9. nucleus for severe tremor in anti-MAG neuropathy. 109 Shahed J, Poysky J, Kenney C, Simpson R, Mov Disord 2009; 24(14):2157–8. Jankovic J. GPi deep brain stimulation for Tourette 122 Bandt SK, Anderson D, Biller J. Deep brain stimula- syndrome improves tics and psychiatric comorbidi- tion as an effective treatment option for post- ties. Neurol 2007; 68(2):159–60. midbrain infarction-related tremor as it presents 110 Servello D, Porta M, Sassi M, et al. Deep brain with Benedikt syndrome. J Neurosurg 2008; stimulation in 18 patients with severe Gilles de la 109(4):635–9. Tourette syndrome refractory to treatment: the 123 Pahwa R, Lyons KE, Kempf L, et al. Thalamic surgery and stimulation. J Neurol Neurosurg Psychiat stimulation for midbrain tremor after partial heman- 2008; 79(2):136–42. gioma resection. Mov Disord 2002; 17(2):404–7. 111 Dehning S, Mehrkens JH, Muller N, Botzel K. 124 Sato K, Nakagawa E, Saito Y, et al. Hyperkinetic Therapy-refractory Tourette syndrome: beneficial movement disorder in a child treated by globus outcome with globus pallidus internus deep brain pallidus stimulation. Brain Dev 2009; 31(6):452–5. stimulation. Mov Disord 2008; 23(9):1300–2. 125 Kaufman CB, Mink JW, Schwalb JM. Bilateral 112 Shields DC, Cheng ML, Flaherty AW, et al. deep brain stimulation for treatment of medically Microelectrode-guided deep brain stimulation for refractory paroxysmal nonkinesigenic dyskinesia. Tourette syndrome: within-subject comparison of J Neurosurg 2009 Oct 2. different stimulation sites. Stereotact Funct 126 Yamada K, Goto S, Soyama N, et al. Complete Neurosurg 2008; 86(2):87–91. suppression of paroxysmal nonkinesigenic dyskine- 113 Welter ML, Mallet L, Houeto JL, et al. Internal sia by globus pallidus internus pallidal stimulation. pallidal and thalamic stimulation in patients with Mov Disord 2006; 21(4):576–9. Tourette syndrome. Arch Neurol 2008; 65(7):952–7. 127 Oropilla JQ, Diesta CC, Itthimathin P, et al. Both 114 Zabek M, Sobstyl M, Koziara H, Dzierzecki S. Deep thalamic and pallidal deep brain stimulation for brain stimulation of the right nucleus accumbens in myoclonic dystonia. J Neurosurg 2009. a patient with Tourette syndrome. Case report. 128 Kurtis MM, San Luciano M, Yu Q, et al. Clinical and Neurol Neurochir Pol 2008; 42(6):554–9. neurophysiological improvement of SGCE myo- 115 Porta M, Brambilla A, Cavanna AE, Servello D, clonus-dystonia with GPi deep brain stimulation. Sassi M, Rickards H, et al. Thalamic deep brain stim- Clin Neurol Neurosurg 2004; 112(2):149–52. ulation for treatment-refractory Tourette syndrome: 129 Kuncel AM, Turner DA, Ozelius LJ, et al. Myoclonus two-year outcome. Neurol 2009; 73(17):1375–80. and tremor response to thalamic deep brain 116 Martinez-Torres I, Hariz MI, Zrinzo L, et al. stimulation parameters in a patient with inherited Improvement of tics after subthalamic nucleus deep myoclonus-dystonia syndrome. Clin Neurol brain stimulation. Neurol 2009; 72(20):1787–9. Neurosurg 2009; 111(3):303–6. 117 Guridi J, Rodriguez-Oroz MC, Arbizu J, et al. 130 Plaha P, Khan S, Gill SS. Bilateral stimulation of the Successful thalamic deep brain stimulation for ortho- caudal zona incerta nucleus for tremor control. static tremor. Mov Disord 2008; 23(13):1808–11. J Neurol Neurosurg Psychiat 2008 May; 79:504–13. 118 Espay AJ, Duker AP, Chen R, et al. Deep brain 131 Hyam JA, Aziz TZ, Bain PG. Post-deep brain stimulation of the ventral intermediate nucleus of stimulation–gradual non-stimulation dependent the thalamus in medically refractory orthostatic decrease in strength with attenuation of multiple tremor: preliminary observations. Mov Disord 2008; sclerosis tremor. J Neurol 2007 Jul; 254:854–60. 23(16):2357–62. 132 Nandi D, Aziz TZ. Deep brain stimulation in the 119 Krauss JK, Weigel R, Blahak C, et al. Chronic spinal management of neuropathic pain and multiple scle- cord stimulation in medically intractable orthostatic rosis tremor. J Clin Neurophysiol 2004 Jan; 21:31–9.

Albanese_c05.indd 68 12/24/2011 6:40:04 AM Overview of Surgical Treatment Possibilities in Hyperkinetic Disorders 69

133 Alterman RL, Miravite J, Weisz D, et al. Sixty hertz 141 Koller WC, Lyons KE, Wilkinson SB, et al. Long-term pallidal deep brain stimulation for primary torsion safety and efficacy of unilateral deep brain stimulation dystonia. Neurol 2007 Aug 14; 69(7):681–8. of the thalamus in essential tremor. Mov Disord 2001 134 Parr JR, Green AL, Joint C, et al. Deep brain stimula- May; 16:464–8. tion in childhood: an effective treatment for early 142 Lim DA, Khandhar SM, Heath S, et al. Multiple onset idiopathic generalised dystonia. Arch Dis Child target deep brain stimulation for multiple sclerosis 2007 Aug; 92:708–11. related and poststroke Holmes’ tremor. Stereotact 135 Bittar RG, Yianni J, Wang S, et al. Stereotactic and Funct Neurosurg 2007; 85:144–9. Functional Neurosurgery Resident Award: deep 143 Wishart HA, Roberts DW, Roth RM, et al. Chronic brain stimulation for generalized dystonia and deep brain stimulation for the treatment of tremor in spasmodic torticollis: rate and extent of postoperative multiple sclerosis: review and case reports. J Neurol improvement. Clin Neurosurg 2005; 52:379–83. Neurosurg Psychiat 2003 Oct; 74:1392–7. 136 Bajwa RJ, de Lotbiniere AJ, King RA, et al. Deep 144 McMaster J, Gibson G, Castro-Prado F, et al. brain stimulation in Tourette’s syndrome. Mov Neurosurgical treatment of tremor in anti-myelin- Disord 2007 Jul 15; 22:1346–50. associated glycoprotein neuropathy. Neurol 2009 137 McMaster J, Gibson G, Prado F, et al. Neurological Nov 17; 73:1707–8. treatment of tremor in anti-myelin-associated glyco- 145 Ruzicka E, Jech R, Zarubova K, et al. VIM thalamic protein neuropathy. Neurol 2009 Nov 17; 73: stimulation for tremor in a patient with IgM 1707–8. paraproteinaemic demyelinating neuropathy. Mov 138 Berk C, Carr J, Sinden M, et al. Thalamic deep brain Disord 2003 Oct; 18:1192–5. stimulation for the treatment of tremor due to 146 Valldeoriola F, Regidor I, Minguez-Castellanos A, multiple sclerosis: a prospective study of tremor and et al. Efficacy and safety of pallidal stimulation in pri- quality of life. J Neurosurg 2002 Oct; 97:815–20. mary dystonia: results of the Spanish multicentric 139 Maciunas RJ, Maddux BN, Riley DE, et al. Prospective study. J Neurol Neurosurg Psychiat 2010 Jan; 81:65–9. randomized double-blind trial of bilateral thalamic 147 Capelle HH, Weigel R, Krauss JK. Bilateral pallidal deep brain stimulation in adults with Tourette stimulation for blepharospasm-oromandibular syndrome. J Neurosurg 2007 Nov; 107:1004–14. dystonia (Meige syndrome). Neurol 2003 Jun 24; 140 Hamel W, Herzog J, Kopper F, et al. Deep brain 60(12):2017–18. stimulation in the subthalamic area is more effective 148 Gill S, Curran A, Tripp J, et al. Hyperkinetic than nucleus ventralis intermedius stimulation for movement disorder in an 11-year-old child treated bilateral intention tremor. Acta Neurochir (Wien) with bilateral pallidal stimulators. Dev Med Child 2007 Aug; 149:749–58. Neurol 2001 May; 43:350–3.

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Albanese_p02.indd 71 12/24/2011 6:40:45 AM CHAPTER 6 Essential Tremor Julián Benito-León1 and Elan D. Louis2 1 Department of Neurology, University Hospital “12 de Octubre,” and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain 2 The G.H. Sergievsky Center, Department of Neurology, and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

Introduction (simple essential tremor) was first used by Burresi in Italy in 1874 to describe an 18-year-old man Tremor is an involuntary, rhythmic, muscle with severe, isolated action tremor. By the mid-20th movement involving oscillations of one or more parts century, the familial distribution and core motor of the body, resulting from the contraction of oppos- feature (action tremor of the arms) of ET had ing muscle groups [1–4]. Essential tremor (ET) is the already been well-documented by clinicians [11]. most common of the many tremor disorders and is By the early 20th century, the term “essential also one of the most common neurological disorders tremor” began to appear in the medical literature among adults [1–9]. The traditional view of ET, as a with greater frequency [12]. For many years, ET monosymptomatic condition, is being replaced, as a was also referred to as “benign essential tremor” spectrum of clinical features, with both motor and [12]; however, the adjective “benign” is slowly non-motor elements, including ataxia, parkinsonism, being abandoned in recognition of the often cognitive impairment, dementia, depressive symp- disabling nature of the disorder [1–4]. toms, and sensory (e.g. mild olfactory dysfunction and hearing impairment) abnormalities [10], are Phenomenology and other increasingly being observed and documented. The clinical features landscape for ET is shifting in a number of important ways in recent years as clinical and postmortem General characteristics studies increase our understanding of this common The tremor of ET is typically a postural or kinetic disorder. New insights into the pathogenesis of ET, in tremor (i.e. tremor during voluntary motion) most particular, could advance the development of effec- commonly affecting the arms and hands [1–4]. tive neuroprotective and symptomatic therapies. In most cases, it is slightly asymmetric, with the tremor being of greater amplitude in one arm than Historical background the other [13]. During the physical examination, the affected References to tremor have been recorded from body areas should be identified along with each body affected people throughout the course of human area’s activity state when the tremor occurs (e.g. at existence [11, 12]. The term tremore semplice essenziale rest, maintaining an extended posture, or voluntary

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(A) (B) Video 6.1 Essential tremor The patient, a woman with essential tremor, is performing the finger-nose-finger maneuver. A kinetic tremor with an intentional component is evident. The tremor is more severe in the left than right arm. A head tremor is also apparent. While attempting to pour, the kinetic tremor results in spilling.

Figure 6.1 An ET patient’s attempt (A) to draw an Archimedes spiral (B).

movement) [1–4]. The frequency of the tremor is between 4 and 12 Hz, and is inversely related to age, http://bit.ly/sYMswc with older patients generally exhibiting tremor frequencies that are at the lower end of this range [14]. Kinetic arm tremor is the hallmark feature of ET Presence of a positive family history and occurs during a voluntary movement, for Family history of ET-like tremor is commonly instance during finger-to-nose testing, while noted and, depending on the study, is present in pouring or drinking, or drawing Archimedes’ spirals anywhere from 17 to 100% of patients [19]. Most (Figure 6.1) [1–4, 14]. The kinetic tremor in ET studies indicate the presence of other reportedly often has an intentional component; for example, affected first- or second-degree relatives in 30–50% during visually guided movements such as the of patients, with young onset cases and those finger-to-nose maneuver, the amplitude of the ascertained from clinical rather than population- tremor increases as the target is approached [15] based studies being more likely to report an (see Video 6.1). Kinetic tremor leads to difficulties affected relative [19, 20]. Within families, there with eating, drinking, writing, dressing, and various can be considerable heterogeneity in terms of other activities of daily living [1–4, 14]. The ampli- tremor distribution, age of onset, and rate of tude of kinetic tremor is usually greater than that progression [12]. of postural tremor [14]. Postural tremors become obvious when the patient keeps his arms out- Age at onset stretched against gravity in front of his body (e.g. ET can begin at any age. However, some data extending the upper limbs horizontally) [1–4]. suggest a bimodal distribution in age of onset with A rest tremor of the arms is observed occasionally peaks in the second decade and sixth to later in ET patients. If present, it typically occurs when decades, and other data suggesting only one late- the arms are supported against gravity and life peak [1–4, 21]. One study compared data from completely at rest (e.g. while the patient is lying a tertiary referral setting and a population-based down, while he is seated and his hands are resting setting [21]. In the latter setting, a peak in later life in his lap, or during normal stance and ambulation) was clearly present but a young-onset peak was [1–4, 16, 17]. One study showed that patients with barely discernible. By contrast, in the tertiary rest tremor had kinetic tremor that was more referral setting, age of onset was clearly bimodal severe, more disseminated, and of longer duration [21]. This appearance of a large early-life peak in than ET patients without rest tremor [18]. clinic-based studies is likely due to the preferential referral to treatment centers of patients with Medical history young-onset, familial ET (i.e. a referral bias During the medical history, the clinician should resulting in the impression of a large, young-onset collect several types of data. peak) [21].

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Anatomical distribution and severity setting reported embarrassment [42]. Embarrassment The tremor of ET is typically an asymmetric kinetic is not only common, but it is also a major motivator and postural tremor, most commonly affecting arms for treatment [42]. In a study in New York found and hands, but other areas of the body may be that the experience of embarrassment nearly dou- affected, especially the head (i.e. neck), voice, jaw, bled the odds of using tremor medication [42]. An tongue, and legs [1–4, 22–25]. Head tremor is usually embarrassment questionnaire for ET patients has of the side-to-side (no–no) type although it may also recently been developed and validated and promises be of the up–down (yes–yes) type or a rotational to facilitate the assessment and measurement of type. In different settings, the proportion of patients embarrassment in ET [43]. with head tremor ranges from 34 to 53%, and with jaw tremor from 7.5 to 18.0% [1–4, 22–25]. Presence of additional symptoms or signs Depending on its definition, “isolated” head tremor that may suggest an alternative diagnosis (i.e. head tremor in the absence of arm tremor) is Patients with tremor due to other disorders such rarer, occurring in few if any ET patients [26]. as hyperthyroidism, Wilson disease, dystonia or In general, ET is a progressive disorder, with Parkinson disease (PD) frequently have concomi- disease duration and age each being independent tant symptoms or signs that lead the clinician to contributors to tremor severity [27–29]. Over time, these diagnoses [1–4]. For example, patients with tremor can spread from the arms to the head hyperthyroidism may complain of nervousness, pal- (especially in women); the converse (initial pitations, hyperactivity, increased sweating, heat involvement of the head with subsequent spread to hypersensitivity, fatigue, increased appetite, weight the arms) is rare and should suggest an alternative loss, insomnia, weakness, and frequent bowel diagnosis to ET [1–4, 12]. movements (occasionally diarrhea) [44, 45]. There are few data on the rate of progression Hypomenorrhea may also be present [44, 45]. Signs in ET. However, it seems that most ET cases exhibit may include warm and moist skin, tachycardia, wid- a progressive worsening in tremor with time. Thus, ened pulse pressure, atrial fibrillation, irritability, in a study, the average annual increase in tremor and sweating. Elderly patients, particularly those severity from baseline was estimated to be between with toxic nodular goiter, may present with symp- 3.1% and 5.3% and the median annual increase toms more akin to depression or dementia (apa- from baseline was between 1.8% and 2.0% [30]. thetic or masked hyperthyroidism) [46]. Patients In a large clinical sample, older age of onset was with PD often complain of slowness and limb stiff- associated with more rapid tremor progression [31]. ness and, on examination, have two or more cardi- ET is not always a benign condition and it may nal features of PD [1–4]. Psychiatric manifestations negatively impact on patient’s health-related often accompany Wilson disease [47, 48], ranging quality of life (HRQoL) [32–37] and morale [38]. from frank psychosis, delusions and hallucinations, Indeed, more than 90% of ET patients who come to to more subtle signs, such as difficulties with school treatment centers for tremor report disability [39], work or job performance, personality changes, emo- and many patients with severe, advanced ET are tionality, loss of sexual inhibition, insomnia, and unable to perform basic daily activities such aggressiveness [43, 44]. Diagnosis relies on a high as feeding or dressing themselves [12]. Almost one- clinical suspicion, typical neurological symptoms, quarter of patients who seek medical attention are presence of Kayser–Fleischer rings, and reduced compelled to change jobs or retire, and 60% decide serum ceruloplasmin concentration [47, 48]. not to apply for jobs or promo tions because of disabling shaking [12, 39]. Even among population- Administration of pharmaceutical agents dwelling cases, the large majority report disability or exposure to toxins that may induce with more than one daily task [39–41]. or alleviate tremor Embarrassment is a prevalent feature of ET [42]. An inventory of all current medications, as well as In one study, 58.2% of ET cases seen in a clinical information on caffeine intake, is also mandatory

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in PD [55, 56]. Yet in PD, kinetic tremor is often Box 6.1 Differential diagnosis of mild relative to rest tremor and the patient also has essential tremor other signs of the disease (e.g. diminished facial Parkinson disease expression, a reduction in normal arm swing, and Enhanced physiologic tremor Dystonic tremor general body slowness) [1–4, 56]. By contrast, Wilson disease when rest tremor occurs in ET patients, it usually Meige syndrome does so in the setting of a severe kinetic tremor of Primary writing tremor and isolated voice tremor long duration [1–4]. In addition, the postural Epilepsia partialis continua tremor of ET usually produces wrist flexion and Generalized repetitive myoclonus Ramsay–Hunt syndrome (progressive myoclonic ataxia) extension whereas, in PD, wrist rotation is Metabolic or endocrinologic alterations commonly seen, as is thumb flexion and extension (e.g. hypoglycemia, hyperthyroidism, hypocalcemia, etc.) [1–4]. Mild cogwheeling may occur in ET, but this is without rigidity [1–4]. In general, the tremor of PD does not involve the voice and although it rarely [1–4]. Medications that can exacerbate tremor involves the head it may involve the chin and include amiodarone, bronchodilators, cinnarizine, perioral structures [1–4, 55]. cyclosporine A, flunarizine, fluoxetine, lithium, Enhanced physiologic tremor is an 8–12 Hz pos- methyl phenidate, metoclopramide, neuroleptics, tural and kinetic tremor that may occur in the limbs nifedipine, phenelzine, phenylpropanolamine, pred- and voice (but not the head) and may be further nisone, procainamide, pseudoephedrine, theophyl- exacerbated by emotion and by medications [1–4, line, tricyclic antidepressants, and valproic acid 57, 58]. Its amplitude is generally lower than that [1–4]. The tremor of ET may temporarily abate of ET. Although quantitative computerized tremor after ethanol intake [1–4]. The improvement is typ- analysis, with accelerometers attached to the arms, ically reported to begin after 10 to 15 minutes and which exists in some tertiary treatment settings, continue for approximately 3 hours [1–4, 49, 50]. may be useful in differentiating mild ET from marked enhanced physiological tremor, there are Differential diagnosis limitations, as approximately 8% of young and Arriving at the correct diagnosis is dependent on elderly adults have an electromyography (EMG)- the medical history; the clinical distinction between acceleration pattern that is indistinguishable from kinetic, postural, intention, and rest tremors; and mild ET [59]. the recognition of additional clinical signs. The dif- ET must also be differentiated from dystonic ferential diagnosis includes a number of conditions tremor (tremor occurring in the setting of focal, in which kinetic, postural, intention, or rest tremors segmental, and generalized dystonias) [59]. In occur or in which combinations of these different some cases, dystonic tremor may be very rhythmic, types of tremors co-occur (Box 6.1) [1–4, 51, 52]. especially when there is relatively little muscular ET may be the most overdiagnosed movement coactivation [1–4, 59] and, for this reason, mild disorder and studies have shown that 30–50% of tremulous cervical dystonia (torticollis) is often individuals who are assigned the diagnosis of ET misdiagnosed as ET [1–4]. However, there are a have other neurological diseases (e.g. PD or number of features that aid in the differentiation of dystonia) rather than ET [53, 54]. Classically, PD is dystonic tremor and ET. In general, in ET patients, characterized by a rest tremor that dampens with head tremor is characterized by rhythmic (i.e. action, whereas ET is characterized as a kinetic regular) oscillations, whereas in torticollis it tends tremor that resolves upon rest [55]. However, to be irregular, occurs with tilting of the head or this is an oversimplification. Indeed, PD can be chin, varies in intensity with changes in neck or accom panied by different forms of tremor. A head position, and may completely disappear when combination of rest, postural, and kinetic tremors the head is allowed to assume the position of constitutes the most frequent tremor constellation the dystonic pulling (“null point”) [1–4, 59, 60].

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There are other neurological findings that may be Epilepsia partialis continua is a rare form of focal helpful in distinguishing this entity from ET, status epilepticus that can cause rhythmic muscle including the presence of dystonic posturing in the jerks in the extremities. Characteristic features limbs or torticollis in the neck and hypertrophy enable it to be distinguished from ET [66]. Typical of involved dystonic musculature [1–4, 59]. In clinical signs of epilepsia partialis continua are as addition, persistently focal tremor in one extremity, follows: combination of the repetitive myoclonic jerky and irregular tremors, gestes antagonistes, or jerks with hemiparesis or, less frequently, with selective responsiveness to antidystonic therapeutic other cortically-generated deficits; monomorphic, agents should point to the diagnosis of dystonic simple, brief excursions of the affected limb; tremor [1–4, 59]. irregular occurrence of the jerks; involvement of Also in the differential diagnosis are a series of very distal muscle groups; and increase in amplitude conditions that may be misclassified as tremor, and frequency after physical exercise or psychic including myoclonus, clonus, asterixis, and focal exertion [66]. In addition, electroencephalography motor epilepsy. often shows abnormal spikes, which help the Myoclonus is a brief muscle jerk, which may clinician to arrive at the correct diagnosis [66]. occur in repetitive trains and may be mistaken for tremor. Surface electromyography typically shows Laboratory workup periodic muscle burst durations of less than 50 ms There are currently no laboratory findings that are [61]. Isolated whole-body tremulousness should unique to ET [1–4]. Hence, the purpose of laboratory raise the suspicion of generalized polymyoclonus, investigation is to help to exclude other disorders. confirmed using routine surface EMG. Recognition Among certain patients, recommended screening is important because the differential diagnosis investigations include thyroid function tests and, includes autoimmune disorders and drug-induced especially if the patient is under 40 years of age, myoclonus [61, 62]. diagnostic studies to exclude Wilson disease (e.g. Clonus is an involuntary muscular contraction serum ceruloplasmin) [1–4]. alternating in rapid succession with relaxation. It In the last decade, functional imaging of the occurs around joints and is stimulated through the dopamine transporter (DAT) has been introduced stretch reflex. Passive stretching increases clonus but [67, 68]. DAT imaging detects presynaptic dopamine not tremor, aiding in the differentiation [1–4, 63]. neuronal dysfunction and thereby assists with the However, in selected cases, action-induced clonus differentiation of conditions with and without can mimic tremor [64]. such dopamine deficits (i.e. parkinsonism vs. ET) Asterixis (negative myoclonus) is a disorder of [67, 68]. The DAT scan is usually normal in ET motor control characterized by brief, arrhythmic [69] (and in drug-induced tremors) whereas it is interruptions of sustained voluntary muscle abnormal in PD or other parkinsonian syndromes contraction; it is usually observed as a brief lapse of [67, 68]. In one study, however, DAT imaging posture [65]. It manifests as a bilateral flapping showed that the pattern of dopaminergic loss over tremor affecting various parts of the body (especially time is different between ET and PD, but both the hands and arms) and occurs with a frequency disorders exhibit impairment of DAT in the caudate of 3–5 Hz during active maintenance of posture [65]. nucleus [70]. Asterixis can be differentiated from tremor on the In the last several years, transcranial sonography basis of the irregularity of the movements [65]. In has also been shown to be useful in the differ- addition, the electromyographic features consist of entiation between PD and ET [71, 72]. In a cessation of electrical activity for 35 to 200 ms in transcranial sonography study, bilateral substantia multiple muscles, during which time posture may nigra hyperechogenicity >0.20 cm2 was found in be overcome by gravity, followed by an equally 91% of 80 PD patients, 10% of 80 healthy subjects, abrupt reactivation of motor units and a restorative and 13% of 30 ET patients [72]. Substantia nigra jerk of the affected body part [65]. hyperechogenicity in ET patients might correspond

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to an increased risk of developing PD later in life Box 6.3 Tremor Research Group criteria [72]. In some tertiary care centers, quantitative Definite essential tremor computerized analysis of tremor may distinguish Postural tremor in the arms which increases during enhanced physiological and other tremors from the action in the absence of any condition or drug known tremor of ET [1–4, 73]. to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, and in the Clinical diagnostic criteria absence of Parkinson disease (PD) and dystonia. Head The diagnosis of ET is based on history and physical tremor may or may not be present. examination [1–4]. Several clinical criteria have Probable essential tremor been proposed, including those proposed in the Postural tremor in the arms without increase during action in the absence of any condition or drug known Consensus Statement on Tremor by the Movement to cause enhanced physiological tremor and in the Disorder Society (Box 6.2) [74]; these criteria have absence of cerebellar symptoms and signs, and in the also been modified slightly by the Tremor Research absence of PD and dystonia. Vocal and head or neck Group (Box 6.3) [75]; and those by the National tremor in the absence of any condition or drug known Institutes of Health Essential Tremor Consortium to cause enhanced physiological tremor and in the absence of cerebellar symptoms and signs, and in the (Box 6.4) [76]. The Washington Heights-Inwood absence of PD and dystonia. Genetic Study of ET criteria (Box 6.5) are also useful, Possible essential tremor particularly for genetic and epidemiological studies, Postural tremor in the arms and action tremor in arms in in which the distinction between ET and enhanced the absence of any condition or drug known to cause physiological tremor is important [77–80]. The use enhanced physiological tremor and in the absence of of different classification schemes may stimulate cerebellar symptoms and signs, but in the presence of PD and dystonia. discussion among physicians regarding the definition

of ET; however, the lack of consensus may be an impediment to tremor research. Box 6.2 Consensus statement of the Movement Disorder Society Tremor assessment and health-related on Tremor quality of life measurements Inclusion criteria Once a diagnosis of ET has been established, - Bilateral, largely symmetric postural or kinetic the treating physician may identify patients with tremor involving hands and forearms that is visible and persistent. more severe disease manifestations in order to initi- - Additional or isolated tremor in head but absence ate treatment. There are a several validated scales of abnormal posturing. that are useful in the assessment of tremor severity Exclusion criteria and disability. In general, clinical rating scales grade - Other abnormal neurologic signs (especially tremor amplitude in each body region during spe- dystonia). cific postures or tasks. Among the preferred scales - Presence of known causes of enhanced physiologic tremor. used to measure the severity of tremor is the - Historical or clinical evidence of psychogenic tremor. Fahn–Tolosa–Marin clinical evaluation scale [81], - Convincing evidence of sudden onset or stepwise clinical rating scales designed by Bain et al. [82], deterioration. and a series of clinical rating scales, disability - Historical or clinical evidence of psychogenic origins. questionnaires and performance-based tests designed - Convincing evidence of sudden onset or evidence of stepwise deterioration. by Louis et al. [77–80]. - Primary orthostatic tremor There is increasing recognition that the global - Isolated voice tremor well being of patients with chronic neurological - Isolated position- or task-specific tremor disease is an important outcome in research and - Isolated tongue or chin tremor clinical practice alike [83, 84]. Subjective (i.e. self- - Isolated leg tremor reported) measures of health-related quality of life

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(HRQoL) may serve to alert clinicians to areas that Box 6.4 National Institutes of Health would otherwise be overlooked [83, 84]. Data on essential tremor consortium HRQoL in ET have been reported in a small number Tremor severity scale of studies [32–37]; however, most of these have 0 none sampled highly selected ET patients with severe 1 minimal (barely noticeable) and disabling tremor who were seen in treatment 2 obvious, noticeable but probably not disabling (<2 cm excursions) settings. In one community-based study of HRQoL 3 moderate, probably partially disabling in ET [35], 32 ET cases and 32 matched controls (2 cm to 4 cm excursions) were compared using the Rand-SF36 [35]. The 4 severe, coarse, and disabling results demonstrated poorer overall HRQoL in ET (>4 cm excursions) cases than in controls. Recently, a 30-item, ET-specific HRQoL scale – the Quality of Life in Definite essential tremor Essential Tremor Questionnaire (QUEST) – was 2+ amplitude rating for bilateral arm tremor or developed [36, 37] and will be useful in terms of 2+ amplitude rating in one arm and 1+ amplitude rating assessing and advancing our understanding of in other arm ET-specific HRQoL. or 1+ amplitude rating in at least one arm and predominant cranial/cervical tremor with 2+ amplitude rating Head tremor is rhythmic with no directional Box 6.5 Washington Heights-Inwood preponderance and without asymmetry of cervical genetic study of ET criteria muscles. Tremor ratings Exclusion: obvious secondary causes (coexistent • 0: No visible tremor dystonia allowed; coexistent Parkinson’s disease (PD) • +1: Low amplitude, barely perceivable tremor, or disallowed) intermittent tremor. Possible essential tremor • +2: Tremor is of moderate amplitude (1–2 cm) and 1+ bilateral arm tremor usually present. It is clearly oscillatory. or • +3: Large amplitude (>2 cm), violent, jerky tremor Isolated 2+ cranial/cervical tremor resulting in difficulty completing the task due to or spilling or inability to hold a pen to paper. Convincing history of ET 1. On examination, a +2 postural tremor of at least Exclude: obvious secondary causes (e.g. enhanced one arm (a head tremor may also be present, physiologic tremor, drug-induced or toxic tremor, but is not sufficient for the diagnosis). coexistent peripheral neuropathies) 2. On examination, there must be a +2 kinetic tremor Coexistent dystonia allowed during at least four tasks, or a +2 kinetic tremor on Coexistent PD allowed if there is a convincing history one task and a +3 kinetic tremor on a second task. of pre-existing essential tremor Tasks include pouring water, using a spoon to drink Possible essential tremor water, drinking water, finger-to-nose manoeuvre, and drawing spirals. Isolated 1+ cranial/cervical tremor or 3. If on examination the tremor is present in the Task- or position-specific arm tremor dominant hand, then by report it must interfere or with at least one activity of daily living (eating, Unilateral arm tremor drinking, writing, and using the hands). If on or examination the tremor is not present in the Orthostatic tremor dominant hand, then this criterion is irrelevant. Unrateable essential tremor 4. Medications, hyperthyroidism, ethanol, or dystonia Tremor is coexistent with other neurologic disease, are not potential etiological factors. therapy with antitremor or tremor-promoting drugs, 5. Not psychogenic (bizarre features, inconsistent in untreated thyroid disease, caffeine withdrawal/ character, patient is distractible, other psychiatric abstention, etc. features on examination).

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Associated findings In an incidence cohort from the same population, ET patients demonstrate abnormalities in tandem ET cases with tremor onset after age 65 years were gait that are milder yet otherwise indistinguishable twice as likely to develop incident dementia than from those seen in patients with cerebellar diseases were controls (relative risk [RR] = 1.98, p = 0.01), [85–89]. These gait disturbances are seen more fre- whereas ET cases with tremor onset ≤ age 65 years quently in ET patients with longer disease duration and controls were equally likely to develop incident and who are at an advanced stage of ET [85–89]. dementia [101]. In a second population-based These tandem gait abnormalities provide clinical study of elders in New York, ET was also associated evidence of cerebellar dysfunction in ET [1–4], and with both increased odds of prevalent dementia these gait abnormalities in ET can temporarily and increased risk of incident dementia [100], with improve with ethanol intake [49, 50, 89]. In a ORs and RRs similar to those reported in the study study, the ingestion of ethanol to a mean blood level in Spain. In both studies, the large majority of sub- of 0.45% led to a transient improvement of ataxia jects with dementia received clinical diagnoses of in ET patients yet produced a worsening of gait Alzheimer disease (AD). Although additional stud- parameters in controls [82]. ies are needed, these two studies suggest that the The weight of emerging evidence is indicating presence of dementia appears to be greater than that ET is also associated with a series of non-motor expected for age (i.e. a disease-associated feature manifestations, including cognitive deficits [90–98], rather than an age-associated feature) and that dementia [99–101], personality changes [102], there are links between ET and AD [99–101]. depressive symptoms [103], possible mild olfactory There is also an accumulating body of evidence dysfunction [104–106], and hearing impairment documenting the links between ET and PD [110, [107, 108]. 111]. Family studies have clearly shown the Mild cognitive deficits, mainly in frontal-executive co-occurrence of the two diseases within some fam- function and memory, have been reported to occur ilies as well as the presence of action tremor in a in ET patients in 9 studies [90–98], including a disproportionately large number of PD families population-based case–control study of largely [111, 112]. In addition, several modern postmor- treatment-naive ET patients [95]; these studies tem studies have demonstrated the greater pres- indicate that a frontosubcortical-type dysfunction ence of brainstem Lewy bodies in ET cases than in occurs in some ET patients. In one of these controls [113, 114], raising the possibility that some studies [95], ET patients were more likely to com- ET cases have a form of Lewy body disease [113, plain of forgetfulness than were controls, suggest- 114]. The link between ET and PD has been for- ing that these mild cognitive deficits are not mally quantified in a population-based study in completely subclinical and may affect HRQoL. Spain, which demonstrated that the risk of develop- Indeed, in a population-based study of ET in Spain, ing incident PD was 4.3 times higher in ET cases lower cognitive test scores were associated with than in age-matched controls without ET [115]. more reported functional difficulty, indicating that Distinct definable personality traits might be lower cognitive test scores in ET, rather than being present in some ET patients. In a cross-sectional clinically inconsequential, seem to have a clinical– study that used the Tridimensional Personality functional correlate [109]. Questionnaire, ET patients had higher scores than An association between elderly-onset ET and did controls in the personality domain of harm prevalent dementia was found in the above- avoidance, suggesting a personality with increased mentioned population-based study in Spain [99]. levels of pessimism, fearfulness, and shyness [103]. ET cases with tremor onset after age 65 years were A study in Germany, which used a different method 70% more likely to be demented than were con- of assessing personality, also noted case–control trols (odds ratio = 1.70, p = 0.03), whereas ET cases differences in personality, with the ET patients with earlier age of tremor onset (≤ 65 years) and showing more passivity than controls [34]. Further controls were equally likely to be demented [99]. studies are needed. Aside from personality features,

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depressive symptoms might be more prevalent in than 20 prevalence studies, estimates of crude ET than in the rest of the population. In a prevalence varied substantially from 0.008% to population-based study, prevalent ET cases were 22% (i.e. an approximate 3,000-fold difference twice more likely than controls to report depression between the lowest and highest estimates) [9]. This and three times more likely to be taking wide range in estimates may be the result of a antidepressant medications [103]. In prospective number of methodological issues [119]: (1) there is analyses, baseline self-reported depression a broad variability of the surveyed populations in (adjusted RR = 1.78, p = 0.018) was associated with terms of age structure, ethnic origin and com- incident ET. These prospective data suggest that the position; (2) many studies have not defined ET and mood disorder in ET may be more than a secondary the remaining studies have defined it differently; response to disease manifestations; this mood (3) there is no test to validate a clinical diagnosis of disorder may be a primary feature of the underlying ET and therefore final diagnoses depend on the disease [103] – as is the situation in both PD and experience of the study personnel; (4) kinetic Huntington disease. tremor may be a feature of diverse disorders of Mild olfactory dysfunction has been detected in the central and peripheral nervous systems [1–4]; ET patients in some studies [104–106] but not in (5) kinetic tremor of the arms may be found to others [116]; when observed, this dysfunction is some extent as a normal finding in the aging milder than that observed in patients with PD population [1–4]; and (6) referral bias from [117]. As in PD, this possible dysfunction does not clinic-based and hospital record-based studies correlate with disease duration or severity, suggest- might provide low estimates of ET prevalence. In ing that it occurs early in the disease process [104]. addition, a major limitation of many of the studies Finally, hearing impairment in ET has been is the use of screening questionnaires rather than reported in two case-control studies [107, 108]. the direct examination of subjects to ascertain cases Data from a tertiary referral center showed that [7]. The range of prevalence estimates in subjects ET was associated with both subjective and objec- who are greater than 60 years of age is narrower tive measures of hearing loss [107]. Along the (0.1–0.5%) if one only selects those studies that are same lines, in a population-based study, ET patients population-based and that specify how they define reported more hearing impairment than did ET [9]. How does the prevalence of ET compare matched-controls [108]. The basis for this possible with other neurologic disorders of later life? In a hearing impairment is unknown. However, both population-based study in central Spain (NEDICES), central and peripheral nervous system mechanisms the prevalence of ET [4.8% (95% confidence have been suggested [107, 108]. interval [CI] = 4.2–5.4)] [6] was higher than the prevalence for all types of parkinsonism [2.2% (95% CI, 1.8–2.6)] [120] and similar to that of Epidemiology cerebrovascular disease, including stroke and transient ischemic attack [4.9% (95% CI 4.3–5.5)] Prevalence and incidence [121]. However, it was slightly less than that of ET is a global condition, affecting human beings in dementia [5.8 (95% CI 5.2–6.5)] [122]. a variety of settings, ranging from the remote East- The incidence of ET has been estimated in only ern Highlands of Papua New Guinea to the urban two studies [8, 123]. A prospective, population- area of Madrid, Spain [6, 118]. The prevalence of based study of individuals in Spain (the NEDICES ET increases with advancing age [5–7]. In a study of study), who were aged 65 years or older, reported a multiethnic community in northern Manhattan, an adjusted incidence of ET of 616 per 100,000 New York, more than 1 in 5 individuals in the oldest person-years [8]. This incidence estimate was age group (≥95 years of age) had this disease [5]. substantially higher than that reported using In general, there are no gender differences among data from in the Rochester Epidemiology Project the majority of studies [5–7]. In a review of more (incidence of 58.6 per 100,000 among those aged

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60 to 69 years; 76.6 per 100,000 among those [5]. Taking into account that that study [5] did not aged 70 to 79 years; and 84.3 per 100,000 among rely on a screening questionnaire, ethnic differences those ≥ 80 years) [123]. In the latter study [123], could exist, although this requires further entry into the medical record system as an ET case investigation. The prevalence appeared to be low in would have required that the symptoms and signs the residents of Arabic villages in northern Israel be severe enough to be recognized by the patient [126]. Another study performed in Singapore, and deemed important enough by the treating comparing Singaporean Chinese, Malays, and medical doctor to require a comment in the medical Indians, showed that the prevalence rate of ET was record [123], and this may have contributed to the marginally higher in Indians than in Chinese [127]; lower estimate of incidence. In both studies [8, no Malays with ET were found [127]. 123], the incidence increased with advancing age. Although many kindreds with autosomal dominant inheritance of ET have been described, no ET Mortality genes have been identified to date [19]. Three Mortality in ET has not been well studied. In one susceptibility loci have been found, on chromosomes longitudinal retrospective study that used the records 2p22, 3q13, and 6p [128–131]. A genome-wide linkage system at the Mayo Clinic, survival of ET association study has revealed that the LINGO1 patients was similar to that of a historical control gene is associated with an increased risk for ET in group [123]. In that study, the mean age at diagnosis European and American populations [132]. This was 58 years, and the mean length of follow-up was has been also confirmed in a study in Asians [133]. 9.7 years; therefore, cases were not all followed into LINGO1 has potent, negative regulatory influences advanced age, when the risk of mortality in ET is on neuronal survival and is also important in likely to rise. By contrast, in a prospective, regulating both central-nervous-system axon regen- population-based study in Spain (the NEDICES eration and oligodendrocyte maturation [132, 133]. study), which enrolled a contemporary rather than Current data indicates that non-genetic (envi- historical control group, the risk of mortality was ronmental) factors may also play an important role slightly but significantly increased in ET cases in disease etiology [134]. First, in twin studies, (adjusted relative risk [RR] = 1.45, 95% CI = 1.01– pairwise concordance in monozygotic twins was 2.08, p = 0.04) [124], suggesting that ET could be a 60% [135] in one study and 77–93% in another disease of both increased morbidity and mortality. study [136]. Second, more than 50% of ET patients Deaths from pneumonia were more common in the report a negative family history [137]. One ET cases than in the controls [124]. Additional neurotoxin that has begun to emerge from prospective, population-based studies are needed. epidemiological studies is harmane (1-methyl-9H- pyrido[3,4-b]indole) [138–141]. This is based on the published observation that blood harmane Risk factors and etiology concentration was elevated in ET patients from the Neurological Institute of New York compared with Aging is the risk factor most consistently associated control subjects (100 cases and 100 controls in with an increased incidence and prevalence of ET initial sample – 2000–2002) [138] and 150 cases [5–9]. However, there are no gender differences in and 135 controls in a replicate sample – 2002–2007 most of the studies [5–7]. Little is known about racial [139]. Harmane is a neurotoxin that is present in differences in the prevalence of ET. In a classic study the diet (especially in numerous meats such as in the biracial population of Copiah county, chicken, beef, fish, and pork, yet also in many Mississippi, prevalence ratios were similar between vegetables) and it is also produced endogenously; whites and African-Americans [125]. In a community- exogenous exposure is thought to be the main based survey in Manhattan, N.Y., the authors found a source of the body’s harmane [140, 142]. It is significant ethnic difference in the prevalence of ET known that administration of harmane to a wide with the prevalence among whites being the lowest variety of laboratory animals produces severe

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action tremor resembling ET [142]. Harmane is structurally similar to MPTP, a neurotoxin closely linked with PD [142]. Aside from harmane, blood lead has also been found to be modestly but significantly elevated in ET cases when compared with controls in separate studies in the United States and in Turkey [143, 144]. Lead is a neurotoxin that can cause cerebellar damage and tremor [143, 144]. Controlled, quantitative postmortem studies have demonstrated pathological changes, including Purkinje cell loss, in the cerebellum in ET [106, 107]. Ethanol is often used for symptomatic relief in ET [49, 50, 89]. However, ethanol is a well- established Purkinje cell toxin, resulting in Purkinje cell loss [145]. In a population-based study, higher Figure 6.2 Cerebellar cortical section of an ET case levels of chronic ethanol consumption were associ- (Bielschowsky stain). The red arrows indicate the ated with an increased risk of developing ET [146]. abundance of Purkinje cell axonal swellings (torpedoes). Further studies are required to explore whether (See color plate 6.2) higher consumption levels are a continued source of underlying cerebellar neurotoxicity in patients to be mediated by a neuronal loop involving who already manifest this disease [146]. cerebello-thalamo-cortical pathways [1–4, 150–158]. It has long been known that PD is inversely A broad array of neuroimaging methods used in associated with smoking cigarettes [147]. Using a a growing number of studies, including functional population-based, case-control design, cigarette magnetic resonance imaging studies [150], posi- smoking habit was assessed in 221 prevalent ET and tron emission tomography [151], [1H] magnetic 663 matched controls. Smokers were nearly half as resonance spectroscopic imaging studies [152], likely to have ET as were never smokers (adjusted diffusion tensor imaging studies [153], voxel-based OR = 0.58, p = 0.004) [148]. In an incidence cohort morphometry studies [154, 156] and studies using from the same population, baseline, heavy cigarette other automated volumetric methods [155] now smoking was also associated with a lower risk of point to the presence not only of functional and incident ET (adjusted RR = 0.29, p = 0.03) [149]. metabolic abnormalities in the ET cerebellum, but The genetic and the non-genetic environmental of structural abnormalities in both the cerebellar hypotheses for ET might not be mutually exclusive; gray and white matter as well. for instance, environmental factors might trigger Moreover, postmortem studies provide evi- the expression of underlying susceptibility geno- dence of degenerative changes in the cerebellum in types or underlying susceptibility genotypes might many ET cases [113, 114, 157–159], with a six-fold increase the toxicity of environmental exposures. increase in Purkinje cell axonal swellings (torpe- The identification of these environmental factors is does) (Figure 6.2) and an approximate 40% important as it would open the way toward pri- reduction in the number of Purkinje cells [113, mary disease prevention through a reduction in 114, 157–159]. In a quantitative, controlled study exposure to these factors. comparing 33 ET cases to 21 controls, the mean number of Purkinje cells per 100x field was reduced in ET cases and there were also approximately Pathophysiology 7 times as many torpedoes in ET cases [106]. Two cases also had degeneration of the dentate nucleus Clinical and neuroimaging data point to cerebellar [113]. Other structural abnormalities in ET cases involvement in ET, and the tremor of ET is thought were Purkinje cell heterotopias and Purkinje cell

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dendrite swellings [113]. Eight (24.2%) of the 33 methods aimed at alleviating the anxiety or stress ET brains had Lewy bodies in the brainstem, mainly that may exacerbate tremor. in the locus ceruleus, and normal cerebella [113]. Lifestyle changes may be of benefit in some Other reports have also noted an increase in brain- patients. These changes include restricting caffeine stem Lewy body pathology in ET cases compared intake or other stimulants that may increase symp- with controls [114] while some others have not toms. The transient antitremor effects of ethanol [159], so the role of Lewy body pathology requires are well known [49, 50, 89]. Ethanol binds to the

further study. In general, however, the pathological GABAA receptor, thereby enhancing GABAergic findings in brains from ET patients seem to be both neurotransmission [161, 162]. However, tremor heterogeneous and neurodegenerative [113, 114, can rebound after the effect of ethanol wears off 157–159]. As evidence of clinical heterogeneity and [1–4, 49, 50, 89]. Ethanol should not be recom- pathologic heterogeneity in ET emerges, this raises mended as a maintenance therapy for patients who the question as to whether it will at some point be search for tremor reduction throughout the day, possible to reformulate this condition as a cluster of because of its known deleterious effects on general separable clinical-pathological entities, that is, a health as well as its potential deleterious effects as a family of diseases — the essential tremors [160]. Purkinje cell toxin [145]. No medication has been shown to provide a cure in ET patients. However, there are several treatments Treatment that can lessen tremor in some patients [1–4]. The issue is that such treatments for ET have side effects General considerations and it is important to carefully consider in each As with other chronic diseases, it is important to patient whether the benefits outweigh any side consider the psychological and social impact of the effects [1–4]. Of interest is that in a study, nearly illness on patients. ET patients may be unable to one of every three ET patients who had been continue full-time work, so financial problems may prescribed medication for tremor had discontinued rise. Physicians should coordinate the help of other pharmacotherapy [163]. This underscores the healthcare professionals to address these social and inadequacy of current pharmacotherapeutic options psychological issues. The impact of the disease on for this disorder [163]. the patient’s family should also be taken into Treatment should be initiated when the tremor account. It may be useful for ET patients to bring begins to interfere with the patient’s ability to per- their spouse or partner to a consultation, to help form daily activities, or if the tremor is embarrassing them better understand the disease and to discuss to the patient [1–4]. Surgery is the final option for their difficulties and concerns. patients who have not responded adequately to Patient-centered associations may be of help in medications [1–4]. As a general rule, the four most offering individual and group support, education, important rules for physicians when initiating and advice. Through such interactions, patients treatment for ET are: (1) to “start low and go slow” may benefit in learning ways to cope with the in order to minimize adverse drug events and to many practical day-to-day difficulties that arise for maximize patient tolerance [1–4]; (2) to select each those living with this disease. medication according to patients’ preferences and There are physical and psychological measures comorbidity. For instance, a benzodiazepine would as well as certain lifestyle changes that may be be a good choice for ET patients who have comorbid helpful in patients with mild ET. Application of anxiety disorder, a β-adrenergic-receptor antago- weights to affected limbs may decrease tremor nist in those patients with associated hypertension, amplitude in some patients; for instance, strap- and topiramate for patients with migraine or obesity ping 1- to 2-pound weights to the wrist could [1–4]; (3) to gradually taper and withdraw a given improve hand stability. Furthermore, some patients medication if it is not useful at a dose that causes may experience modest benefits from relaxation adverse effects: and (4) to add a second medication

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Table 6.1 Pharmacological agents for the treatment of essential tremor.

Pharmacological agent Dosage Potential side effects

Propranolol 60–320 mg/d Reduced arterial pressure, reduced pulse rate, tachycardia, bradycardia, impotency, drowsiness, exertional dyspnoea, confusion, headache, dizziness Long-acting propranolol 80–320 mg/d Skin eruption, transient dizziness Primidone Up to 1,000 mg/d Sedation, drowsiness, fatigue, nausea, giddiness, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, acute toxic reaction Nadolol 120–240 mg/d None Sotalol 75–200 mg/d Decreased alertness Atenolol 50–150 mg/d Lightheadedness, nausea, cough, dry mouth, sleepiness Nimodipine 120 mg/d Headache, heartburn, orthostatic hypotension Gabapentin 1,200–1,800 mg/d Lethargy, fatigue, decreased libido, dizziness, nervousness, shortness of breath Topiramate Up to 400 mg/d Appetite suppression, weight loss, paraesthesias, anorexia, concentration difficulties Levetiracetam 1000 mg/d Behavioral side effects (from hostility to aggressive behaviour) Zonisamide 100–200 mg/d Ataxia, dizziness, somnolence, agitation, anorexia Alprazolam 0.75–2.75 mg/d Sedation, fatigue, potential for abuse Clonazepam 0.5–6 mg/d Drowsiness Clozapine 6–75 mg/d Sedation, potential agranulocytosis (0.8% at one year) Olanzapine 20 mg/d Drowsiness, sedation, weight gain, diabetes 1-octanol Up to 64 mg/kg Unusual taste Botulinum toxin A (hand tremor) 50–100 U Hand/finger weakness, reduced grip strength, pain at injection site, stiffness, cramping, haematoma, paraesthesias Botulinum toxin A (head tremor) 40–400 U Neck weakness, post-injection pain Botulinum toxin A (voice tremor) 0.6–15 U Breathiness, weak voice, swallowing difficulty

Adapted from Zesiewicz TA, Elble R, Louis ED, et al. [164].

if the benefit of the first medication is only partial. antagonism; propranolol may be used as initial Some patients require only intermittent tremor therapy to treat limb tremors in ET [165, 166], and reduction (for example, when attending a social perhaps head tremor, although data for this last event or engaged in a meeting). In these cases, pro- indication is limited [164]. The initial dosage is pranolol (10–40 mg orally) approximately half an 10 mg propranolol, one to three times daily with hour before the event may be of benefit [1–4]. titration in 10–20 mg increments to an upper limit of 320 mg/day [164, 165]. The dose range for chil- Pharmacological agents dren is less clear, but dosing for other indications, Table 6.1 shows the pharmacological agents that are such as migraine, ranges from 1 to −3 mg/kg/day in used in the treatment of ET [164]. Propranolol and divided doses [173]. The long-acting once-daily primidone, administered either as monotherapy or preparation is as effective as conventional propran- in combination, are the two first-line medications olol [166]. Long-acting once-daily preparation, in in the treatment of ET [32, 165–172]. Each of these capsules taken once daily in the morning or even- is estimated to be effective in anywhere between ing, may be preferred for maintenance [166]. 30 and 70% of patients [165]. Propranolol is a Primidone, an anticonvulsant medication, has non-selective β-adrenoceptor antagonist, whose also been effective in placebo-controlled trials [32, β main action is probably peripheral 2-receptor 167–172]. Tolerability is a frequent problem and it

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is recommended that primidone be initiated with approximately 1/8 of a 25 mg tab and increasing a dose of 12.5 mg/day, and increased gradually slowly [190, 191]. However, hematologic moni- to doses of 500–1,000 mg/day as tolerated [32, toring is necessary, since this drug is associated 167–172]. Drowsiness and unsteadiness, the most with agranulocytosis [192]. Olanzapine (20 mg/ common side effects, which sometimes require day), another atypical antipsychotic, significantly the withdrawal of the agent, may be seen in decreased tremor in one study [193]; however, approximately 20% of patients [32, 167–172]. side effects associated with this drug (substantial Propranolol and primidone seem to be equally weight gain, development of dyslipidemia and efficacious [169]. type II diabetes mellitus) may limit its use [194]. Other medications may be used with varying Finally, 1-Octanol (an 8-C alcohol currently used efficacy in patients who do not achieve an as a food-flavoring agent) significantly reduced adequate response with primidone and propranolol tremor in a randomized, placebo-controlled pilot in ET (Table 6.1) [164]. Among these medications, trial of a single oral dose of 1 mg/kg [195]. other β-adrenoceptor antagonists such as nadolol Intramuscular botulinum toxin A injection may (120–240 mg/day), sotalol (75–200 mg/day), and be used in those patients with wrist tremor who atenolol (50–150 mg/day), may have antitremor fail treatment with oral agents [196, 197]. However, efficacy in ET patients [174, 175]. Nimodipine, our recommendation is only use botulinum toxin A a calcium channel blocker, may be useful to when the main manifestation of ET is a simple reduce tremor at 30 mg qid [176]. Gabapentin wrist flexion-extension tremor (rather than tremor (1,200–1,800 mg/day), an anticonvulsant struc- of the shoulder, elbow or fingers and rather than turally similar to the GABA, resulted in significant complex, multi-planar wrist tremors). On the other reduction in tremor compared with placebo in hand, existing data are insufficient to draw a two trials [177, 178]; however, a third study conclusion on the use of intramuscular botulinum identified no difference between gabapentin and toxin A injection in the treatment of head and placebo [179]. Topiramate (up to 400 mg/day), voice tremor [198–200]. In general, however, the another anticonvulsant medication that enhances benefits must be considered in conjunction with GABA activity, may be useful in reducing tremor the common adverse effect of muscle weakness in ET [180, 181]. However, adverse effects, such as associated with intramuscular botulinum toxin cognitive difficulty and parasthesias, may reduce A injection [196]. its potential use [182]. Levetiracetam, another anticonvulsant medication, at a single dose of Surgical treatment 1,000 mg/day, was of benefit in reducing arm Advances in surgical interventions offer patients an tremor in a double-blind placebo controlled trial alternative treatment modality when pharmaco- [183], but not in another study [184]. Zonisamide therapy is inadequate. Surgical treatment for ET (100–200 mg/day) may be useful for modest has been used since the early 1950s [201]. The tremor reduction in some medically refractory optimal target was determined to be the ventralis ET patients [185], especially those with head intermedius (VIM) nucleus of the thalamus [201], tremor [186]. Other GABAergic medications, such since tremor is thought to be mediated by a as alprazolam (0.75–2.75 mg/day) [187] and neuronal loop involving cerebello-thalamo-cortical clonazepam (0.5–6 mg/day) [188], may improve pathways [1–4]. Both thalamotomy and thalamic tremor. However, clonacepam was not useful in VIM nucleus deep brain stimulation (DBS) offer another study, and the dropout rate was as high as high rates of tremor reduction in the contralateral 40% due to adverse effects such as drowsiness arm [202, 203]. In general, the magnitude of [189]. Antipsychotic medications have also been improvement from surgery is large, and patients’ tested in ET. Thus, clozapine, has been found to disability scores improve dramatically [196, 197]. reduce tremor at doses of 6–75 mg/day, with a However, DBS has been shown to have fewer starting dose of 12.5 mg/d po or less, introducing adverse effects [202, 203].

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Stereotactic thalamotomy and gamma years, a panoply of previously unrecognized motor knife thalamotomy and non-motor features has emerged. In addition, Stereotactic thalamotomy has been demonstrated to emerging pathological studies are providing evi- provide long-term efficacy for medically intractable dence that ET is likely to be a neurodegenerative tremor in ET [202–206]. It is less expensive than DBS disease or diseases. As with other progressive neu- and no hardware remains in the body [196–200]. rological disorders of later life (e.g. motor neuron Although the efficacy of thalamotomy and thalamic disease and PD), ET might represent a family of However, DBS are similar [202, 203], thalamotomy related diseases that show heterogeneity at etiolog- is associated with a higher complication rate, includ- ical, clinical and pathological levels. Although a ing dysarthria, dysequilibrium, weakness, and cogni- small number of medications can provide partial tive deterioration [202–207]. Bilateral thalamotomy relief from tremor, the pharmacological treatment is usually avoided since it is associated with a higher of ET is not optimal and some patients with severe risk of dysarthria and a risk of cerebral hemorrhage tremor undergo surgery, which is generally effec- [204–207]. tive. It is necessary to continue the search for newer Gamma knife thalamotomy for ET is still under and better medications that result in greater tremor study; there is difficulty in targeting a defined control and improve HRQoL. area for lesioning because electrophysiologic guidance is not possible [208, 209]. However, recent studies suggest that gamma knife thalamotomy provides tremor relief that is similar to References that provided by stereotactic thalamotomy or thalamic DBS, but it is safer than either of these 1 Louis ED (2001) Essential tremor. N Engl J Med alternatives and, in addition, long-term follow up 345:887–91. indicates that relief of tremor is well maintained 2 Louis ED (2005) Essential tremor. Lancet Neurol [208, 209]. 4:100–10. 3 Benito-León J, Louis ED (2006) Essential tremor: Thalamic deep brain stimulation emerging views of a common disorder. Nat Clin Pract Thalamic VIM nucleus DBS has replaced thalam- Neurol 2:666–78. otomy in the surgical treatment of parkinsonism 4 Benito-León J, Louis ED (2007) Clinical update: diag- and ET because it is reversible, adaptable, and nosis and treatment of essential tremor. Lancet well tolerated even by patients undergoing 369:1152–4. 5 Louis ED, Thawani SP, Andrews HF (2009) Prevalence bilateral surgery [33, 210–213]. The main advan- of essential tremor in a multiethnic, community-based tage of thalamic DBS is that it is adjustable and study in northern Manhattan, New York, N.Y. adverse effects from stimulation can be controlled Neuroepidemiol 32:208–14. by reducing stimulation. However, it is expensive, 6 Benito-León J, Bermejo-Pareja F, Morales JM, et al. there is a foreign body implant, it is necessary (2003) Prevalence of essential tremor in three elderly to optimize parameters and there is hard- populations of central Spain. Mov Disord 18:389–94. ware maintenance, including battery replacement 7 Dogu O, Sevim S, Camdeviren H, et al. (2003) [33, 210–213]. Prevalence of essential tremor: door-to-door neurologic exams in Mersin Province, Turkey. Neurol 61:1804–6. 8 Benito-León J, Bermejo-Pareja F, Louis ED: Neurological Conclusion Disorders in Central Spain (NEDICES) Study Group (2005) Incidence of essential tremor in three elderly populations of central Spain. Neurol 64:1721–5. ET is one of the most common neurological disor- 9 Louis ED, Ottman R, Hauser WA (1998) How common ders among adults. For many years, ET was viewed is the most common adult movement disorder? as a monosymptomatic condition, characterized Estimates of the prevalence of essential tremor through- only by a kinetic arm tremor, yet over the last 10 out the world. Mov Disord 13:5–10.

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10 Benito-León J (2008) Essential Tremor: from a mono- population-based and clinic-based case samples. Mov symptomatic disorder to a more complex entity. Disord 24:2281–5. Neuroepidemiol 31:191–2. 27 Elble RJ (2000) Essential tremor frequency decreases 11 Louis ED, Broussolle E, Goetz CG, et al. (2008) with time. Neurol 55:1547–51. Historical underpinnings of the term essential tremor 28 Louis ED, Jurewicz EC, Watner D (2003) Community- in the late 19th century. Neurol 71:856–9. based data on associations of disease duration and age 12 Critchley M (1949) Observations on essential tremor with severity of essential tremor: implications for (heredofamilial tremor). Brain 72:113–39. disease pathophysiology. Mov Disord 18:90–3. 13 Louis ED, Wendt KJ, Pullman SL, Ford B (1998) Is 29 Rajput A, Robinson CA, Rajput AH (2004) Essential essential tremor symmetric? Observational data from tremor course and disability: a clinicopathologic study a community-based study of essential tremor. Arch of 20 cases. Neurol 62:932–6. Neurol 55:1553–9. 30 Louis ED, Agnew A, Gillman A, Gerbin M, Viner AS 14 Brennan KC, Jurewicz E, Ford B, et al. (2002) Is (2011) Estimating annual rate of decline: prospective, essential tremor predominantly a kinetic or a postural longitudinal data on arm tremor severity in two tremor? A clinical and electrophysiological study. Mov groups of essential tremor cases. J Neurol Neurosurg Disord 17:313–16. Psychiatry 82:761–5. 15 Deuschl G, Wenzelburger R, Loffler K, et al. (2000) 31 Louis ED, Faust PL, Vonsattel JP, et al (2009) Older Essential tremor and cerebellar dysfunction. Clinical onset essential tremor: More rapid progression and and kinematic analysis of intention tremor. Brain more degenerative pathology. Mov Disord 123:1568–80. 24:1606–12. 16 Koller WC, Rubino FA (1985) Combined resting 32 Sasso E, Perucca E, Calzetti S (1998) Double-blind postural tremors. Arch Neurol 42:683–4. comparison of primidone and phenobarbital in essen- 17 Rajput AH, Rozdilsky B, Ang L, Rajput A (1993) tial tremor. Neurol 38: 808–10. Significance of parkinsonian manifestations in essen- 33 Sydow O, Thobois S, Alesch F, Speelman JD (2003) tial tremor. Can J Neurol Sci 20:114–17. Multicentre European study of thalamic stimulation 18 Cohen O, Pullman S, Jurewicz E, et al. (2003) Rest in essential tremor: a six year follow up. J Neurol tremor in patients with essential tremor: prevalence, Neurosurg Psychiat 74:1387–91. clinical correlates, and electrophysiologic characteris- 34 Lorenz D, Schwieger D, Moises H, Deuschl G (2006) tics. Arch Neurol 60:405–10. Quality of life and personality in essential tremor 19 Deng H, Le W, Jankovic J (2007) Genetics of essential patients. Mov Disord 21:1114–18. tremor. Brain 130:1456–1464. 35 Nguyen HV, Ngian V, Cordato D, et al. (2007) Quality 20 Louis ED, Ottman R (2006) Study of possible factors of life in a random sample of community dwelling associated with age of onset in essential tremor. Mov older patients with essential tremor. Acta Neurol Disord 21:1980–6. Scand 11:289–92. 21 Louis ED, Dogu O (2007) Does age of onset in essential 36 Troster AI, Pahwa R, Fields JA, et al. (2005) Quality tremor has a bimodal distribution? Data from a ter- of life in Essential Tremor Questionnaire (QUEST): tiary referral setting and a population-based study. devel opment and initial validation. Parkinsonism Neuroepidemiol 29:208–12. Relat Disord 11:367–73. 22 Louis ED, Ford B, Frucht S (2003) Factors associated 37 Martínez-Martín P, Jiménez-Jiménez FJ, Carroza with increased risk of head tremor in essential tremor: García E, et al. (2010) Most of the Quality of Life in a community-based study in northern Manhattan. Essential Tremor Questionnaire (QUEST) psycho- Mov Disord 18:432–6. metric properties resulted in satisfactory values. J 23 Lou JS, Jankovic J (1991) Essential tremor: clinical Clin Epidemiol 63:767–73. correlates in 350 patients. Neurol 41:234–8. 38 Louis ED, Benito-León J, Bermejo-Pareja F: Neuro- 24 Ashenhurst EM (1973) The nature of essential tremor. logical Disorders in Central Spain (NEDICES) Study Can Med Assoc J 109:876–8. Group (2008) Philadelphia Geriatric Morale Scale in 25 Louis ED, Rios E, Applegate LM, et al. (2006) Jaw essential tremor: a population-based study in three tremor: prevalence and clinical correlates in three Spanish communities. Mov Disord 23:1435–40. essential tremor case samples. Mov Disord 21:1872–8. 39 Louis ED, Barnes L, Albert SM, et al. (2001) Correlates 26 Louis ED, Dogu O (2009) Is isolated head tremor: Part of functional disability in essential tremor. Mov Disord of the clinical spectrum of essential tremor? Data from 16:914–20.

Albanese_c06.indd 88 12/24/2011 6:48:40 AM Essential Tremor 89

40 Louis ED, Ford B, Frucht S, et al. (2001) Risk of tremor 59 Deuschl G (2003) Dystonic tremor. Rev Neurol (Paris) and impairment from tremor in relatives of patients 159:900–5. with essential tremor: A community-based family 60 Jankovic J, Mejia NI (2005) Dystonic tremor. In: Lyons study. Ann Neurol 49:761–9. KE, Pahwa R, eds. Handbook of Essential Tremor and 41 Bain PG, Findley LJ, Thompson PD, et al. (1994) Other Tremor Disorders. Taylor & Francis, Boca Raton, A study of heredity of essential tremor. Brain 11: FL, pp 221–6. 805–24. 61 Vercueil L (2006) Myoclonus and movement disorders. 42 Louis ED, Rios E (2009) Embarrassment in essential Neurophysiol Clin 36:327–31. tremor: prevalence, clinical correlates and therapeutic 62 McKeon A, Pittock SJ, Glass GA, et al. (2007) Whole- implications. Parkinsonism Relat Disord 15:535–8. body tremulousness: isolated generalized polymyo- 43 Traub RE, Gerbin M, Mullaney MM, Louis ED (2010) clonus. Arch Neurol 64:1318–22. Development of an essential tremor embarrassment 63 Rossi A, Mazzocchio R, Scarpini C (1990) Clonus in assessment. Parkinsonism Relat Disord 16:661–665. man: a rhythmic oscillation maintained by a reflex 44 Nayak B, Hodak SP (2007) Hyperthyroidism. mechanism. Electroencephalog Clin Neurophysiol Endocrinol Metab Clin North Am 36:617–56. 75:56–63. 45 Nygaard B (2007) Hyperthyroidism. Am Fam 64 Fraix V, Delalande I, Parrache M, et al. (2008) Action- Physician 76:1014–16. induced clonus mimicking tremor. Mov Disord 46 Bailes BK (1999) Hyperthyroidism in elderly patients. 23:285–8. AORN J 69:254–8. 65 Gokula RM, Khasnis A, Asterixis J (2003) Postgrad 47 Pfeiffer RF (2007) Wilson’s Disease. Semin Neurol Med 49:272–5. 27:123–32. 66 Bien CG, Elger CE (2008) Epilepsia partialis continua: 48 Mak CM, Lam CW (2008) Diagnosis of Wilson’s semiology and differential diagnoses. Epileptic Disord disease: a comprehensive review. Crit Rev Clin Lab Sci 10:3–7. 45:263–90. 67 Marshall V, Grosset D. Role of dopamine transporter 49 Growdon JH, Shahani BT, Young RR (1975) The imaging in routine clinical practice. Mov Disord effect of alcohol on essential tremor. Neurol 25: 2003:18:1415–23. 259–62. 68 Marshall V, Grosset DG (2003) Role of dopamine 50 Koller WC, Biary N (1984) Effect of alcohol on trem- transporter imaging in the diagnosis of atypical tremor ors: comparison with propranolol. Neurol 34:221–2. disorders. Mov Disord 18(Suppl 7):S22–27. 51 Deuschl G (1999) Differential diagnosis of tremor. 69 Arabia G, Novellino F, Morelli M, et al. (2010) Mixed J Neural Transm (Suppl) 56:211–20. tremors with integrity of nigrostriatal system: a clini- 52 Bhidayasiri R (2005) Differential diagnosis of common cal and DAT-SPECT follow-up study. Mov Disord tremor syndromes. Postgrad Med J 81:756–62. 25:662–4. 53 Jain S, Lo SE, Louis ED (2006) Common misdiagnosis 70 Isaias IU, Marotta G, Hirano S, et al. (2010) Imaging of a common neurological disorder: how are we mis- essential tremor. Mov Disord 25:679–86. diagnosing essential tremor? Arch Neurol 63: 71 Doepp F, Plotkin M, Siegel L, et al. (2008) Brain paren- 1100–04. chyma sonography and 123I-FP-CIT SPECT in 54 Schrag A, Münchau A, Bhatia KP, et al. (2000) Parkinson’s disease and essential tremor. Mov Disord Essential tremor: an overdiagnosed condition? 23:405–10. J Neurol 247:955–9. 72 Budisic M, Trkanjec Z, Bosnjak J, et al. (2009) 55 Carr J (2002) Tremor in Parkinson’s disease. Distinguishing Parkinson’s disease and essential Parkinsonism Relat Disord 8:223–4. tremor with transcranial sonography. Acta Neurol 56 Kraus PH, Lemke MR, Reichmann H (2006) Kinetic Scand 11:17–21. tremor in Parkinson’s disease-an underrated symp- 73 Louis ED, Pullman SL (2001) Comparison of clinical tom. J Neural Transm 11:845–53. vs. electrophysiological methods of diagnosing of 57 Raethjen J, Pawlas F, Lindemann M, et al. (2000) essential tremor. Mov Disord 16:668–73. Determinants of physiologic tremor in a large normal 74 Deuschl G, Bain P, Brin M (1998) Consensus statement population. Clin Neurophysiol 11:1825–37. of the Movement Disorder Society on Tremor. Ad Hoc 58 Elble RJ (2003) Characteristics of physiologic tremor Scientific Committee. Mov Disord 13(Suppl 3):2–23. in young and elderly adults. Clin Neurophysiol 75 Bain P, Brin M, Deuschl G, et al. (2000) Criteria for the 114:624–35. diagnosis of essential tremor. Neurol 54(11Suppl 4):S7.

Albanese_c06.indd 89 12/24/2011 6:48:40 AM 90 Chapter 6

76 Chouinard S, Louis ED, Fahn S (1997) Agreement 91 Gasparini M, Bonifati V, Fabrizio E, et al. (2001) among movement disorder specialists on the clinical Frontal lobe dysfunction in essential tremor: a pre- diagnosis of essential tremor. Mov Disord 12:973–6. liminary study. J Neurol 24:399–402. 77 Louis ED, Ottman RA, Ford B et al. (1997) The 92 Lombardi WJ, Woolston DJ, Roberts JW, Gross RE Washington Heights Essential Tremor Study: (2001) Cognitive deficits in patients with essential methodologic issues in essential-tremor research. tremor. Neurol 57:785–90. Neuroepidemiol 16:124–33. 93 Troster AI, Woods SP, Fields JA, et al. (2002) 78 Louis ED, Ford B, Lee H, Andrews H (1998) Does a Neuropsychological deficits in essential tremor: an screening questionnaire for essential tremor agree expression of cerebello-thalamo-cortical pathophysi- with the physicians’ examination? Neurol 50: ology?. Eur J Neurol 9:143–51. 1351–7. 94 Lacritz LH, Dewey R Jr, Giller C, Cullum CM (2002) 79 Louis ED, Wendt KJ, Albert SM, et al. (1999) Validity Cognitive functioning in individuals with “benign” of a performance-based test of function in essential essential tremor. J Int Neuropsychol Soc 8:125–9. tremor. Arch Neurol 56:841–6. 95 Benito-León J, Louis ED, Bermejo-Pareja F: 80 Louis ED, Barnes LF, Wendt KJ, et al. (2000) Validity Neurological Disorders in Central Spain (NEDICES) and test-retest reliability of a disability questionnaire Study Group (2006) Population-based case-control for essential tremor. Mov Disord 15:516–23. study of cognitive function in essential tremor. Neurol 81 Fahn SE, Tolosa E, Marin C (1993) Clinical rating 66:69–74. scale for tremor. In: Jankovic J, Tolosa E (eds). 96 Sahin HA, Terzi M, Uçak S, et al. (2006) Frontal Parkinson’s Disease and Movement Disorders. 2nd edn. functions in young patients with essential tremor: a Williams & Wilkins, Baltimore, MD, pp 271–80. case comparison study. J Neuropsychiat Clin Neurosci 82 Bain PG, Findley LJ, Atchison P, et al. (1993) Assess- 18:64–72. ing tremor severity. J Neurol Neurosurg Psychiat 97 Higginson CI, Wheelock VL, Levine D, et al. (2008) 56:868–73. Cognitive deficits in essential tremor consistent with 83 Benito-León J, Morales JM, Rivera-Navarro J (2002) frontosubcortical dysfunction. J Clin Exp Health-related quality of life and its relationship to Neuropsychol 15:1–6. cognitive and emotional functioning in multiple 98 Woods SP, Scott JC, Fields JA, et al. (2008) Executive sclerosis patients. Eur J Neurol 9:497–502. dysfunction and neuropsychiatric symptoms predict 84 Mitchell AJ, Benito-León J, González JM, Rivera- lower health status in essential tremor. Cogn Behav Navarro J (2005) Quality of life and its assessment Neurol 21:28–33. in multiple sclerosis: integrating physical and psycho- 99 Benito-León J, Louis ED, Bermejo-Pareja F: logical components of wellbeing. Lancet Neurol 4: Neurological Disorders in Central Spain Study Group 556–66. (2006) Elderly-onset essential tremor is associated 85 Singer C, Sánchez-Ramos J, Weiner WJ (1994) Gait with dementia. Neurol 66:1500–5. abnormality in essential tremor. Mov Disord 9: 100 Thawani SP, Schupf N, Louis ED (2009) Essential 193–6. tremor is associated with dementia: prospective pop- 86 Deuschl G, Wenzelburger R, Loffler K, et al. (2000) ulation-based study in New York. Neurol 73:621–5. Essential tremor and cerebellar dysfunction. Clinical 101 Bermejo-Pareja F, Louis ED, Benito-León J: and kinematic analysis of intention tremor. Brain Neurological Disorders in Central Spain (NEDICES) 12:1568–80. Study Group (2007) Risk of incident dementia in 87 Stolze H, Petersen G, Raethjen J, et al. (2001) The essential tremor: a population-based study. Mov gait disorder of advanced essential tremor. Brain Disord 22:1573–80. 12:2278–86. 102 Chatterjee A, Jurewicz EC, Applegate LM, Louis ED 88 Bove M, Marinelli L, Avanzino L, et al. (2006) (2004) Personality in essential tremor: further evi- Posturographic analysis of balance control in patients dence of non-motor manifestations of the disease. with essential tremor. Mov Disord 21:192–8. J Neurol Neurosurg Psychiat 75:958–61. 89 Klebe S, Stolze H, Grensing K, et al. (2005) Influence 103 Louis ED, Benito-León J, Bermejo-Pareja F: of alcohol on gait in patients with essential tremor. Neurological Disorders in Central Spain (NEDICES) Neurol 65:96–101. Study Group (2007) Self-reported depression 90 Vermilion K, Stone A, Duane D (2001) Cognition and and anti-depressant medication use in essential affect in idiopathic-essential tremor. Mov Disord tremor: cross-sectional and prospective analyses in a 16(Suppl 1):S30. population-based study. Eur J Neurol 14:1138–46.

Albanese_c06.indd 90 12/24/2011 6:48:40 AM Essential Tremor 91

104 Louis ED, Bromley SM, Jurewicz EC, Watner D (2002) 118 Hornabrook RW, Nagurney JT (1976) Essential Olfactory dysfunction in essential tremor: a deficit tremor in Papua, New Guinea. Brain 99:659–72. unrelated to disease duration or severity. Neurol 119 Benito-León J (2009) How common is essential 59:1631–3. tremor?. Neuroepidemiol 32:215–16. 105 Louis ED, Jurewicz EC (2003) Olfaction in essential 120 Benito-León J, Bermejo-Pareja F, Rodríguez J, et al.: tremor patients with and without isolated rest Neurological Disorders in Central Spain (NEDICES) tremor. Mov Disord 18:1387–9. Study Group (2003) Prevalence of PD and other 106 Applegate LM, Louis ED (2005) Essential tremor: types of parkinsonism in three elderly populations of mild olfactory dysfunction in a cerebellar disorder. central Spain. Mov Disord 18:267–4. Parkinsonism Relat Disord 11:399–402. 121 Díaz-Guzmán J, Bermejo-Pareja F, Benito-León J, 107 Ondo WG, Sutton L, Dat Vuong K, et al. (2003) et al. (2008) Neurological Disorders in Central Hearing impairment in essential tremor. Neurol Spain (NEDICES) Study Group. Prevalence of 61:1093–7. stroke and transient ischemic attack in three elderly 108 Benito-León J, Louis ED, Bermejo-Pareja F: populations of central Spain. Neuroepidemiol Neurological Disorders in Central Spain (NEDICES) 30:247–53. Study Group (2007) Reported hearing impairment in 122 Bermejo-Pareja F, Benito-León J, Vega S, et al. essential tremor: a population-based case-control (2009) Consistency of clinical diagnosis of dementia study. Neuroepidemiol 29:213–17. in NEDICES: a population-based longitudinal study 109 Louis ED, Benito-León J, Vega-Quiroga S, Bermejo- in Spain. J Geriat Psychiat Neurol 22:246–55. Pareja F (2010) Cognitive and motor functional 123 Rajput AH, Offord KP, Beard CM, Kurland LT (1984) activity in nondemented community-dwelling essen- Essential tremor in Rochester, Minnesota: a 45-year tial tremor cases. J Neurol Neurosurg Psychiat study. J Neurol Neurosurg Psychiat 47:466–70. 81:997–1001. 124 Louis ED, Benito-León J, Ottman R, Bermejo-Pareja F: 110 Shahed J, Jankovic J (2007) Exploring the relation- Neurological Disorders in Central Spain (NEDICES) ship between essential tremor and Parkinson’s Study Group (2007) A population-based study disease. Parkinsonism Relat Disord 13:67–76. of mortality in essential tremor. Neurol 69: 111 Yahr MD, Orosz D, Purohit DP (2003) Co-occurrence 1982–9. of essential tremor and Parkinson’s disease: clinical 125 Haerer AF, Anderson DW, Schoenberg BS (1982) study of a large kindred with autopsy findings. Prevalence of essential tremor. Results from the Parkinsonism Relat Disord 9:225–31. Copiah County study. Arch Neurol 39:750–1. 112 Louis ED, Levy G, Mejia-Santana H, et al. (2003) 126 Inzelberg R, Mazarib A, Masarwa M, et al. (2006) Risk of action tremor in relatives of tremor-dominant Essential tremor prevalence is low in Arabic villages and postural instability gait disorder PD. Neurol in Israel: door-to-door neurological examinations. 61:931–6. J Neurol 25:1557–60. 113 Louis ED, Faust PL, Vonsattel JP, et al. (2007) 127 Tan LC, Venketasubramanian N, Ramasamy V, et al. Neuropathological changes in essential tremor: (2005) Prevalence of essential tremor in Singapore: 33 cases compared with 21 controls. Brain 13: a study on three races in an Asian country. 3297–307. Parkinsonism Relat Disord 11:233–9. 114 Ross GW, Dickson DW, Cersosimo M, et al. (2004) 128 Gulcher JR, Jónsson P, Kong A, et al. (1997) Mapping Pathological investigation of essential tremor of a familial essential tremor gene, FET1, to chromo- [Abstract]. Neurol 62(Suppl 5):A537–8. some 3q13. Nat Genet 17:84–7. 115 Benito-León J, Louis ED, Bermejo-Pareja F: 129 Higgins JJ, Loveless JM, Jankovic J, Patel PI (1998) Neurological Disorders in Central Spain Study Group Evidence that a gene for essential tremor maps to (2009) Risk of incident Parkinson’s disease and par- chromosome 2p in four families. Mov Disord kinsonism in essential tremor: a population based 13:972–7. study. J Neurol Neurosurg Psychiat 80:423–5. 130 Deng H, Le WD, Guo Y, et al. (2005) Extended study 116 Shah M, Muhammed N, Findley LJ, Hawkes CH of A265G variant of HS1BP3 in essential tremor and (2008) Olfactory tests in the diagnosis of essential Parkinson disease. Neurol 65:651–2. tremor. Parkinsonism Relat Disord 14:563–8. 131 Shatunov A, Sambuughin N, Jankovic J, et al. (2006) 117 Haehner A, Hummel T, Reichmann H (2009) Genomewide scans in North American families Olfactory dysfunction as a diagnostic marker for reveal genetic linkage of essential tremor to a region Parkinson’s disease. Expert Rev Neurother 9:1773–9. on chromosome 6p23. Brain 12:2318–31.

Albanese_c06.indd 91 12/24/2011 6:48:40 AM 92 Chapter 6

132 Stefansson H, Steinberg S, Petursson H, et al. (2009) 148 Benito-León J, Louis ED, Bermejo-Pareja F: Variant in the sequence of the LINGO1 gene confers Neurological Disorders in Central Spain (NEDICES) risk of essential tremor. Nat Genet 41:277–9. Study Group (2008) Population-based case-control 133 Tan EK, Teo YY, Prakash KM, Li R, et al. (2009) study of cigarette smoking and essential tremor. Mov LINGO1 variant increases risk of familial essential Disord 23:246–52. tremor. Neurol 73:1161–2. 149 Louis ED, Benito-León J, Bermejo-Pareja F: 134 Louis ED (2001) Etiology of essential tremor: should Neurological Disorders in Central Spain (NEDICES) we be searching for environmental causes? Mov Study Group (2008) Population-based prospective Disord 16:822–9. study of cigarette smoking and risk of incident essen- 135 Tanner CM, Goldman SM, Lyons KE, et al. (2001) tial tremor. Neurol 70:1682–7. Essential tremor in twins: an assessment of genetic 150 Bucher SF, Seelos KC, Dodel RC, et al. (1997) vs. environmental determinants of etiology. Neurol Activation mapping in essential tremor with functional 57:1389–91. magnetic resonance imaging. Ann Neurol 41:32–40. 136 Lorenz D, Frederiksen H, Moises H, et al. (2004) High 151 Jenkins IH, Bain PG, Colebatch JG, et al. (1993) concordance for essential tremor in monozygotic A positron emission tomography study of essential twins of old age. Neurol 62:208–11. tremor: evidence for overactivity of cerebellar con- 137 Louis ED, Ottman R (1996) How familial is familial nections. Ann Neurol 34:82–90. tremor?. Genetic epidemiology of essential tremor. 152 Louis ED, Shungu DC, Chan S, et al. (2002) Metabolic Neurol 46:1200–5. abnormality in patients with essential tremor: a pro- 138 Louis ED, Zheng W, Jurewicz EC, et al. (2002) ton magnetic resonance spectroscopic imaging study. Elevation of blood beta-carboline alkaloids in essen- Neurosci Lett 33:17–20. tial tremor. Neurol 59:1940–4. 153 Shin DH, Han BS, Kim HS, Lee PH (2008) Diffusion 139 Louis ED, Jiang W, Pellegrino KM, et al. (2008) tensor imaging in patients with essential tremor. Elevated blood harmane (1-methyl-9H-pyrido[3,4-b] AJNR Am J Neuroradiol 29:151–153. indole) concentrations in essential tremor. Neuro- 154 Quattrone A, Cerasa A, Messina D, et al. (2008) toxicol 29:294–300. Essential head tremor is associated with cerebellar 140 Louis ED, Zheng W, Applegate L, et al. (2005) Blood vermis atrophy: A volumetric and voxel-based harmane concentrations and dietary protein con- morphometry MR imaging study. AJNR Am J sumption in essential tremor. Neurol 65:391–6. Neuroradiol 29:1692–7. 141 Louis ED, Zheng W, Mao X, Shungu DC (2007) Blood 155 Cerasa A, Messina D, Nicoletti G, et al. (2009) harmane is correlated with cerebellar metabolism in Cerebellar atrophy in essential tremor using an auto- essential tremor: a pilot study. Neurol 69:515–20. mated segmentation method. AJNR Am J Neuroradiol 142 Pfau W, Skog K (2004) Exposure to beta-carbolines 30:1240–3. norharman and harman. J Chromatog B Analyt 156 Benito-León J, Alvarez-Linera J, Hernández- Technol Biomed Life Sci 80:115–26. Tamames JA, et al. (2009) Brain structural changes 143 Louis ED, Jurewicz EC, Applegate L, et al. (2003) in essential tremor: voxel-based morphometry at Association between essential tremor and blood lead 3-Tesla. J Neurol Sci 28:138–42. concentration. Environ Health Perspect 11:1707–11. 157 Louis ED, Vonsattel JP (2007) The emerging neuropa- 144 Dogu O, Louis ED, Tamer L, et al. (2007) Elevated thology of essential tremor. Mov Disord 23:174–82. blood lead concentrations in essential tremor: a case- 158 Axelrad JE, Louis ED, Honig LS, et al. (2008) Reduced control study in Mersin, Turkey. Environ Health Purkinje cell number in essential tremor: a postmor- Perspect 11:1564–8. tem study. Arch Neurol 2008; 65:101–7. 145 Andersen BB (2004) Reduction of Purkinje cell volume 159 Shill HA, Adler CH, Sabbagh MN, et al. (2008) in cerebellum of alcoholics. Brain Res 10:10–18. Pathologic findings in prospectively ascertained 146 Louis ED, Benito-León J, Bermejo-Pareja F (2009) essential tremor subjects. Neurol 70:1452–5. Population-based study of baseline ethanol con- 160 Louis ED (2009) Essential tremors: a family of sumption and risk of incident essential tremor. neurodegenerative disorders? Arch Neurol 66: J Neurol Neurosurg Psychiat 80:494–7. 1202–8. 147 Allam MF, Campbell MJ, Hofman A, et al. (2004) 161 Louis ED (1999) A new twist for stopping the shakes? Smoking and Parkinson’s disease: systematic review Revisiting GABAergic therapy for essential tremor. of prospective studies. Mov Disord 19:614–21. Arch Neurol 56:807–8.

Albanese_c06.indd 92 12/24/2011 6:48:40 AM Essential Tremor 93

162 Mostile G, Jankovic J (2010) Alcohol in essential 177 Ondo W, Hunter C, Vuong KD, Schwartz K, tremor and other movement disorders. Mov Disord Jankovic J (2000) Gabapentin for essential tremor: 2010 25:2274–84. a multiple-dose, double-blind, placebo-controlled 163 Louis ED, Rios E, Henchcliffe C (2010) How are we trial. Mov Disord 15:678–682. doing with the treatment of essential tremor (ET)? 178 Gironell A, Kulisevsky J, Barbanoj M, López-Villegas D, Eur J Neurol 17:882–4. Hernández G, Pascual-Sedano B (1999) A rand- 164 Zesiewicz TA, Elble R, Louis ED, et al. (2005) Practice omized placebo-controlled comparative trial of parameter: therapies for essential tremor: report of gabapentin and propranolol in essential tremor. Arch the Quality Standards Subcommittee of the American Neurol 56:475–480. Academy of Neurology. Neurol 64:2008–20. 179 Pahwa R, Lyons K, Hubble JP, et al. (1998) Double- 165 Tolosa ES, Loewenson RB (1975) Essential tremor: blind controlled trial of gabapentin in essential treatment with propranolol. Neurol 25:1041–4. tremor. Mov Disord 13:465–467. 166 Cleeves L, Findley LJ (1988) Propranolol and pro- 180 Connor GS, Edwards K, Tarsy D (2008) Topiramate pranolol-LA in essential tremor: a double blind com- in essential tremor: findings from double-blind, parative study. J Neurol Neurosurg Psychiat placebo-controlled, crossover trials. Clin Neuro- 51:379–84. pharmacol 31:97–103. 167 Findley LJ, Cleeves L, Calzetti S (1985) Primidone in 181 Ondo WG, Jankovic J, Connor GS, et al. (2006) essential tremor of the hands and head: a double Topiramate in essential tremor: a double-blind, blind controlled clinical study. J Neurol Neurosurg placebo-controlled trial. Neurol 66:672–677. Psychiat 48:911–15. 182 Blum D, Meador K, Biton V, et al. (2006) Cognitive 168 Sasso E, Perucca E, Fava R, Calzetti S (1990) effects of lamotrigine compared with topiramate in Primidone in the long-term treatment of essential patients with epilepsy. Neurol 67:400–406. tremor: a prospective study with computerized 183 Bushara KO, Malik T, Exconde RE (2005) The effect quantitative analysis. Clin Neuropharmacol 13: of levetiracetam on essential tremor. Neurol 64: 67–76. 1078–1080. 169 Gorman WP, Cooper R, Pocock P, Campbell MJ 184 Elble RJ, Lyons KE, Pahwa R (2007) Levetiracetam (1986) A comparison of primidone, propranolol, is not effective for essential tremor. Clin and placebo in essential tremor, using quantitative Neuropharmacol 30:350–356. analysis. J Neurol Neurosurg Psychiatry 49:64–68. 185 Ondo WG (2007) Zonisamide for essential tremor. 170 O’Suilleabhain P, Dewey RB Jr (2002) Randomized Clin Neuropharmacol 30:345–349. trial comparing primidone initiation schedules for 186 Song IU, Kim JS, Lee SB, et al. (2008) Effects of zon- treating essential tremor. Mov Disord 17:382–386. isamide on isolated head tremor. Eur J Neurol 171 Koller WC, Royse VL (1986) Efficacy of primidone in 15:1212–1215. essential tremor. Neurol 36:121–124. 187 Huber SJ, Paulson GW (1988) Efficacy of alprazolam 172 Koller WC, Vetere-Overfield B (1989) Acute and for essential tremor. Neurol 38:241–243. chronic effects of propranolol and primidone in 188 Biary N, Koller W (1987) Kinetic predominant essen- essential tremor. Neurol 39:1587–1588. tial tremor: successful treatment with clonazepam. 173 Ashrafi MR, Shabanian R, Zamani GR, Mahfelati F Neurol 37:471–474. (2005) Sodium Valproate versus Propranolol in pae- 189 Thompson C, Lang A, Parkes JD, Marsden CD (1984) diatric migraine prophylaxis. Eur J Paediatr Neurol A double-blind trial of clonazepam in benign essen- 9:333–338. tial tremor. Clin Neuropharmacol 7:83–88. 174 Koller WC (1983) Nadolol in essential tremor. Neurol 190 Pakkenberg H, Pakkenberg B (1986) Clozapine in 33:1076–1077. the treatment of tremor. Acta Neurol Scand 73: 175 Leigh PN, Jefferson D, Twomey A, Marsden CD 295–297. (1983) Beta-adrenoreceptor mechanisms in essential 191 Ceravolo R, Salvetti S, Piccini P, Lucetti C, Gambaccini G, tremor; a double-blind placebo controlled trial of Bonuccelli U (1999) Acute and chronic effects of metoprolol, sotalol and atenolol. J Neurol Neurosurg clozapine in essential tremor. Mov Disord 14: Psychiatry 46:710–715. 468–472. 176 Biary N, Bahou Y, Sofi MA, Thomas W, al Deeb SM 192 Opgen-Rhein C, Dettling M (2008) Clozapine- (1995) The effect of nimodipine on essential tremor. induced agranulocytosis and its genetic determi- Neurol 45:1523–1525. nants. Pharmacogenomics 9:1101–1111.

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193 Yetimalar Y, Irtman G, Kurt T, Bas¸og˘lu M (2005) of the thalamus in essential tremor. Mov Disord Olanzapine versus propranolol in essential tremor. 16:140–3. Clin Neurol Neurosurg 10:32–35. 204 Goldman MS, Ahlskog JE, Kelly PJ (1992) The 194 Kantrowitz JT, Citrome L (2008) Olanzapine: review symptomatic and functional outcome of stereotactic of safety 2008. Expert Opin Drug Saf 7:761–769. thalamotomy for medically intractable essential 195 Bushara KO, Goldstein SR, Grimes GJ Jr, Burstein tremor. J Neurosurg 76:924–8. AH, Hallett M (2004) Pilot trial of 1-octanol in essen- 205 Jankovic J, Cardoso F, Grossman RG, Hamilton WJ tial tremor. Neurol 62:122–124. (1995) Outcome after stereotactic thalamotomy for 196 Simpson DM, Blitzer A, Brashear A, et al. (2008) parkinsonian, essential, and other types of tremor. Assessment: Botulinum neurotoxin for the treat- Neurosurg 37:680–6. ment of movement disorders (an evidence-based 206 Akbostanci MC, Slavin KV, Burchiel KJ (1999) review): report of the Therapeutics and Technology Stereotactic ventral intermedial thalamotomy for the Assessment Subcommittee of the American Academy treatment of essential tremor: results of a series of 37 of Neurology. Neurol 70:1699–1706. patients. Stereotact Funct Neurosurg 72:174–7. 197 Brin MF, Lyons KE, Doucette J, et al. (2001) A rand- 207 Schuurman PR, Bruins J, Merkus MP, et al. (2002) omized, double masked, controlled trial of botuli- A comparison of neuropsychological effects of num toxin type A in essential hand tremor. Neurol thalamotomy and thalamic stimulation. Neurol 59: 56:1523–8. 1232–9. 198 Pahwa R, Busenbark K, Swanson-Hyland EF, et al. 208 Kondziolka D, Ong JG, Lee JY, et al. (2008) Gamma Botulinum toxin treatment of essential head tremor. Knife thalamotomy for essential tremor. J Neurosurg Neurol 1995:822–4. 10:111–17. 199 Warrick P, Dromey C, Irish JC, et al. (2000) 209 Young RF, Li F, Vermeulen S, Meier R (2010) Gamma Botulinum toxin for essential tremor of the voice Knife thalamotomy for treatment of essential tremor: with multiple anatomical sites of tremor: a crossover long-term results. J Neurosurg 112:1311–7. design study of unilateral versus bilateral injection. 210 Tröster AI, Fields JA, Pahwa R, et al. Neuropsycho- Laryngoscope 11:1366–74. logical and quality of life outcome after thalamic 200 Hertegard S, Granqvist S, Lindestad PA (2000) stimulation for essential tremor. Neurol 1999; Botulinum toxin injections for essential voice tremor. 53:1774–80. Ann Otol Rhinol Larnygol 10:204–9. 211 Pahwa R, Lyons KL, Wilkinson SB, et al. (1999) 201 Pahwa R, Lyons K, Koller WC (2000) Surgical treat- Bilateral thalamic stimulation for the treatment of ment of essential tremor. Neurol 54(11 Suppl 4): essential tremor. Neurol 53:1447–50. S39–44. 212 Taha JM, Janszen MA, Favre J (1999) Thalamic deep 202 Schuurman PR, Bosch DA, Bossuyt PM, et al. (2000) brain stimulation for the treatment of head, voice, A comparison of continuous thalamic stimulation and bilateral limb tremor. J Neurosurg 91:68–72. and thalamotomy for suppression of severe tremor. 213 Zhang K, Bhatia S, Oh MY, Cohen D, Angle C, N Engl J Med 34:461–8. Whiting D (2010) Long-term results of thalamic deep 203 Pahwa R, Lyons KE, Wilkinson SB, et al. (2001) brain stimulation for essential tremor. J Neurosurg Comparison of thalamotomy to deep brain stimulation 112:1271–6.

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The definition, classification lateral hand movements) and decreases or and diagnosis of tremor disappears during initiation of voluntary activity. Rest tremor can reappear after few seconds when The term tremor defines a rhythmic, oscillatory a position is maintained and then is termed movement caused by alternating or synchronous re-emergent tremor [3]. Action tremor is that which contractions of antagonist muscles. It is the most appears with voluntary muscle contraction and can common form of involuntary movement, but only be postural, isometric and kinetic. Postural tremor is a small proportion of patients with tremor look for present when maintaining a posture against gravity. medical attention. Isometric tremor appears with sustained muscle Tremor has accompanied humanity from the contraction against a rigid object, and can occur in very early beginnings. In the Ayurveda (the litera- isolation or accompanying other types of tremor. ture of the system of health used in India from Kinetic tremor can appear during any voluntary 5000 to 3000 BC) tremor seemed to be defined by movement. There is the simple kinetic tremor which the term kampa. Also in Egypt were found hiero- appears during voluntary movements not target glyphs thought to mean “trembling.” References to directed, and the intentional tremor which is triggered tremor also appear in writings of Hippocrates when the limb is reaching a target. Usually, the (460 BC), Galen (2nd century), and Galileo amplitude of intentional tremor increases when (17th century) [1]. goal-directed movements are performed and has Tremors can be classified according to their typical amplitude fluctuations. These types of phenomenology, distribution, frequency, and tremor appear when cerebellum or its pathways are etiology, but in this chapter tremors are defined and involved, and sometimes it is difficult to distinguish classified following the consensus statement of the intentional tremor and ataxia. Task-specific kinetic Movement Disorder Society on tremor [2]. tremor is defined as a kinetic tremor that increases Rest tremor is produced when the affected part is or appears predominantly or exclusively during at rest, without voluntary muscle activation and specific tasks, like primary writing tremor which fully supported against gravity. Rest tremor is the occurs when writing. An example of task-specific main feature of Parkinson’s disease (PD). In PD rest tremor can be seen in Video 7.1, which shows tremor amplitude increases with mental or motor tremor appearing in the right hand several seconds activity (counting backwards, walking, and contra after holding a handbag, in a patient otherwise

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be recommended. Drug-induced tremor usually Video 7.1 Task-specific tremor responds to beta-blockers like those induced by (“handbag” tremor) valproate or lithium; a partial response can be seen Patient complained of tremor when holding a bag. This in some peripheral neuropathic tremors and in “handbag tremor” can be seen on the video. No other neurological signs and no progression of tremor over hyperthyroidism and stress-induced tremors the past 15 years.

Tremor in Parkinson’s disease

The typical parkinsonian tremor is a rest tremor. It is an asymmetric 3–4 Hz moderate amplitude tremor that usually involves the thumb (the rhythmic http://bit.ly/sJ295N movement of this finger against the index finger is called “pill rolling”). It may involve other body parts, such as the forearm pronation/supination move- asymptomatic. An unusual variant of kinetic ments), the legs (adduction/abduction), and jaw. tremor is position-specific tremor, which appears only Head tremor is only rarely seen. in certain postures. Rest tremor usually worsens with cognitive tasks In this chapter, tremors other than essential and tremor of the hand is often brought out by tremor and psychogenic tremors that are described walking. elsewhere in this book, will be reviewed. Some patients with PD do not have tremor while in others tremor is the main symptom and domi- nates the clinical picture throughout the course of Enhanced physiological tremors the entire illness. In some of these cases the rest of the motor symptomatology may remain relatively Physiological tremor refers to the invisible mechanical mild and are sometimes called “benign tremulous vibration of a body parts present in every normal Parkinson’s disease.” They frequently have a slowly subject. It is usually apparent during action and progressive course and a low risk of dementia. while maintaining a posture, with an 8 to 12 Hz PD patients can also present with postural tremor, frequency. Enhanced physiologic tremor (EPT) is a defined as a 6–8 Hz moderate amplitude tremor visible, predominantly postural high frequency that appears immediately on stretching out the tremor occurring in absence of any neurological arms and is usually asymmetrical. Some patients disease that can cause tremor. exhibit only this kind of tremor and so can be easily This definition includes tremors of different misdiagnosed as essential tremor patients. A low- causes, typically those elicited by endogenous or amplitude and high-frequency (8–12 Hz) kinetic exogenous intoxications producing postural tremor. tremor is also present in many parkinsonian patients, Mechanical and sometimes central oscillations and is frequently quite disturbing since it interferes cause physiological tremor which can be enhanced with actions such as drinking or eating. by emotional stress, fatigue, exercise, hypoglyce- A fourth kind of tremor in PD, called re-emergent mia, thyrotoxicosis, alcohol withdrawal, pheochro- tremor, has been described. It consists of an asymmet- mocytoma, hypothermia, and a number of different ric 3–4 Hz tremor that appears on stretching out the drugs. arms after a few seconds in this new position [3]. Treatment of the cause of tremor enhancement The exact origin of the parkinsonian tremors is is the main issue in EPT, but if such cause is not still unknown and it is unclear whether intrinsic evident or eliminating it fails to suppress the tremor cellular oscillators versus network oscillators sufficiently a beta-blocker like propranolol can underlie the tremor [4].

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18F-fluorodopa PET striatal uptake does not Cerebellar tremor syndromes necessarily correlate with tremor severity, suggesting that dopamine is not the only affected neuro- The most common type of cerebellar tremor is transmitter and resting tremor is not always intention tremor, a kinetic, goal-directed, action associated with striatal lesions. In PD, the severity of tremor. The term cerebellar tremor is frequently rest tremor has been found to correlate with a used as a synonym for intention tremor, although decrease in median raphe 5-HT1A receptor binding, several clinical forms of tremor have been described as measured by 11C-WAY 100635 PET [5]. This in cerebellar disorders [16–17]. observation suggests that midbrain tegmental rather Intention tremor increases in severity as the than nigrostriatal pathology may be more relevant extremity approaches its target. When tremor only to the pathogenesis of parkinsonian rest tremor. occurs as the target is reached, it is known as terminal Antiparkinsonian medications and deep brain tremor. Classically the cerebellar tremor is elicited by stimulation (DBS) are effective treatments for PD a finger-to-nose and heel-to-shin test. This can be the postural and rest tremor. Dopa minergic drugs such only minimal sign of cerebellar dysfunction. In as L-dopa, dopamine agonists, MAO B Inhibitors, cerebellar diseases tremor can initially start with and amantadine are useful in the treatment of terminal tremor and, as the disease advances, occur tremor [6–8]. Anticholinergic agents (said to have during all action movements. Initially the extremities better effect on tremor than on akinetic–rigid symp- are affected but if it progresses it can involve axial toms) reduce the tremor but due to their side effects structures. Onset as head tremor is rare. they are considered as second line treatment and not Cerebellar tremor is usually considered as used for elderly patients. Another drug sometimes symptomatic tremor, and other signs of cerebellar recommended for refractory rest tremor in PD is clo- pathology – such as abnormalities of gait, speech zapine [9]. and ocular movements, alternate movement DBS of the ventral intermediate (VIM) thalamic disturbances, and dysmetria – can be present. nucleus was originally proposed as a treatment for Cerebellar intention tremor has an irregular tremor in PD [10] and indeed it is efficacious to frequency and amplitude and usually the oscilla- reduce rest tremor amplitude in PD patients [11]. tions are perpendicular to the direction of move- However, STN and GPi DBS are efficacious not only ment. Commonly the cerebellar tremor is described on tremor, but also on rigidity, bradykinesia, and as 3–5 Hz frequency tremor, but the frequency is postural instability, which makes these the preferred inversely proportional to limb inertia, and therefore neurosurgical targets even in patients where tremor depends on the part of the body affected. In the is the predominant symptom [12]. In a recent study upper limbs kinetic tremor has a frequency of comparing different DBS targets in PD there was a 3–8 Hz, and in lower limbs of 3 Hz. When present in trend to a better outcome of motor signs, tremor the trunk causing a partial sway, the frequency is included, in STN-DBS patients and fewer adverse 2–4 Hz. In cerebellar disorders, postural tremor can events in the GPi-DBS group [13]. Occasionally PD also occur, affecting the head and also the limbs. If patients have a rest tremor that responds poorly or the action tremor is intense, rest tremor can be seen only partially to levodopa. In such cases, even because the patient is unable to relax completely. though the lack of levodopa response could be The diagnosis of cerebellar tremor can be done considered a contraindication for surgery, DBS can when the following conditions are fulfilled: Pure or be recommended if the tremor is disabling [14]. A dominant intention tremor, unilateral or bilateral; DAT scan is warranted in such patients, in order to tremor frequency below 5 Hz (mostly below 4 Hz); confirm the diagnosis of PD, as a PD-like tremor, and postural tremor possibly present but no rest possibly related to hand dystonia, has been found tremor [2]. to be a cause of Scans Without Evidence of Another cerebellar tremor is titubation, a low- Dopaminergic Deficit (SWEDDs – see below) [15]. frequency oscillation of the trunk or the head. This

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is usually caused by lesions of the cerebellum or its authors hypothesized that improvement occurs by efferent/afferent pathways. As the amplitude often stimulating the main brainstem visceral component increases during the movement, it is a very disabling of the vagus, and the nucleus tractus solitarius, tremor [17]. which modulates central pattern generators linked Other postural and positional tremors are only to both olive complex pathway and swallowing [28]. considered to be cerebellar in origin if other cerebellar signs are present. Cerebellar tremors are due to lesions of the Dystonic tremor syndromes lateral cerebellar nuclei, the superior cerebellar peduncle, or the pathways where they are involved. Dystonia is defined as involuntary, sustained, Classically, a lesion within a cerebellar hemisphere patterned, and often repetitive contractions of or nuclei leads to an action tremor on the ipsilateral opposing muscles that cause abnormal postures, side of the body. Midline cerebellar disease may twisting movements, or both [29, 30]. Patients cause tremor of both arms, the head, and the trunk. who clinically present rhythmic dystonic move- Multiple sclerosis (MS) is the most common ments can be misdiagnosed as essential tremor or cause of the cerebellar tremor in young people and parkinsonian tremor rather than primary dystonia. can contribute to worsen a disability. Other causes A helpful clinical review has been done recently of cerebellar tremor include tumors and strokes, as by Lalli et al. [31]. well as cerebellar metabolic and neurodegenerative Dystonic tremor is defined clinically as an action diseases. (either postural or kinetic) tremor occurring in a There is no established treatment for cerebellar body part which is affected by dystonia. It is a focal tremor. Since it is a common source of disability in tremor, with irregular amplitudes and frequency, MS, several medical and surgical treatments are usually under 7 Hz, and is not seen during com- described in patients with this condition with limited plete rest [2]. Dystonic tremor can occur both in evidence of effectiveness. Isoniazide in high doses primary and secondary dystonia. Dystonic tremor [18, 19], carbamazepine [20], propranolol [21], as a component of dystonia is more obvious when gluthetimide [22], and ondansetron [23] have been the patient voluntarily attempts to move in the reported to provide some relief. Most trials were of direction opposite to the force of the dystonia. It is small population and of short duration. One patient exacerbated by muscle contraction and tends to with MS and bilateral arm tremor improved with decrease in amplitude with sensory tricks, as in intrathecal baclofen [24]. Oral cannabinoids in tremulous spasmodic torticollis or dystonic head large randomized-controlled trials appear to be tremor, which does not happen in essential tremor ineffective [25]. Tremor reduction can be obtained [32, 33]. Electromyographic recordings show that with stereotactic thalamotomy or, more recently, bursts of muscle contraction occurs in an unsyn- with thalamic deep brain stimulation. It remains chronized activity of agonists and antagonists unclear whether DBS in multiple sclerosis tremor is muscles with a variable amplitude (3–12 Hz) and superior to thalamotomy and whether patients duration (50–300 ms) [34]. These studies can be show an overall improvement in quality of life and useful in differentiating dystonic tremor from activities of daily living since studies were small and essential tremor and also in conditions where information on the long-term functional outcome tremor and dystonia are present. [35] Dystonic is scarce [26]. tremor may resemble myoclonus if accompanied Physiotherapy, tremor-reducing orthoses, and by jerk-like movements, and is not unusual to limb cooling can achieve some functional improve- find myoclonus in patients with dystonic tremor. ment in tremor on MS [27]. In fact, when 45 patients with dystonia and tremor One study described improvement in postural were studied with electromyography (EMG), cerebellar tremor and dysphagia with vagus nerve 15 (33%) had EMG features consistent with stimulation of 3 patients with multiple sclerosis. The myoclonus [36].

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Video 7.2 Dystonic head tremor Box 7.1 Drugs frequently causing tremor Head tremor in a patient with mild torticollis and • Antidopaminergic agents laterocollis, that improves with a sensory trick Neuroleptics (haloperidol, risperidone) (touching of the chin). Gastrointestinal prokinetics (metoclopramide, cimetidine) Tetrabenazine • Lithium • Antidepressants (e.g. amitriptiline, SSRIs) • Anticonvulsants (e.g. valproate) • Antiarrithmics: amiodarone, procainamide http://bit.ly/ueqF7o • Bronchodilators (salbutamol) • Metilxantines ( teophiline, caffeine) • Immunosuppressants (tacrolimus, ciclosporine, Video 7.2 illustrates a dystonic head tremor in a α-interferon) young woman with mild cervical dystonia. The • Drugs of misuse (ethanol, cocaine, MDMA, nicotine) tremor improves when the patient touches the chin • Chemotherapy drugs (tamoxifen, citarabine, (example of a “sensory trick”). Tremor associated with ifosfamide) dystonia is defined as a postural tremor that appears • Hormones: adrenaline/epinefrine, in a body part not affected by dystonia in a dystonic medroxiprogesterone patient. Its etiology remains unclear. About 25% of • Antibiotics: co-trimexazole (trimethoprim- patients with cervical dystonia have upper limb pos- sulfamethoxazole), amphotericin B tural tremor that is undistinguishable from enhan- For additional information see Morgan and Sethi [71] ced physiological tremor or essential tremor [37]. Another study compared 11 patients with ET and 19 patients with cervical dystonia (9 “ET-like” and 10 tures suggestive of dystonia such as the presence of dystonic arm tremors) and showed differences subtle hand dystonia, thumb extension tremor, between both dystonic tremors and essential tremor. lack of true bradykinesia, “flurries” or task/position- Moreover, they defined two subgroups of patients specific tremor, head tremor, and dystonic voice with cervical dystonia and arm tremor, one with a (Box 7.2) [38–40]. late and simultaneous onset of arm tremor and tor- The lack of progression in these patients to ticollis, and another with an early onset of arm develop features other than tremor and dystonia tremor and later development of torticollis. These supports the diagnosis of a non-parkinsonian groups do not correspond to the currently proposed disorder, and the different outcome of SWEDDs to clinical subdivision of “dystonic tremor”and “tremor that of patients with true PD has been reported in associated with dystonia” [35]. several longitudinal studies [40–42]. The main differences between rest parkinsonian Finally, tremor as an isolated finding is not tremor, essential tremor, and dystonic tremor can uncommon in patients with a family history of be described in Box 7.1. dystonia, especially those with a known genetic Recently, in several randomized trials of dopa- mutation [43]. Such patients have been classified minergic medication in early Parkinson disease, 4% as having dystonia gene-associated tremor. In some to 15% of patients had normal presynaptic nigros- cases, isolated tremor can be the initial manifestation triatal dopaminergic imaging. These cases have of dystonia [44]. been labeled as SWEDDs [15]. Some of these The exact physiopathology of the various patients have been described as exhibiting a form of dystonic tremors is unknown, but could be related dystonic tremor. The tremor in such cases involves to the same basal ganglia dysfunction observed in mostly the hands, and these individuals have fea- dystonia.

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neurological signs. A delay in development of Box 7.2 Metabolic and toxic causes tremor is one of the hallmarks of this clinical entity, of tremor usually from 4 weeks to 2 years after an initial Metabolic diseases Toxins insult. Stroke and trauma to the midbrain are the • Hyperthyroidism • Nicotine most common causes of Holmes tremor. Bithalamic • Hyperparathyroidism • Alcohol infarction with no midbrain structural lesions has • Hypoglycemia •CO been described as a cause of Holmes tremor [51]. • Hyponatremia • Mercury Infectious causes as brain tuberculomas [52], toxo- • Hypomagnesemia • Lead plasmosis [53, 54], and neuroparacoccidioimycosis • Hypocalcemia • Toluene [55] affecting midbrain structures have been • Vitamin BI2 deficiency • Naphthalene described. A case of HSV-1 cerebral pedunculitis as a cause of Holmes tremor has been reported [56]. • Hepatic encephalopathy • DDT Holmes tremor can be caused by midbrain • Kidney disturbances • Manganese neoplasms [57], can be part of paraneoplastic • Chronic hepatocerebral • Lindan syndrome [58, 59], and has also been described degeneration • Arsenic after radiation therapy in the midbrain region [60]. • Eosinophilia myalgia • Kepone syndrome Usually Holmes tremor results from lesions of the • Cyanide brainstem/cerebellum and thalamus, but lesions • Dioxins affecting pathways in other zones can cause the same clinical features. Pathological [61] and neuroimaging with PET studies [62] have suggested that Treatment with botulinum toxin can result in concomitant damage to the cerebellothalamic and marked improvement of dystonic tremors [45, 46]. nigrostriatal systems are needed to cause Holmes Good results have been described with deep brain tremor [63]. It is now believed that Holmes tremor stimulation of globus pallidus or ventrolateral is most likely a result of the interruption of a com- thalamus in severe generalized dystonia [47] bination of pathways in the midbrain tegmentum, Subthalamic deep brain stimulation was also namely rubro-cerebello-rubral loop, rubrospinal beneficial in several cases of tremor and dystonia fibers, dopaminergic nigrostriatal fibers, and the [48, 49]. Postural tremor associated with dystonia serotonergic brainstem telencephalic fibers [62, 64]. can respond to drugs used in essential tremor, such The treatment of Holmes tremor is generally as beta-blockers or benzodiazepines, as well as considered to be difficult, although spontaneous botulinum toxin. improvement may occur. Some patients had acceptable response to levodopa alone [62, 65] or in combination with dopaminergic drugs like cabergoline Holmes tremor or ropinirole, clonazepam [66], carbamazepine [67], or anticholinergic drugs. Two reports suggest Gordon Holmes in 1904 published a series of that levetiracetam can also be useful [68, 69]. 9 cases with an unusual combination of rest, Treatment of structural lesions responsible for postural, and kinetic tremors of the extremities and the tremor may be of help. Heran et al., for example, he suggested a lesion of red nucleus as the cause reported a case of Holmes tremor that improved [50]. This unusual tremor has been also known as after the drainage of neuroepithelial cysts [70]. The rubral tremor, midbrain tremor, thalamic tremor, treatment of infectious diseases is indicated in myorrythmia, and Benedikt syndrome. appropriate cases, but the resolution of underlying The key features of the tremor are the presence lesions may not correlate with improvement of the of rest tremor, an exacerbation by sustained tremor. posture, and a further amplification with move- Patients with longstanding tremor and stable ment. The tremor is usually accompanied by other medical illness may be considered for stereotactic

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Video 7.3 Holmes tremor Video 7.4 Drug-related tremor in a patient This patient is now 28. At age 21 she suffered from with segmental dystonia a midbrain post-traumatic hemorrhage (see video inset Patient affected of craneocervical dystonia and mild showing current MRI of the midbrain lesion). Six months head and arms postural tremor of 10 years’ duration. after the injury she developed severe postural and Tremor worsened markedly after starting citalopram resting tremor of the left upper limb, with wide (as shown in the video) and improved to “pre-citalopram” amplitude and low frequency (3–4 Hz). The videotape levels after its withdrawal (not shown). shows postural, kinetic and rest tremor of the left limb, associated to ipsilateral dysmetria at the finger-to-nose maneuver. Rest tremor is associated with mild dystonic posturing. [Video courtesy of Alberto Albanese, MD, Milan, Italy]

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Box 7.3 Main drugs that can cause tremor http://bit.ly/t2gSyX • Antidopaminergic agents Neuroleptics (haloperidol, risperidone) thalamotomy or thalamic stimulation in the Gastrointestinal prokinetics (metoclopramide, nucleus ventralis intermedius, from which signifi- cimetidine) cant tremor improvement has been reported [71]. Tetrabenazine • Lithium • Antidepressants (amitriptiline, SSRIs) Drug- and toxic-induced tremors • Anticonvulsants: Valproate • Antiarrithmics: amiodarone, procainamide Drug- and toxic-induced tremors can manifest • Bronchodilators (Salbutamol) all kind of different tremors, depending on the • Metilxantines (teofiline, caffeine) causative substance and the patient’s individual pre- • Immunosuppressants (tacrolimus, ciclosporine, disposition [72]. The list of drugs and toxins that α-interferon) induce or exacerbate tremors is growing each year. • Drugs (ethanol, cocaine, MDMA, nicotine) The most common presentation of drug-related • Chemotherapy drugs (tamoxifen, citarabine, tremor is an enhanced physiological tremor-like ifosfamide) and postural-intentional tremor similar to essential • Hormones: adrenaline/epinefrine, tremor. Drugs causing tremor include sympatho- medroxiprogesterone mimetics (bronchodilators), cardiovascular drugs • Antibiotics: co-trimexazole (trimethoprim- (amiodarone, calcium-channel blockers), mood sulfamethoxazole), amphotericin B stabilizers (lithium), antiepileptic drugs (valproate, For additional information see Morgan and Sethi [71] topiramate), or antidepressants (tryciclics and SSRI). The patients shown in Video 7.4 illustrates an example of a drug-aggravated tremor. In this case Antidopaminergic agents like neuroleptics, the patient has idiopathic craneocervical dystonia and often vestibular sedatives (flunarizine) or and longstanding postural and head tremor that prokinetic–antiemetic drugs (metoclopramide) can markedly worsens while taking citalopram. After cause rest as well as other tremors. Other dopa- the drug is withdrawn the tremor returns to its mine-depleting drugs that can cause tremor and pretreatment level (Box 7.3). parkinsonism are tetrabenazine, reserpine, and

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methyldopa. These drugs can induce rest tremor in Box 7.4 Toxics that can cause tremor drug-induced parkinsonism, rabbit syndrome when the tremor is involving mainly the lips, and tardive • Nicotine tremor. Tardive tremor is a rare tremor seen after • Alcohol the long-term intake of antidopaminergic drugs, •CO and is mainly postural with a 3–5 Hz frequency, • Mercury although rest and intentional tremor can be pre- • Lead sent. For these tremors tetrabenazine or clozapine • Toluene can be useful [73]. Alcohol, known to suppress • Naphthalene essential and other forms of tremor [74], can also • DDT induce tremor upon withdrawal following chronic • Manganese ingestion. This alcohol withdrawal tremor might be • Lindan a variant of the enhanced physiological tremor • Arsenic caused by anxiety or emotional stress, but it is reported that withdrawal tremor had a higher • Kepone amplitude compared to patients with anxiety or • Cyanide stress-related tremors [75]. Chronic alcoholism • Dioxins results in cerebellar degeneration, where a 3 Hz leg For additional information see Morgan and Sethi [71] tremor and upper extremity have been demonstrated [76]. Alcohol abuse alone or combined with common [83] and the association of the potential hepatic encephalopathy can cause various types tremor-inducing effect of some of these toxins has of tremor, asterixis, and cerebellar dysfunction. long been known. Chronic exposure to heavy Alcohol withdrawal is occasionally complicated by metals, like mercury and lead, cause mainly transient basal ganglia dysfunction manifested by postural tremor and ataxia; manganese exposure, parkinsonism or chorea [77]. These syndromes are instead, can result in a typical rest tremor and distinct from the movement disorders complicating parkinsonism. Insecticides and herbicides, like acquired hepatolenticular degeneration occurring kepone, DDT, dioxin and methylbromide, are in some chronic alcoholics [78]. known causes of tremor and other neurological Smoking cigarettes and nicotine has been asso- disturbances (Box 7.4). Toluene is also a solvent by ciated with increased tremor amplitude in normal which chronic exposure causes postural tremor, individuals [79]. Caffeine has been reported that besides visual impairment, nystagmus, and pyrami- can induce a new onset of tremor or exacerbate dal signs [84]. The treatment in drug- and toxic- a previously existing tremor [80]. Caffeine trem- induced tremors is to avoid exposure to them and oric effect was thought for a long time to result sometimes, if that is not enough, drugs for essential from its inhibition of phosphodiesterase, stimula- tremor can be useful. When tremor occurs in a tion of catecholamine release and through its reasonable time-frame following ingestion of direct effect on muscle. In one survey, however, a particular food or beverage, it is considered to be where doses of 150 and 450 mg/day of caffeine a food-induced tremor which can take the form of an were given to subjects, no increase on tremor was enhanced physiological tremor, and can precipitate shown if patients followed a normal diet. Only the or increase essential tremor, cerebellar tremor, or association of caffeine and starving increased tremor associated to peripheral neuropathy [85]. postural hand tremor [81]. Measuring tremor with an accelerometer after 375 mg of caffeine did not increase physiologic, essential tremor or parkinso- Orthostatic tremor nian tremor at 1, 2, or 3 hours after intake [82]. There are more than 850 neurotoxic chemicals Orthostatic tremor (OT) is characterized by a subjective found in workplaces, of which 65 are the most feeling of unsteadiness on standing with a rapid

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(13 to 18 Hz) tremor of the legs that disappears Palatal tremor when walking or sitting. At this frequency, the tremor is best appreciated by the examiner placing Palatal tremor (PT), also referred to as palatal his hands on the standing patient’s legs, whereas a myoclonus, is characterized by rhythmic move- noise like a helicopter can be heard by placing a ments of the soft palate, usually vertical oscillations stethoscope on the thighs. The diagnosis is based on at 1–3Hz. There are two forms of PT or palatal electromyographical findings of a unique tremor myoclonus, symptomatic (SPT) and essential frequency and high coherence between antagonis- (EPT), differing clinical and pathophysiologically. tic and contralateral muscle groups. OT is generally An objective ear click can be found mainly in considered an idiopathic disorder as brain imag- essential palatal tremor whereas in symptomatic PT ing and other investigations are usually normal. about a 30% of patients can present pendular nys- Only rarely has OT been described in patients tagmus and in variable proportions ataxia and with pontine lesions [86], aqueductal stenosis, or dysarthria. relapsing polyneuropathy [87], cerebellar degen- In a series of 287 patients with PT, about a quar- eration, or following head trauma. Orthostatic ter of the cases were essential (tensor veli palatini tremor-plus has been described when additional contraction) whereas the rest were symptomatic neurological features are found, like parkinsonism, (levator veli palatini contraction) due mostly to tardive dyskinesias or RLS [88]. In PD there two lesions in the triangle of Guillain and Mollaret different types of orthostatic tremor that have been (dentate nucleus, red nucleus and inferior olivary described. One type consists of a slow OT (range nucleus). The etiology in about 70% of cases is a 4–7 Hz) that is thought to be related to a dopamine vascular infarct [97–98]. deficiency which improves with L-Dopa or a MRI of the brainstem with proton density or DA-agonist. A fast (13–18 Hz) OT that is not thought T2-weighted images can show a hyperintense signal to be related to dopamine deficiency and improves in the region of the inferior olive that can represent with clonazepam has also been described [89–90]. the hypertrophic degeneration of these structures A recent report describes a case of slow OT in a found in the autopsy of patients with symptomatic patient with multiple sclerosis with a lesion in the palatal tremor. It is thought that the lesion of the pedunculus cerebellaris medius with bad response dentato-olivary pathway causes the cells of the to treatment [91]. inferior olive to synchronize. This rhythm is then Idiopathic OT is thought to be caused by a central carried through the inferior cerebellar peduncle to oscillator which, based on the findings in secondary the contralateral cerebellar hemisphere and, thus, cases, would be located in the posterior fossa [88]. interferes with physiological regulations producing 15 In primary cases, studies with H2 O-PET indicate the hyperkinesia of brainstem muscles. involvement of the cerebellum, basal ganglia, and Essential palatal tremor has no currently cortex [92]. There is no significant difference in demonstrable cause, and no accompanying physi- 123I-FP-CIT SPECT findings between controls and cal or radiological signs, and is almost certainly patients with longstanding OT [93]. heterogeneous. Clonazepam is the most used drug but obtains a There are some studies that support a central partial response. Other antitremoric drugs such as origin, a mechanical/peripheral origin, a voluntary propranolol or primidone have a little effect. In a movement, and even a psychogenic disorder as recent double-blind placebo-controlled crossover responsible for this problem [99]. study of 6 patients with gabapentin, a symptomatic In some cases, injection of botulinum toxin into benefit has been reported [94]. L-Dopa can improve the tensor veli palatini can be useful to reduce the OT associated with PD. Recent reports suggest that ear click. If there are associated abnormal eye patients with severe OT can be successfully treated movements, injection of botulinum toxin in with bilateral or unilateral thalamic (VIM, ventralis these muscles can be useful too. In these last cases intermedius nucleus) DBS [95–96]. responses to clonazepam are described.

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Task-specific tremors Stroke-induced tremor

Task-specific tremor is a rare type of tremor with Strokes in midbrain, superior cerebellar peduncle, unknown pathophysiology. The most studied task- and cerebellum can be frequently followed by specific tremor is primary writing tremor. In clinical tremor, but in other locations are extremely practice there are other task-specific tremors, most uncommon. In a review of 62 cases of thalamic and of them in musicians or sportspeople who perform subthalamic lesions no case of isolated tremor was very precise repetitive motor tasks [100]. found [111]. Isolated tremor secondary to stroke is Primary writing tremor is defined as a writing very rare, and is usually associated with other neu- difficulty caused by tremor triggered by active rological signs. Intention tremor with cerebellar pronation of the forearm. It can be divided into a signs and Holmes tremor are the types more pure task-induced tremor (that appears only during frequently reported, but irregular, low-amplitude writing; type A) and another tremor present not and high-frequency tremors – some associated with only during the writing action but also when the dystonia after thalamic lesions – have also been patient’s hand takes the position used in writing described [112]. Immediate onset after stroke has (positionally sensitive, type B) [101]. been described, with a better prognosis than late This tremor has a frequency between 5 and –7 Hz, onset, but stroke-related tremor usually begins appears with pronosupination of the hand, and is weeks to months after insult, with secondary asymmetrical. Sometimes postural tremor or dysto- neuronal changes probably being involved. nia (“mirror dystonia”) in the contralateral hand or In the management of stroke-induced tremor the coexisting dystonia can be observed, suggesting a associated neurological signs must be considered. relationship between task-specific tremor and In general, in stroke-induced tremor pharmacolog- task-specific-dystonia [102]. In neurophysiological ical treatment is disappointing when there is a studies, alternating tremor in agonist and antago- cerebellar component. A case with yes–yes head nists muscles or co-contraction of both muscles can tremor after a right occipital and bilateral cerebellar be demonstrated, the latter again suggesting a stroke with response to botulinum toxin A has relationship to dystonia [103]. been reported [113]. In spite of being the most studied task-specific tremor, even today there is no unanimous opinion about the origin of primary writing tremor and it Tremor in systemic disorders could be classified as a tremulous form of focal dystonia (writer’s cramp, WC), a form of essential Tremor is a well-known symptom of thyrotoxicosis, tremor, or a different and primary disorder. Some and is indistinguishable from enhanced physiologi- studies point to these differences, such as cal tremor clinically or by EMG. Moderate correla- Ljubisavljevic et al. who describe distinct changes tion between tremor intensity and thyroid hormone in central inhibition in PWT compared to those levels have been reported [114]. Treatment of previously reported on writer’s cramp [104]. These thyrotoxicosis results in rapid improvement. results differ from those seen in studies with PET, In hypothyroidism, tremor associated with where the increased activation of premotor cortical cerebellar signs can be seen. Tremor is a common and cerebellar areas coincide in PWT, WC, and ET manifestation in Wilson disease, being the most [105, 106]. frequent sign in several series, but it is not so Propranolol and injections of botulinum toxin common as the initial symptom. Postural type have been tested for this disease with generally tremor is the most prevalent; it usually starts in one mixed results. Some patients have a good response limb and may eventually spread to the whole body. to physiotherapy and rehabilitation [107]. In severe It may vary from mild rest tremor in fingers to cases, thalamotomy or thalamic stimulation might coarse tremor in all members, trunk, and cephalic be an option [108–110]. segment. “Wing beating tremor” is one of the

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Highly active antiretroviral therapy (HAART) has Box 7.5 Metabolic disorders that been shown to be effective in the reduction of can cause tremor neurologic complications of HIV infection, and • Hyperthyroidism resolution of parkinsonism with normalization of • Hyperparathyroidism CD4 count in an AIDS patient with HAART alone • Hypoglycemia has been reported [119]. • Hyponatremia In certain autoimmune diseases tremor can be a • Hypomagnesemia neurological finding, like bilateral tremor in a • Hypocalcemia patient with antiphospholipid syndrome secondary • Vitamin BI2 deficiency to systemic lupus erythematosus [120]. Tremor as • Hepatic encephalopathy an early manifestation of systemic lupus erythema- • Kidney disturbances tosus that disappeared with corticosteroid treatment has also been reported. • Chronic hepatocerebral degeneration Isolated tremor in paraneoplastic syndromes is • Eosinophilia myalgia syndrome not common, but there is a report of a patient who For additional information see Morganand Sethi [71] developed severe orthostatic tremor (OT) as the sole presenting anti-Hu paraneoplastic manifesta- characteristic symptoms of Wilson disease and tion of small cell lung cancer (SCLC) [121]. Recently consists of a proximal tremor of high amplitude, orolingual tremor as a presentation of anti-Hu better seen when the patients stretch the arms. paraneoplastic syndrome has been reported [122]. Lesions in dentato-rubro-thalamic tracts are Other systemic diseases, causing liver dysfunc- probably involved in the genesis of this tremor tion, like cirrhosis, hemochromatosis [123], and (Box 7.5). variegate phorphyria [124] have been described as In a retrospective study at tertiary centers with causes of tremor. Metabolic disorders involving HIV patients, a 2–3% incidence of clinically relevant renal function or ions can also cause tremor. movement disorders was reported [115]. Tremor in AIDS patients may be seen as part of parkinsonian syndrome or may occur as an isolated phenome- Post-traumatic tremor non. This typically occurs as a mild bilateral postural tremor, but often is symmetrical and may occur at Tremor can be caused by traumatic lesion in several rest. Tremor is common in patients with HIV- anatomic locations, from cerebral cortex, basal associated dementia, ranging from 5.5 to 44% of ganglia, thalamus, midbrain, and cerebellum to patients [116], but can also occur in early stages of peripheral nerves. Other neurological findings are HIV infection in the absence of a central nervous usually associated, but CT/MRI may not show such system disorder [117]. Holmes tremor has been lesions which can occur at a cellular level. described in AIDS patients as a result of opportun- In cases of minor head trauma post-traumatic istic lesions in the midbrain, such as tuberculosis, tremor is generally transient and non-disabling, toxoplasmosis, or lymphoma. Drug-induced tremor characterized like an enhanced physiologic or may be seen as part of parkinsonian syndrome due essential tremor [125]. In severe head injury, post- to antiemetic or neuroleptic drugs. Trimetoprim- traumatic tremor is usually a delayed sequelae, and sulfametoxazole can cause rest tremor or bilateral can appear a few days to months after injury. The high-frequency, low-amplitude postural and kinetic most common form in these cases is a combination tremor [118]. In the management of isolated of kinetic and rest tremor or Holmes tremor [126]. tremor or parkinsonism in HIV patients, recogni- Post-traumatic parkinsonism with rest tremor tion of possible opportunistic infections and drugs caused by repeated head trauma has been described, causing tremor is important, and it can improve as in the “punch drunk” syndrome or pugilistic with the treatment of the underlying conditions. encephalopathy seen in boxers [127].

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Tremor resulting from peripheral nerve injuries Neuropathic tremor is rare, and is usually associated with dystonia or reflex sympathetic dystrophy (RSD). In a series of Neuropathic tremor refers to tremor occurring in RSD, a distal tremor with a 7.2 Hz frequency was association with peripheral neuropathies. Most observed that disappeared when RSD was treated extensively documented is the tremor occurring in [128]. Also tremor of the 4th and 5th fingers immune-mediated demyelinating and in heredi- secondary to ulnar nerve entrapment in Guyon’s tary peripheral neuropathies, which are the most canal has been reported, with disappearance after frequent neuropathic tremors. surgery in a typist subjected to repeated hand In some patients with Guillain–Barré syndrome, movement [129]. specially the rare relapsing form [135, 136], and The mechanisms underlying post-traumatic also in chronic inflammatory demyelinating poly- tremor are not entirely known, but functional neuropathy (CIDP), tremor has been described changes in afferent neuronal input to the spinal [137]. Tremor in CIDP may appear during a relapse cord and secondary affection of higher brainstem and disappear during remission, and can subside and subcortical centers are probably involved [130]. with immunomodulating treatment [137]. Midbrain lesions are an identified hallmark of In Charcot-Marie-Tooth disease, the presence of diffuse axonal injury, a frequent finding in rapid tremor is known as Roussy-Levy syndrome and is deceleration trauma. Initial presentation of diffuse currently included in the hereditary motor sensory axonal injury is generalized brain edema, and in a neuropathy (HMSN) type I. In HMSN I tremor is series of severe head injuries the presence of kinetic present in 40%, and consists of a postural tremor tremor correlated to the presence of brain edema with rest component but without other parkinson- on initial CT [126]. ism features. It involves mostly the hands, and Tremor in post-traumatic parkinsonism stems response to alcohol can be seen [138]. from presumed midbrain injury as a result of shear- Another neuropathy associated with tremor is ing forces produced by repeated rotational impacts the demyelinating neuropathy associated with of the head [131]. monoclonal protein, usually IgM. This monoclonal Spontaneous remission of post-traumatic head protein typically represents the monoclonal gam- injury tremor is possible, resolving within 1 year mopathy of undetermined significance (MGUS). after onset [132]. In a series with a follow-up of This entity is also known as CIDP-MGUS, IgM 3.9 years after severe head injury, over half of neuropathy, or antimyelin associated glycoprotein the patients recovered spontaneously from (MAG) neuropathy. Its clinical features are: male tremor [126]. predominance, older age of onset, slow progres- Whenever and wherever possible, treatment of sion, predominantly sensory manifestations like the cause is often beneficial, like in compression sensory ataxia, and poor response to immunomod- neuropathy and reflex sympathetic dystrophy. If no ulating therapies [139]. Upper extremity tremor obvious cause besides a previous traumatism can be occurs in 40–90% of patients with IgM demyelinat- found, or other neurological conditions are associ- ing polineuropathy, and it is mainly a mild postural ated, pharmacological therapies are less beneficial. tremor more distal than proximal, with a frequency Clonazepam, carbamazepine, levodopa, proprano- of 3–6 Hz. Tremor severity has no relationship to lol alone or in combination with valproic acid can the severity of motor or sensory signs [137, 140]. be tried. Botulinum toxin injections may be helpful Tremor may also occur in certain forms of to relieve the tremor temporarily, but the secondary inherited motor neuron disease such as spinal weakness of arm muscles may limit the usefulness muscular atrophy and X-linked bulbospinal atro- of this treatment. phy (Kennedy disease). In Kennedy disease more Thalamotomy and, lately, thalamic deep brain than 80% of patients had postural tremor [141]. stimulation can be useful in severe post-traumatic Hypoesthesia, proximal weakness, gynecomastia, tremor [133, 134]. and facial/tongue fasciculations can help to the

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diagnosis of the last one. Tremor can be seen in review: report of the Quality Standards Subcommittee peripheral neuropathies associated with diabetes of the American Academy of Neurology. Neurol 2002; mellitus, uremia, and treatment with amiodarone. 58(1):11–17. Peripheral neuropathies cause slow nerve 7 Horstink M, et al. Review of the therapeutic manage- conduction which increases the delay of a stretch ment of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies reflex response, leading to enhancement of the and the Movement Disorder Society-European tremor. A central component can also be involved Section. Part I: early (uncomplicated) Parkinson’s in the pathophysiology of tremor associated with disease. Eur J Neurol 2006; 13(11):1170–85. peripheral neuropathy, despite normal anatomical 8 Horstink M, et al. Review of the therapeutic manage- neuroimaging. Bain et al. suggested that tremor in ment of Parkinson’s disease. Report of a joint task patients with IgM paraproteinaemic neuropathy is force of the European Federation of Neurological due to a specific cerebellar functional disturbance Societies (EFNS) and the Movement Disorder caused by the delayed and distorted afferent input Society-European Section (MDS-ES). Part II: late rather than to absence of sensory input [142]. (complicated) Parkinson’s disease. Eur J Neurol 2006; Neuropathic tremor is often mild but if bother- 13(11):1186–202. some or interferes with activities, therapies such as 9 Bonuccelli U, et al. Clozapine in Parkinson’s disease tremor. Effects of acute and chronic administration. propranolol or primidone, used for essential tremor, Neurol 1997; 49(6):1587–90. can be an option. Tremor in CIDP and also in IgM 10 Benabid AL, et al. Combined (thalamotomy and demyelinating neuropathy does not respond to stimulation) stereotactic surgery of the VIM thalamic immunomodulating therapies and modest improve- nucleus for bilateral Parkinson disease. Appl ment from propranolol and clonazepam have been Neurophysiol 1987; 50(1–6):344–6. described [137, 142]. Two case reports suggest that 11 Pollak P, et al. Long-term effects of chronic stimulation pregabaline could be useful to improve tremor in of the ventral intermediate thalamic nucleus in both neuropathies, IgM neuropathy, and CIDP different types of tremor. Adv Neurol 1993; 60: [143, 144]. 408–13. In few selected cases of severe neuropathic 12 Sturman MM, et al. Effects of subthalamic nucleus tremor, a beneficial effect of deep brain stimulation stimulation and medication on resting and postural tremor in Parkinson’s disease. Brain 2004; 127(Pt 9): of the ventral intermediate thalamic nucleus has 2131–43. been described [145–147]. 13 Moro E, et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson’s References disease. Mov Disord 2010; 25(5):578–86. 14 Bronstein JM, et al. Deep Brain Stimulation for 1 Louis ED. Essential tremor. Arch Neurol 2000; Parkinson Disease: An Expert Consensus and Review 57(10):1522–4. of Key Issues. Arch Neurol 2010. 2 Deuschl G, Bain, Brin M. Consensus statement of the 15 Fahn S. Does levodopa slow or hasten the rate of pro- Movement Disorder Society on Tremor. Ad Hoc gression of Parkinson’s disease? J Neurol 2005; 252 Scientific Committee. Mov Disord 1998; 13 Suppl Suppl 4; IV37–42. 3:2–23. 16 Hallett M, Massaquoi SG. Physiologic studies of dys- 3 Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor metria in patients with cerebellar deficits. Can J of Parkinson’s disease. J Neurol Neurosurg Psychiat Neurol Sci 1993; 20 Suppl 3:S83–92. 1999; 67(5):646–50. 17 Fahn S, Cerebellar tremor: clinical aspects, in 4 Bergman H, Deuschl G. Pathophysiology of Parkinson’s Movement disorders: tremor. Findley L, Capildeo R, disease: from clinical neurology to basic neuroscience Editor. 1984, Macmillan: London. pp 355–364. and back. Mov Disord 2002;17 Suppl 3(3):S28–40. 18 Hallett M, et al. Controlled trial of isoniazid therapy 5 Doder M, et al. Tremor in Parkinson’s disease and sero- for severe postural cerebellar tremor in multiple tonergic dysfunction: an 11C-WAY 100635 PET study. sclerosis. Neurol 1985; 35(9):1374–7. Neurol 2003; 60(4):601–5. 19 Bozek CB, et al. A controlled trial of isoniazid therapy 6 Miyasaki JM, et al. Practice parameter: initiation of for action tremor in multiple sclerosis. J Neurol 1987; treatment for Parkinson’s disease: an evidence-based 234(1):36–9.

Albanese_c07.indd 107 12/24/2011 6:49:44 AM 108 Chapter 7

20 Sechi GP, et al. Treatment of cerebellar tremors with 36 Jedynak CP, Bonnet AM, Agid Y. Tremor and idiopathic carbamazepine: a controlled trial with long-term dystonia. Mov Disord 1991; 6(3):230–6. follow-up. Neurol 1989; 39(8):1113–5. 37 Deuschl G, et al. Hand tremor in patients with spas- 21 Koller WC, Pharmacologic trials in the treatment of modic torticollis. Mov Disord 1997; 12(4):547–52. cerebellar tremor. Arch Neurol 1984; 41(3):280–1. 38 Bajaj NP, et al. Accuracy of clinical diagnosis in 22 Aisen ML, et al. Glutethimide treatment of disabling tremulous parkinsonian patients: a blinded video action tremor in patients with multiple sclerosis and study. J Neurol Neurosurg Psychiat 2010. traumatic brain injury. Arch Neurol 1991; 48(5):513–5. 39 Schwingenschuh P, et al. Distinguishing SWEDDs 23 Rice GP, et al. Ondansetron, a 5-HT3 antagonist, patients with asymmetric resting tremor from improves cerebellar tremor. J Neurol Neurosurg Parkinson’s disease: a clinical and electrophysiological Psychiat 1997; 62(3):282–4. study. Mov Disord 2010; 25(5):560–9. 24 Weiss N, et al. Attenuation of cerebellar tremor with 40 Schneider SA, et al. Patients with adult-onset dystonic implantation of an intrathecal baclofen pump: the role tremor resembling parkinsonian tremor have scans of gamma-aminobutyric acidergic pathways. Case without evidence of dopaminergic deficit (SWEDDs). report. J Neurosurg 2003; 99(4):768–71. Mov Disord 2007; 22(15):2210–5. 25 Zajicek J, et al. Cannabinoids for treatment of spasticity 41 Marshall VL, et al. Successful antiparkinsonian medi- and other symptoms related to multiple sclerosis cation withdrawal in patients with Parkinsonism and (CAMS study): multicentre randomised placebo- normal FP-CIT SPECT. Mov Disord 2006; 21(12): controlled trial. Lancet 2003; 362(9395):1517–26. 2247–50. 26 Yap L, Kouyialis A, Varma TR, Stereotactic neurosur- 42 Jennings DL, et al. (123I) beta-CIT and single-photon gery for disabling tremor in multiple sclerosis: thalam- emission computed tomographic imaging vs clinical otomy or deep brain stimulation? Br J Neurosurg evaluation in Parkinsonian syndrome: unmasking an 2007; 21(4):349–54. early diagnosis. Arch Neurol 2004; 61(8):1224–9. 27 Koch M, et al. Tremor in multiple sclerosis. J Neurol 43 Deng H, Le W, Jankovic J. Genetics of essential tremor. 2007; 254(2):133–45. Brain 2007; 130(Pt 6):1456–64. 28 Marrosu F, et al. Vagal nerve stimulation improves 44 Rivest J, Marsden CD. Trunk and head tremor as cerebellar tremor and dysphagia in multiple sclerosis. isolated manifestations of dystonia. Mov Disord 1990; Mult Scler 2007; 13(9):1200–2. 5(1):60–5. 29 Jankovic J, Fahn S. Dystonic disorders, in Parkinson’s 45 Jankovic J, Schwartz K. Botulinum toxin treatment of disease and movement disorders, E. Tolosa, Editor. 2007, tremors. Neurol 1991; 41(8):1185–8. Lippincott Williams & Wilkins: Philadelphia. pp 331–357. 46 Brin MF, et al. A randomized, double masked, 30 Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; controlled trial of botulinum toxin type A in essential 24(12):1725–31. hand tremor. Neurol 2001; 56(11):1523–8. 31 Lalli S, Albanese A. The diagnostic challenge of 47 Coubes P, et al. Treatment of DYT1-generalised dysto- primary dystonia: evidence from misdiagnosis. Mov nia by stimulation of the internal globus pallidus. Disord 2010; 25(11):1619–26. Lancet 2000; 355(9222):2220–1. 32 Masuhr F, et al. Quantification of sensory trick impact 48 Kitagawa M, et al. Deep brain stimulation of subtha- on tremor amplitude and frequency in 60 patients lamic area for severe proximal tremor. Neurol 2000; with head tremor. Mov Disord 2000; 15(5):960–4. 55(1):114–16. 33 Jankovic J, Mejia N. Dystonic tremor. In Handbook 49 Chou KL, et al. Bilateral subthalamic nucleus deep of Essential Tremor and Other Tremor Disorders. brain stimulation in a patient with cervical dystonia K. Lyons and P. Rahwa, Editors. 2005, Taylor and and essential tremor. Mov Disord 2005; 20(3): Francis Group: Boca Raton, FL. pp 221–226. 377–80. 34 Lucking H, Hellwig B. Uncommon tremors, in 50 Holmes G. On certain tremors in organic cerebral Movement disorders: Handbook of Clinical lesions. Brain 1904; 27:327–375. Neurophysiology, M. Hallett, Editor. 2003, Elsevier: 51 Tan H, et al. Rubral tremor after thalamic infarction in Amsterdam, Boston. pp 397–415. childhood. Pediatr Neurol 2001; 25(5):409–12. 35 Munchau A, et al. Arm tremor in cervical dystonia 52 Benedikt M. in The Classical Brain Stem Syndromes, differs from essential tremor and can be classified by C.C. Thomas, Editor. 1971, Springfield. pp 103–109. onset age and spread of symptoms. Brain 2001; 53 Koppel BS, Daras M. “Rubral” tremor due to midbrain 124(Pt 9):1765–76. Toxoplasma abscess. Mov Disord 1990; 5(3):254–6.

Albanese_c07.indd 108 12/24/2011 6:49:44 AM Other Tremors 109

54 Pezzini A, et al. Holmes’ tremor following midbrain for medically intractable essential tremor. J Neurosurg Toxoplasma abscess: clinical features and treatment of a 1992; 76(6):924–8. case. Parkinsonism Relat Disord 2002; 8(3):177–80. 72 Morgan JC, Sethi KD. Drug-induced tremors. The 55 Teive HA, et al. Holmes’ tremor and neuroparacoc- Lancet Neurol 2005; 4(12):866–876. cidioidomycosis: a case report. Mov Disord 2002; 73 Stacy M, Jankovic J. Tardive tremor. Mov Disord 17(6):1392–4. 1992; 7(1):53–7. 56 Roselli F, et al. Holmes’ tremor associated to HSV–1 74 Rajput AH, et al. Relative efficacy of alcohol and pro- cerebral pedunculitis: a case report. Mov Disord 2007; pranolol in action tremor. Can J Neurol Sci 1975; 22(8):1204–6. 2(1):31–5. 57 Leung GK, Fan YW, Ho SL. Rubral tremor associated 75 Milanov I, Toteva S, Georgiev D. Alcohol withdrawal with cavernous angioma of the midbrain. Mov Disord tremor. Electromyogr Clin Neurophysiol 1996; 1999; 14(1):191–3. 36(1):15–20. 58 Golbe LI, Miller DC, Duvoisin RC. Paraneoplastic 76 Koller W, et al. Tremor in chronic alcoholism. Neurol degeneration of the substantia nigra with dystonia 1985; 35(11):1660–2. and parkinsonism. Mov Disord 1989; 4(2):147–52. 77 Mostile G, Jankovic J. Alcohol in essential tremor and 59 Simonetti F, et al. Paraneoplastic “rubral” tremor: a other movement disorders. Mov Disord 2010. case report. Mov Disord 1998; 13(3):612–4. 78 Ferrara J, Jankovic J. Acquired hepatocerebral degen- 60 Pomeranz S, Shalit M, Sherman Y. “Rubral” tremor eration. J Neurol 2009; 256(3):320–32. following radiation of a pineal region vascular hamar- 79 Shiffman SM, et al. Effects of cigarette smoking and toma. Acta Neurochir (Wien) 1990; 103(1–2):79–81. oral nicotine on hand tremor. Clin Pharmacol Ther 61 Masucci EF, Kurtzke JF, Saini N. Myorhythmia: a 1983; 33(6):800–5. widespread movement disorder. Clinicopathological 80 Jankovic J, Fahn S. Physiologic and pathologic trem- correlations. Brain 1984; 107 (Pt 1):53–79. ors. Diagnosis, mechanism, and management. Ann 62 Remy P, et al. Peduncular ‘rubral’ tremor and Intern Med 1980; 93(3):460–5. dopaminergic denervation: a PET study. Neurol 1995; 81 Wharrad HJ, et al. The influence of fasting and of 45(3 Pt 1):472–7. caffeine intake on finger tremor. Eur J Clin Pharmacol 63 Deuschl G, et al. Function of the cerebellum in 1985; 29(1):37–43. Parkinsonian rest tremor and Holmes’ tremor. Ann 82 Koller W, Cone S, Herbster G. Caffeine and tremor. Neurol 1999; 46(1):126–8. Neurol 1987; 37(1):169–72. 64 Hopfensperger KJ, Busenbark K, Koller WC. Midbrain 83 Leads from the MMWR. Leading work-related diseases tremor, in Handbook of Tremor Disorders, Findley Lj and injuries–United States. JAMA 1986; 255(12):1552, and W.C. Koller, Editors. 1995, Marcel Dekker: New 1555, 1559. York. pp 455–459. 84 Dick F, et al. Neurological deficits in solvent-exposed 65 Findley LJ, Gresty MA. Suppression of “rubral” painters: a syndrome including impaired colour vision, tremor with levodopa. Br Med J 1980; 281(6247):1043. cognitive defects, tremor and loss of vibration sensa- 66 Biary N, et al. Post-traumatic tremor. Neurol 1989; tion. QJM 2000; 93(10):655–61. 39(1):103–6. 85 Manyam BV. Uncommon forms of tremor, in Movement 67 Harmon RL, Long DF, Shirtz J. Treatment of post- Disorders: neurologic principles and practice, RL Watts traumatic midbrain resting-kinetic tremor with com- and WC Koller, Editors. 2004, McGraw-Hill. pp 459–480. bined levodopa/carbidopa and carbamazepine. Brain 86 Benito-Leon J, et al. Symptomatic orthostatic tremor Inj 1991; 5(2):213–8. in pontine lesions. Neurol 1997; 49(5):1439–41. 68 Ferlazzo E, et al. Successful treatment of Holmes tremor 87 McManis PG, Sharbrough FW. Orthostatic tremor: by levetiracetam. Mov Disord 2008; 23(14):2101–3. clinical and electrophysiologic characteristics. Muscle 69 Striano P, et al. Dramatic response to levetiracetam in Nerve 1993; 16(11):1254–60. post-ischaemic Holmes’ tremor. J Neurol Neurosurg 88 Gerschlager W, et al. Natural history and syndromic Psychiat 2007; 78(4):438–9. associations of orthostatic tremor: a review of 41 70 Heran NS, et al. Neuroepithelial cysts presenting with patients. Mov Disord 2004; 19(7):788–95. movement disorders: two cases. Can J Neurol Sci 89 Leu-Semenescu S, et al. Myoclonus or tremor in 2003; 30(4):393–6. orthostatism: an under-recognized cause of unsteadi- 71 Goldman MS, Ahlskog JE, Kelly PJ. The symptomatic ness in Parkinson’s disease. Mov Disord 2007; and functional outcome of stereotactic thalamotomy 22(14):2063–9.

Albanese_c07.indd 109 12/24/2011 6:49:44 AM 110 Chapter 7

90 Thomas A, et al. Dopa-responsive pseudo- orthostatic 108 Ohye C, et al. Primary writing tremor treated by tremor in parkinsonism. Mov Disord 2007; stereotactic selective thalamotomy. J Neurol 22(11):1652–6. Neurosurg Psychiat 1982; 45(11):988–97. 91 Baker M, et al. Slow orthostatic tremor in multiple 109 Minguez-Castellanos A, et al. Primary writing tremor sclerosis. Mov Disord 2009; 24(10):1550–3. treated by chronic thalamic stimulation. Mov Disord 92 Wills AJ, et al. A positron emission tomography 1999; 14(6):1030–3. study of primary orthostatic tremor. Neurol 1996; 110 Racette BA, et al. Thalamic stimulation for primary 46(3):747–52. writing tremor. J Neurol 2001; 248(5):380–2. 93 Trocello JM, et al. Dopaminergic deficit is not the rule in 111 Lee MS, Marsden CD. Movement disorders following orthostatic tremor. Mov Disord 2008; 23(12):1733–8. lesions of the thalamus or subthalamic region. Mov 94 Rodrigues JP, et al. Blinded placebo crossover study Disord 1994; 9(5):493–507. of gabapentin in primary orthostatic tremor. Mov 112 Ferbert A, Gerwig M. Tremor due to stroke. Mov Disord 2006; 21(7):900–5. Disord 1993; 8(2):179–82. 95 Espay AJ, et al. Deep brain stimulation of the ventral 113 Finsterer J, Muellbacher W, Mamoli B. Yes/yes head intermediate nucleus of the thalamus in medically tremor without appendicular tremor after bilateral refractory orthostatic tremor: preliminary observa- cerebellar infarction. J Neurol Sci 1996; 139(2): tions. Mov Disord 2008; 23(16):2357–62. 242–5. 96 Guridi J, et al. Successful thalamic deep brain 114 Milanov I, Sheinkova G. Clinical and electromyo- stimulation for orthostatic tremor. Mov Disord 2008; graphic examination of tremor in patients with 23(13):1808–11. thyrotoxicosis. Int J Clin Pract 2000; 54(6):364–7. 97 Pearce JMS. Palatal Myoclonus (syn. Palatal Tremor). 115 De Mattos JP, et al. Involuntary movements and Eur Neurol 2008; 60:312–315. AIDS: report of seven cases and review of the 98 Deuschl G, Wilms H. Clinical spectrum and physiol- literature. Arq Neuropsiquiatr 1993; 51(4):491–7. ogy of palatal tremor. Mov Disord 2002; 17 Suppl 116 Berger JR, Fischl M, Kelley RE. The neurological 2(2):S63–6. complications of AIDS: frequently the initial mani- 99 Zadikoff C, LAE, Klein C. The “essentials” of essential festation. Neurol 1984; 34(Supplement 1):134–5. palatal tremor: a reappraisal of the nosology. Brain 117 Tse W, et al. Movement disorders and AIDS: a review. 2006; 129:832–840. Parkinsonism Relat Disord 2004; 10(6):323–34. 100 Soland VL, et al. Focal task-specific tremors. Mov 118 Borucki MJ, Matzke DS, Pollard RB. Tremor induced Disord 1996; 11(6):665–70. by trimethoprim-sulfamethoxazole in patients with 101 Bain PG, et al. Primary writing tremor. Brain 1995; the acquired immunodeficiency syndrome (AIDS). 118 (Pt 6):1461–72. Ann Intern Med 1988; 109(1):77–8. 102 Sitburana O, et al. Motor overflow and mirror 119 Hersh BP, Rajendran PR, Battinelli D. Parkinsonism dystonia. Parkinsonism Relat Disord 2009; 15(10): as the presenting manifestation of HIV infection: 758–61. improvement on HAART. Neurol 2001; 56(2): 103 Kachi T, et al. Writing tremor: its relationship to 278–9. benign essential tremor. J Neurol Neurosurg Psychiat 120 Martino D, et al. Atypical movement disorders in 1985; 48(6):545–50. antiphospholipid syndrome. Mov Disord 2006; 104 Ljubisavljevic M, et al. Changes in cortical inhibition 21(7):944–9. during task-specific contractions in primary writing 121 Gilhuis HJ, et al. Paraneoplastic orthostatic tremor tremor patients. Mov Disord 2006; 21(6):855–9. associated with small cell lung cancer. Eur Neurol 105 Odergren T, Stone-Elander S, Ingvar M. Cerebral and 2005; 54(4):225–6. cerebellar activation in correlation to the action- 122 Valentino P, et al. Orolingual tremor as unusual induced dystonia in writer’s cramp. Mov Disord presentation of anti-Hu paraneoplastic syndrome. 1998; 13(3):497–508. Mov Disord 2008; 23(12):1791–2. 106 Wills AJ, et al. A positron emission tomography study 123 Demarquay G, et al. Clinical report of three patients of cerebral activation associated with essential and with hereditary hemochromatosis and movement writing tremor. Arch Neurol 1995; 52(3):299–305. disorders. Mov Disord 2000; 15(6):1204–9. 107 Espay AJ, et al. A writing device improves writing in 124 Aizawa T, et al. Defective hepatic anion transport in primary writing tremor. Neurol 2005; 64(9): variegate porphyria. Am J Gastroenterol 1987; 1648–50. 82(11):1180–5.

Albanese_c07.indd 110 12/24/2011 6:49:45 AM Other Tremors 111

125 Krauss JK, Trankle R, Kopp KH. Posttraumatic linemic polyneuropathies. Incidence and manage- movement disorders after moderate or mild head ment. Arch Neurol 1984; 41(7):711–4. injury. Mov Disord 1997; 12(3):428–31. 138 Cardoso FE, Jankovic J. Hereditary motor- sensory 126 Krauss JK, Trankle R, Kopp KH. Post-traumatic neuropathy and movement disorders. Muscle Nerve movement disorders in survivors of severe head 1993; 16(9):904–10. injury. Neurol 1996; 47(6):1488–92. 139 Saperstein DS, et al. Clinical spectrum of chronic 127 Martland HS. Punch druk. JAMA 1928; 91: acquired demyelinating polyneuropathies. Muscle 1103–1107. Nerve 2001; 24(3):311–24. 128 Deuschl G, Blumberg H, Lucking CH. Tremor in 140 Smith IS. The natural history of chronic demyelinat- reflex sympathetic dystrophy. Arch Neurol 1991; ing neuropathy associated with benign IgM parapro- 48(12):1247–52. teinaemia. A clinical and neurophysiological study. 129 Streib EW. Distal ulnar neuropathy as a cause of Brain 1994; 117 (Pt 5):949–57. finger tremor: a case report. Neurol 1990; 40(1): 141 Sperfeld AD, et al. X-linked bulbospinal neuro- 153–4. nopathy: Kennedy disease. Arch Neurol 2002; 130 Nobrega JC, et al. Movement disorders induced by 59(12):1921–6. peripheral trauma. Arq Neuropsiquiatr 2002; 60(1): 142 Bain PG, et al. Tremor associated with benign IgM 17–20. paraproteinaemic neuropathy. Brain 1996; 119 131 Lampert PW, Hardman JM. Morphological changes (Pt 3):789–99. in brains of boxers. JAMA 1984; 251(20):2676–9. 143 Alonso-Navarro H, et al. Tremor associated with 132 Krauss JK, Jankovic J. Head injury and posttraumatic chronic inflammatory demyelinating peripheral movement disorders. Neurosurgery 2002; 50(5): neuropathy: treatment with pregabalin. Clin 927–39; discussion 939–40. Neuropharmacol 2008; 31(4):241–4. 133 Jankovic J, et al. Outcome after stereotactic 144 Saverino A, et al. Tremor associated with benign thalamotomy for parkinsonian, essential, and other IgM paraproteinaemic neuropathy successfully types of tremor. Neurosurgery 1995; 37(4):680–6; treated with gabapentin. Mov Disord 2001; 16(5): discussion 686–7. 967–8. 134 Martinez-Manas, R, et al. [Thalamic neuro inhibition 145 Bayreuther C, et al. Deep brain stimulation of the in the treatment of post traumatic tremor]. Rev ventral intermediate thalamic nucleus for severe Neurol 2002; 34(3):258–61. tremor in anti-MAG neuropathy. Mov Disord 2009; 135 Thomas PK, et al. Recurrent and chronic relapsing 24(14):2157–8. Guillain-Barre polyneuritis. Brain 1969; 92(3): 146 Breit S, et al. Effective thalamic deep brain stimula- 589–606. tion for neuropathic tremor in a patient with severe 136 Grand’Maison F, et al. Recurrent Guillain-Barre demyelinating neuropathy. J Neurol Neurosurg syndrome. Clinical and laboratory features. Brain Psychiat 2009; 80(2):235–6. 1992; 115 (Pt 4):1093–106. 147 Ruzicka E, et al. VIM thalamic stimulation for tremor 137 Dalakas MC, Teravainen H, Engel WK. Tremor as a in a patient with IgM paraproteinaemic demyelinat- feature of chronic relapsing and dysgammaglobu- ing neuropathy. Mov Disord 2003; 18(10):1192–5.

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Albanese_p03.indd 113 12/24/2011 6:50:45 AM CHAPTER 8 Primary Dystonias Antonio E. Elia1 and Alberto Albanese1,2 1 Istituto Neurologico Carlo Besta, Milan, Italy 2 Istituto di Neurologia, Università Cattolica del Sacro Cuore, Milan, Italy

Historical background attitudes that at first were labile and gradually became more fixed” [3]. He described two Dystonia was one of the last hyperkinetic disorders fundamental patterns: one with flexed arms and to be recognized: the name derives etymologically extended lower limbs, which he called “hemiplegic from a supposed alteration of muscle tone. The term dystonia” and was considered to be related to was coined in 1911 by Oppenheim, who observed putaminal lesions; the other with general flexion, that muscle tone is “hypotonic but also characterized by which was associated with damage to the globus hypertonia and active contractures, which are especially pallidum. Following these observations, the term induced by voluntary movements during standing and dystonia has also been used to encompass postural walking” [1]. He first stated that dystonia was an abnormalities observed in spastic paralysis or fixed organic disease and enriched the clinical observation postural abnormalities [3]. with some characteristic signs: twisted postures of The phenomenology of dystonia coincided with the limbs and trunk associated with muscle spasms, the generalised phenotype for many decades, until bizarre alterations in gait, with buckle, bend, and Marsden and Harrison used the term “torsion twist of the trunk, rapid jerking and sometimes dystonia” to describe “a syndrome characterized rhythmic movements, tendency of symptoms to by dystonic movements and typical posture, progress until the appearance of fixed postural regardless of aetiology and related neuropa- deformity. He is thought to have observed cases of thology” [4]. In June 1975 an international DYT1 dystonia, as he described the progressive limb conference chaired by Stanley Fahn in New York and axial involvement in the affected patients. City laid the way to the modern era and recognized The hereditary nature of this disorder was the clinical features of focal dystonias [5]. David mentioned by Flatau and Sterling [2], who also Marsden’s intuition then provided the intellectual proposed use of the expression “progressive torsion glue for lumping together focal dystonia entities spasm” as they believed that the alteration in muscle that were previously considered independent tone was not the most characteristic clinical sign of nosologic forms (e.g. blepharospasm, torticollis, this condition. “spastic” dysphonia, and writer’s cramp) [4, 6–9]. In the early sixties Denny-Brown identified In 1984, an ad hoc committee of the Dystonia dystonia as a basal ganglia disease and considered Medical Research Foundation documented the it “a disturbance of attitude,” which began with occurrence in all forms of dystonia “of sustained instability of posture, “with a tendency to patterned muscle contractions, frequently causing twist-

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ing and repetitive movements, or abnormal proposed a classification of dystonia based on three postures” [10]; later it was recognized that the axes describing, for each patient, age at disease association of slow tonic posturing with faster onset (early vs. adult), distribution of involved (phasic) movements (sometimes resembling body sites (from focal to generalized), and etiology tremor) is the clinical hallmark of this movement (differentiating idiopathic dystonia syndromes, disorder [10–12]. sporadic or familial, from symptomatic ones) [10, 11]. The first two axes remained unchanged until today, whereas the etiological classification Classification was expanded to include four subgroups of dystonia syndromes: primary, dystonia-plus (i.e. dystonia The classification of dystonia syndromes has with parkinsonism or myoclonic jerks), secondary, changed over time. Fahn and Eldridge [5] first dis- and heredodegenerative [13]. tinguished primary dystonia (with or without The recently published European dystonia hereditary pattern), secondary dystonia (with other Guidelines [14] retain the three axes (Box 8.1) and hereditary neurological syndromes or due to refine the etiological axis distinguishing primary known environmental cause), and psychological (or idiopathic) dystonia syndromes, heredode- forms of dystonia. Later, Fahn, Marsden, and Calne generative (where dystonia is a feature of a genetic

Box 8.1 Classification of dystonia based on three axes.

By etiology • Primary pure dystonia: dystonia is the only clinical sign (apart from tremor) and there is no identifiable exogenous cause or other inherited or degenerative disease. Examples are DYT1 and DYT6 dystonias. • Primary dystonia-plus: dystonia is a prominent sign, but is associated with another movement disorder, for example myoclonus or parkinsonism. There is no evidence of neurodegeneration. For example, DOPA-responsive dystonia (DYT5) and myoclonus-dystonia (DYT11) belong to this category. • Primary paroxysmal: dystonia occurs in brief episodes with normalcy in between. These disorders are classified as idiopathic (often familial although sporadic cases also occur) and symptomatic due to a variety of causes. Three main forms are known depending on the triggering factor. In paroxysmal kinesigenic dyskinesia (PKD; DYT9) attacks are induced by sudden movement; in paroxysmal exercise induced dystonia (PED) by exercise such as walking or swimming, and in the non-kinesigenic form (PNKD; DYT8) by alcohol, coffee, tea, etc. A complicated familial form with PNKD and spasticity (DYT10) has also been described. • Heredodegenerative: dystonia is a feature, among other neurological signs, of a heredodegenerative disorders. Example: Wilson disease. • Secondary: dystonia is a symptom of an identified neurological condition, such as a focal brain lesion, exposure to drugs or chemicals. Examples: dystonia due to a brain tumour, off-period dystonia in Parkinson disease.

By age at onset • Early onset (variably defined as ≤20–30 years): usually starts in a leg or arm and frequently progresses to involve other limbs and the trunk. • Late onset: usually starts in the neck (including the larynx), the cranial muscles or one arm. Tends to remain localised with restricted progression to adjacent muscles.

By distribution • Focal: single body region (e.g. writer’s cramp, blepharospasm) • Segmental: contiguous body regions (e.g. cranial and cervical, cervical and upper limb) • Multifocal: non-contiguous body regions (e.g. upper and lower limb, cranial and upper limb) • Generalised: both legs and at least one other body region (usually one or both arms) • Hemidystonia: half of the body (usually secondary to a structural lesion in the contralateral basal ganglia)

Source: Albanese et al. [14].

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disorder characterized by neurode generation), and forms) or other conditions, such as headache or secondary (or symptomatic) syndromes. Based on scoliosis [17]. the phenotype, primary dystonias are further subdivided into primary pure (with dystonia only), primary plus (with other associated movement disorders) and primary paroxysmal forms Phenomenology of primary (characterized by intermittent symptoms). Age at dystonia onset defines early-onset forms (variably defined as starting before 20–30 years), which usually start in Cardinal features a leg or arm and frequently progress to involve Following David Marsden’s seminal observation other limbs and the trunk, and adult-onset forms, [4], it is commonly accepted that dystonia which usually start in the neck (including the encompasses a combination of movements and larynx), the cranial muscles or one arm and present postures to generate sustained muscle contractions, limited progression to adjacent muscles. The repetitive twisting movements, and abnormal distribution axis defines forms as: focal (if a single postures (torsion dystonia). Dystonic postures can body region is affected), segmental (if contiguous precede the occurrence of dystonic movements and body regions are affected), multifocal (if non- in rare cases can persist without appearance of the contiguous body regions are affected), and latter (so-called fixed dystonia) [12]. Dystonic generalized (if dystonia is present in both legs and movements have specific features that can be at least one other body region). recognized by clinical examination: speed of contractions may be slow or rapid, but at the peak of movement it is sustained; movements almost always have a consistent directional or posture- Epidemiology assuming character. Dystonic movements and postures are commonly aggravated during The prevalence of primary dystonia is difficult to voluntary motion and in milder forms they may ascertain. The estimates range from 2 to 50 cases only be present with specific voluntary actions per million, for early-onset primary dystonia, and (task-specific dystonia). from 30 to 7,320 cases per million for late-onset Dystonic movements may be regular, appearing dystonia. On the basis of the best available preva- as tremor (so-called dystonic tremor [18]). When lence studies, primary dystonia may be 11.1 per fast and jerky, they may resemble myoclonus. 100,000 for early-onset cases in Ashkenazi Jews Dystonic tremor may precede clear abnormal from New York area, 60 per 100,000 for late-onset posturing thus raising doubts about the actual cases in Northern England, and 300 per 100,000 for diagnosis. A tremor similar to essential tremor may late-onset cases in the Italian population over age occur in dystonia and can be mistaken for non- 50 [15]. dystonic tremor, particularly when isolated [17]. The true prevalence of dystonia is probably The diagnosis of dystonia can be missed or delayed underestimated due to a number of reasons. in a number of patients with task- and position- Diagnostic uncertainties and the occurrence of mild specific tremors, particularly primary writing phenotypes (so-called formes frustes) [16] lead tremor, occupational tremors, or isolated voice patients with mild symptoms of dystonia, such as tremor, as typical features of dystonia may develop writer’s cramp, not to seek medical advice. Another only many years after onset. Head or voice tremors related explanation is the delay of the clinical diag- observed in tremulous forms of cervical dystonia nosis, which often requires expert evaluation to be can be very hard to distinguish from essential appreciated. Conditions that are more common or tremor. In contrast to essential tremor involving better acknowledged than dystonia include other the head, dystonic head tremor tends to be more movement disorders (such as Parkinson’s disease, irregular, with directional preponderance, often essential tremor, myoclonus, tics, psychogenic associated with a null point – a position of the head

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in which the tremor ceases. In some cases, family Video 8.1 Primary cervical dystonia history of essential tremor or dystonia may help with the final diagnosis. This is a 30-year-old patient who developed focal cervical dystonia one year before the video. A cranial- cervical trauma had occurred 6 months before disease Associated features onset. The video shows cervical dystonia with a Dystonia has some unique activation/deactiva- predominance of posturing and pain. He has a “geste tion features that can be recognized if appropriately antagoniste” that relieves neck pain and tension while looked for and serve as a basis for the diagnosis: walking. gestes antagonistes (or sensory tricks), mirroring, and overflow. Criteria for identifying these features, when present, have been published recently [16]. Gestes antagonistes have been described in patients with different forms of focal dystonia, who

reduce or even abolish dystonic postures while http://bit.ly/sMeLwt making some specific voluntary movements. For example: cranial dystonia patients can apply pressure on the eyebrows or touch the skin at the side of the eyes to relief blepharospasm; cervical specific task is performed by the homologous dystonia patients can place a hand on the side of opposite unaffected body part. Usually there are the face, the chin, or the back of the head or touch specific tasks that elicit mirror dystonia; they must these areas with one or more fingers to reduce be identified in order to appreciate this feature. For neck contractions; writer’s cramp patients can example, patients with writer’s cramp may present touch the affected arm with the opposite hand. mirror dystonia of the dominant hand while writing Contrasting with the cardinal signs of dystonia, with the non-dominant unaffected hand [21]. gestes are never forceful, but natural and elegant Overflow and mirroring are considered a clinical [16]. The mechanism of action of the gestes is expression of lack of inhibition occurring in debated; their action is not associated with a dystonia [16]. mechanical correction by counter-pressure [19]. It has been observed that gestes do not improve non- Diagnostic algorithm dystonic essential head tremor, are uncommon in A diagnostic algorithm for identifying the features early post-traumatic dystonia, and have atypical of primary dystonia has been proposed [16]. phenomenology in patients with psychogenic According to this schema when all the cardinal dystonia [16]. The geste efficacy may diminish as features of dystonia are observed, the clinical the disease progresses. diagnosis is plainly achieved by physical Overflow and mirroring are two related clinical examination. Otherwise, at least two associated phenomena that reveal or enhance dystonia and features must be observed to reach a clinical prove particularly helpful in cases with mild or diagnosis. EMG observation of features associated inconstant phenomenology. Overflow is an with dystonia is helpful when physical observation unintentional contraction of muscles not primarily is insufficient (Figure 8.1). involved by dystonia, and is usually located in Dystonia can occur at rest, during voluntary neighboring body sites, which are activated at the movement or in paroxysmal form following a spe- peak of dystonic movements [20]. For example, a cific trigger. These features must be appreciated by patient with cervical dystonia may have expert clinical examination. To make the clinical involvement of the unaffected upper limb by the picture more complex, dystonia features can be occasional spread of dystonia activity. Mirror combined or intermixed with other movement dystonia occurs on the affected body side when a disorders in dystonia plus syndromes.

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Hallmark signs: dystonic postures and movements

Both signs Activation/deactivation have complete NO features: gestes (tricks), phenomenology mirroring, overflow

YES

At least two signs are NO EMG mapping present

YES

Features of dystonia are present

YES

Diagnostic criteria for mobile (torsion) dystonia are met

Figure 8.1 Flow chart for the diagnosis of mobile (torsion) dystonia. This stepped approach allows a clinical diagnostic level to be reached on the basis of the criteria listed in Table 8.1. (Reproduced from Albanese and Lalli [16], with permission from Wiley-Blackwell.)

Etiology encoding the protein Torsin A [23]. The disease was originally described among Ashkenazi Jews It has been shown that both genetic predisposition with a relatively homogeneous phenotype and environmental factors play a significant role in characterized by early limb-onset generalized the etiology of primary dystonia syndromes. An dystonia [24]. It was later reported that, particularly appropriate classification takes into account these in Caucasian patients [25], the DYT1 phenotype is two known factors. Genetic defects are known only broader than originally thought. The “classical” for a minority of cases presenting with pure dysto- DYT1 phenotype is characterized by early onset in nia [22]. By contrast, dystonia plus syndromes are a limb, generalization without spread to the by far more precisely classified (Table 8.1). We craniocervical region [25]. In a series of patients describe here the most common forms of primary with early-onset primary dystonia (PD) it has been dystonia, without mentioning paroxysmal dystonia confirmed that dystonia never starts in the syndromes, which are dealt with in Chapter 23. craniocervical region in DYT1 carriers, although craniocervical sites can be involved at later stages Genetically classified primary [26]. It is remarkable that DYT1 patients who dystonia syndromes develop severe generalized involvement may carry DYT1 dystonia out their daily activities with significant adaptation A common cause of generalized primary pure in many cases. Extreme cases have also been dystonia is the GAG deletion in the DYT1 gene observed, ranging from asymptomatic status to

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Table 8.1 DYT genotypes associated with dystonias. The gene name is indicated when known; otherwise, the locus is reported.

Disease (OMIM) Map position Gene Transmission Phenotype

Pure dystonia DYT1 (128100) 9q34 TOR1A AD Generalized early-limb onset dystonia DYT2 (224500) AR Early-onset generalized dystonia with prominent cranial-cervical involvement DYT4 (128101) AD Whispering dysphonia DYT6 (602629) 8p11. 21 THAP1 AD Mixed-type dystonia, early onset generalised with cranial-cervical involvement DYT7 (602124) 18p AD Mixed-type dystonia DYT13 (607671) 1p36. 13–36. 32 AD Mixed-type dystonia DYT17 (612406) 20p11.2–q13.12 AR Segmental or generalized dystonia with severe dysphonia Dystonia plus DYT5/DYT14 (128230) 14q22 GCH1 AD Dopa-responsive dystonia 11p15.5 TH AR Dopa-responsive dystonia 2p13.2 SPR AR Dopa-responsive dystonia DYT11 (159900) 11q23. 1, 7q21 SGCE AD Myoclonus–dystonia DYT12 (128235) 19q12–q13. 2 ATP1A3 AD Rapid onset dystonia parkinsonism DYT15 (607488) 18p11 AD Myoclonus–dystonia DYT16 (612067) 2q31. 3 PRKRA AR Dystonia-parkinsonism Paroxysmal dystonia DYT8 (118800) 2q35 MR1 AD Paroxysmal nonkinesigenic dyskinesia DYT9 (601042) 1p AD Choreoathetosis/spasticity, episodic DYT10 (128200) 16p11. 2-q12. 1 AD Episodic kinesigenic dyskinesia DYT18 (612126) 1p35–p31. 3 SLC2A1 AD Paroxysmal exercise-induced dyskinesia DYT19 (611031) 16q13–q22. 1 AD Episodic kinesigenic dyskinesia DYT20 (611147) 2q31 AD Paroxysmal exercise-induced dyskinesia Heredodegenerative DYT3 (314250) Xq13 TAF1 X-linked Dystonia-parkinsonism

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ATP1A3, ATPase, Na+/K+ transporting; GCH1, guanosine triphosphate cyclohydrolase 1, MR1, Myofibrillogenesis regulator 1, PRKRA, double-stranded RNA-activated protein kinase; SGCE, e-sarcoglycan; SLC2A1, Solute carrier family 2 (facilitated glucose transporter), member 1, SPR, Sepiapterin reductase; TAF1, TATA boxing-binding protein associated factor; TH, Tyrosine hydroxylase; THAP1, Thanatos-associated protein; TOR1A, torsin A gene.

craniocervical involvement or even status dys- than that observed in DYT11 myoclonus-dystonia tonicus [27–30]. [33]; focal dystonia with slow progression and Due to phenotypic heterogeneity, it is not possible occasional later spread even several years after to identify DYT1 patients based only on their onset [34, 35]; late-onset DYT1 forms [27]; rarer clinical presentation. Five other phenotypes have cases of DYT1 dystonia with non-limb presentation, been described in addition to the classical limb- that may present cervical, laryngeal, or trunk onset presentation [26, 31]: generalized dystonia onset [36, 37]. with cranial-cervical involvement, more frequent The gene penetrance is estimated to be around in Europe than in North America [32]; generalized 30% [23, 29], meaning that a high proportion of myoclonic-dystonia, with a phenotype more severe mutation carriers is asymptomatic. This has

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prompted the search for potential endopheno- Immunohistochemical studies have revealed that types to help to identify manifesting as well as in Torsin A is a constituent of Lewy bodies [44]. non-manifesting DYT1 carriers. Two potential endophenotypes are of interest: reduction of striatal DYT6 dystonia D2 receptor binding shown by PET studies [38], The DYT6 locus was originally mapped in two and higher tactile and visuotactile temporal Mennonite families with primary pure dystonia discrimination thresholds or temporal order and autosomal dominant transmission [45]. judgments [39]. These findings need to be con- Mutations in the THAP1 (Thanatos-associated- firmed and integrated into a coherent diagnostic domain containing, apoptosis-associated protein 1) protocol. gene have been found responsible for DYT6 The DYT1 gene is named TOR1A [23]. The disease dystonia with an estimated penetrance of is caused by a unique mutation that deletes one of approximately 60% [46]. In American series THAP1 a pair of GAG triplets from the carboxyl terminal in heterozygous mutations were identified in 9 out of Torsin A. This unique DYT1 haplotype originally 36 (25%) DYT1-negative families with early-onset found in Ashkenazi Jews has also been observed in non-focal PD [47]. European series reported a non-Jewish patients [40] and represents the only lower mutation frequency with an overall pathogenic disease mutation identified in TOR1A. prevalence of 1.0–2.5% in PD cohorts from all over An 18-bp deletion has also been found in families Europe [48, 49]. The spectrum of THAP1 mutations with primary dystonia and myoclonus, but its includes missense, nonsense, and frame-shift pathogenicity has not been ascertained [41]. Torsin mutations of all three exons. A is a heat-shock and ATP-binding protein and a The THAP1 phenotype typically presents with member of the AAA+ superfamily. The normal early-onset dystonia (age range: 9 to 49 years) and protein is widely distributed in many species and is frequent involvement of the cranial-cervical area. located in the endoplasmic reticulum [42, 43]. The motor features often appear in adolescence and may progress rapidly. Speech is commonly affected, because of oro-mandibular or laryngeal involvement (or both). Interestingly, THAP1 mutations Video 8.2 Primary dystonia: DYT1 have been recently found in cases with much later phenotype onset (fifth or sixth decade) and focal or segmental phenomenology involving the cervical or laryngeal This 45-year-old patient has DYT1 dystonia. Dystonia started at age 13 in the right lower limb and impaired district [48, 49]. This suggests that the gene may walking. The disease progressed with dystonia occurring also play a pathogenic role in late-onset, focal or also at rest spreading to generalization. The video segmental PD. shows rest-type tremor and torsional lower limb THAP1 is a member of the family of sequence- instability when standing. Gait is grossly abnormal specific DNA-binding factors. Its function is still with both legs affected by dystonia. Severe torsional posturing is visible in the right lower limb. A right poorly understood, recent studies provided evi- striatal toe with mild dystonic movements of the left dence that THAP1 and TOR1A are interconnected in foot is present at rest. Dystonia during handwriting is a common pathway [50], because wild type THAP1 also shown. represses the expression of TOR1A [51]. THAP1-associated DYT6 dystonia should be considered in patients with early-onset DYT1-negative generalized or segmental dystonia, particularly if cranial involvement is prominent. On average, age at onset is higher than in DYT1 dystonia, and the topographic distribution differs between the two forms. The prevalence of DYT6 dystonia is still http://bit.ly/rzjHUl undetermined.

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generalized picture typically remains asymmetric Video 8.3 Primary dystonia: DYT6 phenotype and involves the four limbs, being more severe in the legs [53]. One important feature of DRD is the This 19-year-old patient carries a point mutation in the occurrence of diurnal fluctuations: patients are THAP1 gene. At age 16 he presented right upper limb dystonia and hand tremor. Two years later he started less affected in the morning and more disabled in to have speech difficulties due to occurrence of the evening [54]. oromandibular task-specific dystonia while talking. Three additional categories of GCH1-linked DRD The videotape shows upper limb dystonic tremor have been recognized [52, 55]: cases with young- (with right hand side prevalence); speech is impaired onset (<20 years) and episodic dystonia, toe by lower cranial dystonia. walking and progressive scoliosis; compound heterozygous GCH1 mutation carriers who develop young-onset severe DRD with early hypotonia, similar to AR-DRD caused by TH mutations; adult- onset DRD manifesting after age 30 years with mild dystonia, resting tremor and non-tremulous parkinsonism. Phenotypic heterogeneity is quite http://bit.ly/tZ8YSB ample and clinical features could not allow the genotype to be predicted even in a large series. Clinical heterogeneity of DRD is a cause of DYT5: dopa-responsive dystonia diagnostic uncertainty. The DRD phenotype can Dopa-responsive dystonia (DRD) is a neurometa- include adult-onset parkinsonism with tremor and bolic disorder classified among the dystonia plus levodopa-induced dyskinesias, leading to possible syndromes. Onset is infantile in most cases and two confusion with patients carrying parkin gene different modes of inheritance have been described. mutations, who often develop a dystonic gait In the autosomal-dominant form (DYT5), hete- disturbance as the initial symptom [56]. The rozygous mutations of GTP-cyclohydrolase I (GCH1) presence of early prominent parkinsonism and cause DRD with reduced penetrance and excellent severe dyskinesias favours parkin mutations. DAT and sustained response to levodopa. Autosomal- scan is normal in DRD patients, but not in parkin recessive forms (AR-DRD) are caused by homozy- disease patients [57, 58]. gous or compound hete rozygous mutations of the The DRD phenotype can be mistaken for spastic tyrosine hydroxylase (TH) or the sepiapterin paraparesis because of brisk lower limb reflexes and reductase (SPR) gene. apparent extensor plantar responses (dystonic toe As this is a treatable condition, a particular extension, known as “striatal toe”). Normal motor effort should be made to establish the correct evoked potentials, unremarkable cranial MRI and diagnosis early. The most common form is positive family history should prompt considera- autosomal-dominant DYT5 DRD (also called tion of a levodopa trial [59]. In one series, up to Segawa’s disease). The classical phenotype 24% of DRD patients were misdiagnosed as having presents with walking difficulties before 20 years, cerebral palsy [60]. Particular care should be put in and progression to segmental or generalized identifying the features of dystonia that lead toward dystonia, sometimes with additional parkinsonian a correct diagnosis. features and sustained response to levodopa [52]. With screening for gene dosage alterations the Parkinsonian features consist of rigidity and rate of detection for GCH1 mutations is over 80% rapidly-induced fatigue with repetitive motor [61, 62]. If genetic testing of GCH1 is negative, tasks, which commonly coexist with dystonia, other genes of the tetrahyhdrobiopterin and dopa- and increased tendon jerks in the affected limb. mine synthesis pathways, like TH and SPR, should By 10–15 years after onset, dystonia gradually be considered, especially if inheritance is recessive spreads to involve all the limbs. The resulting [56, 62]. TH deficiency is the most frequent cause

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of AR-DRD and is associated with a broad pheno- prevalent proximal volvement. M-D has been typic spectrum, ranging from TH-deficient DRD at described to a greater extent in Chapter 14. the mild end to the levodopa-unresponsive infan- In most cases the presenting symptom is myo- tile parkinsonism or progressive infantile encepha- clonus, which may be isolated or associated with lopathy phenotype at the severe end [59]. In mild dystonia. Dystonia is the initial manifestation in cases clinical findings may initially be limited to about 20% of cases [67]. unilateral or asymmetric limb dystonia, postural When present, dystonia is usually mild to tremor, or gait “incoordination.” However, pro- moderate, with torticollis or writer’s cramp as the gression over time may result in the classic dopa- most common manifestations. In patients with responsive dystonic gait disorder. Diurnal variation onset in infancy, gait disturbance, caused by a of motor condition may be present, with worsen- mixture of lower limb dystonia and myoclonus, ing in the afternoon or the evening [53]. Brain have also been described as the initial presentation MRI have not revealed structural or signal abnor- [68]. The phenotype generally evolves to cause mality in individuals with TH-deficient DRD who neck-dominant typical M-D. Large studies suggest have been on treatment for 35 years [63]. Children that screening for SGCE has low yield in patients at the severe end of the spectrum are profoundly with pure dystonia [69]. Family history is frequently disabled by infantile parkinsonism, with onset remarkable, although sporadic cases have also been before 6 months of age, limb rigidity and hypokine- reported [70]. sia, developmental motor delay, and truncal hypo- Usually M-D is compatible with an active life and a tonia. Ptosis and/or oculogyric crises are common. normal lifespan. Both myoclonus and dystonia can These infants are more difficult to treat and worsen at any time during the course of the disease, unusually prone to side effects (dyskinesias and even in old age, and may spread to previously gastrointestinal complications) from levodopa unaffected body regions [71]. A worsening of therapy [53]. Another phenotype associated with myoclonus is not necessarily coupled with a simulta- TH deficiency presents with progressive infantile neous worsening of dystonia [72]. Myoclonus and encephalopathy, cerebral and cerebellar atrophy; dystonia can improve spontaneously or in relation to the patients are severely affected and do not treatment [71], a possibility to be considered when respond to levodopa [64]. planning surgical interventions, such as deep brain Response to a therapeutic trial with levodopa ori- stimulation (DBS). entates towards the diagnosis of DRD [65]. Studies Myoclonus is strikingly alleviated by alcohol in on pterin and dopamine metabolites from cerebro- many, but not all, patients [73], leading to a risk of spinal fluid or a phenylalanine loading test have abuse [74]. Neuropsychiatric features have also also been suggested as diagnostic complements been reported in several M-D patients, who pre- [66], but their predictive value is still uncertain and sented with depression, alcohol abuse, obsessive- both can only be performed in specialized centres. compulsive disorder, anxiety/panic/phobic Because DRD is not easily diagnosed, every patient disorders, and psychosis. Impaired verbal learning with early-onset dystonia without an alternative and memory have also been described in some diagnosis should have an early levodopa trial to families [74–76]. ascertain the diagnosis [14]. Mutations in the epsilon-sarcoglycan gene (SGCE, DYT11) can be detected in over 50% of patients with a typical M-D phenotype and age at DYT11: myoclonus-dystonia onset below 20 [69, 77–79]. As in DRD, the rate of Myoclonus-dystonia (M-D) is a dystonia plus syn- SGCE mutation detection is increased by screening drome that also peaks in childhood. The initial for exon or whole gene deletions (gene dosage) symptoms, usually starting in the first two decades, [72]. Although SGCE mutations are the commonest consist of lightning jerks and dystonia mainly known genetic cause, not all individuals with the affecting the neck and the upper limbs, with a M-D phenotype carry mutations in the SGCE gene,

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supporting the genetic heterogeneity of the disor- cervical dystonia is associated with cranial dysto- der [77, 80]. Patients with a typical M-D phenotype nia or writer’s cramp. No patient had generalized have been shown to map to 18p11, a locus called dystonia. DYT15 [81]. The DYT13 locus was mapped in a large Italian family with prominent craniocervical and upper DYT12: rapid-onset dystonia limb involvement and a pure dystonia phenotype parkinsonism [86, 87]. In the majority of cases onset was in Rapid-onset dystonia parkinsonism (RDP) is a rare infancy or adolescence. Of the 11 definitely affected dystonia-plus syndrome caused by mutations in the individuals, two had generalized dystonia with ATP1A3 gene (DYT12). Onset is in childhood or early onset in the upper limb or in the cervical early adulthood. region [88]. Disability was mild even in generalized The patients develop dystonia, bradykinesia, pos- cases. A peculiar feature of the DYT13 phenotype is tural instability, dysarthria and dysphagia over a prominent cervical or upper limb involvement, period ranging from several hours to weeks with similarly to the DYT6 phenotype, which has triggering factors, such as physical (fever, running, nevertheless been excluded in these patients. childbirth, excessive alcohol ingestion) or psycho- The DYT15 locus was mapped in a large Canadian logical stress in the majority of patients [82]. RDP kindred, whose affected 13 members had alcohol- usually develops over minutes to 30 days and then responsive myoclonic dystonia affecting the upper stabilizes. Delayed worsening of symptoms has limbs, hands, and axial muscles [81]. been reported to occur in few patients 1–9 years The DYT17 dystonia locus was mapped in a single after onset [59]. In addition to rapid onset, other consanguineous Lebanese family with three sisters features suggesting RDP are: prominent bulbar suffering from recessively inherited primary pure involvement and a gradient of dystonia severity dystonia and onset in adolescence [89]. The site of with the cranial region being more severely affected onset was cervical, with progression to segmental than arms and legs. Neither tremor or prominent distribution in two of the sisters and generalization pain have been described at onset [83]. in one. Prominent features were dystonia and dysarthria. Dystonic symptoms did not respond to levodopa. DYT16: dystonia parkinsonism This dystonia-plus syndrome is caused by mutations in the PRKRA (protein-kinase RNA-dependent Video 8.4 Primary dystonia: DYT13 activator) gene. The phenotypic spectrum is char- phenotype

acterized by early onset with focal dystonia leading This patient is the proband of an Italian family linking to walking and writing difficulties. Progression to the DYT13 locus. At age 15 he presented abnormal occurs within few years with facial, cervical, laryn- head movements with a rapid (clonic) component and a geal dystonia and swallowing difficulties. Pyramidal tonic posturing. The clinical picture slowly progressed and psychiatric features are also associated. Brain to a segmental distribution. At age 54, the patient underwent surgical resection of the right imaging is unremarkable [84]. sternocleidomastoid muscle which produced no additional clinical benefit. Mapped loci The DYT7 locus, mapping to the short arm of chromosome 18, was identified in a large German family with autosomal dominant focal pure dystonia phenotype [85]. The mean age at disease onset was 40 years with a prevalent phenotype characterized by focal cervical dystonia. In some patients http://bit.ly/rVzffp a segmental distribution has been reported, where

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Genetically unclassified dystonia patients developed cervical dystonia, and language syndromes impairment (dysarthria or dysphonia) occurred Classified phenotypes in 5. Four patients developed generalization of DYT2 is a recessive pure dystonia phenotype origi- symptoms. In another Swedish family transmission nally described in three consanguineous pedigrees was autosomal dominant with a heterogeneous of Spanish Gypsies. The disease was named “auto- phenotype [97]. There was involvement of the face somal recessive dystonia in Gypsies” and listed as and larynx, and generalization occurred in 3 of the DYT2 [90, 91]. In two of the families the presenta- 10 patients. A family from South Tyrol had 6 tion was similar to that of DYT1 dystonia, consist- affected individuals, 4 of whom developed gener- ing in early limb onset and progression to alization approximately 5 years after onset [98]. generalization; in a third family dystonia presented Limbs were involved at onset in all cases but 1, who with prominent oromandibular and cervical started with cervical dystonia. Upper body involve- involvement [91]. A Sephardic Jewish Iranian fam- ment was observed in 3 of the 4 generalized cases. ily with a similar phenotype and autosomal reces- An Italian family had 6 affected individuals, 1 of sive inheritance has been described separately [92]. whom had severe segmental dystonia [99]. The Three siblings in this family had PD with limb-onset prevalent phenotype was with adult-onset crani- in childhood, and slow progression to generaliza- ocervical dystonia with occasional axial involve- tion with predominant craniocervical involvement. ment but no generalization. Two patients first developed in-turning of the foot In a series of 43 Italian patients with non-DYT1 with gait abnormalities, and all had cervical early-onset dystonia a common phenotype was involvement, facial grimacing, blepharospasm, and identified [26]. This was characterized by cervical involvement of the upper and lower limbs. Two involvement, frequent non-limb onset, relatively patients also had dystonic dysphagia. A third family benign course and uncommon generalization. This with childhood-onset, generalized dystonia, and finding suggests that these non-DYT1 Italian fami- autosomal recessive inheritance also has the DYT2 lies may share a common genetic defect. Their phenotype [93]. peculiar phenotype is similar to the phenotype The DYT4 phenotype refers to a large Australian associated with the DYT6 genotype, which was pedigree with 20 affected members and autosomal ruled out in these subjects. dominant inheritance [94]. Penetrance was com- A focal dystonia with onset in adulthood can be plete in all the examined obligate gene carriers; age the only clinical sign in many patients, who usually at onset varied from 13 to 37 years. Many patients have no or mild progression to a segmental pure presented with “whispering dysphonia”, others had dystonia. The most frequent forms of dystonia with cervical dystonia. Most patients eventually devel- typical sporadic occurrence that remain genetically oped generalized dystonia. Wilson’s disease coex- unclassified are: blepharospasm, oromandibular isted in the same pedigree, but was excluded as a dystonia, spasmodic dysphonia, cervical dystonia or cause of dystonia in the affected individuals [95]. occupational upper limb dystonia. Figure 8.2 shows the appearance of some focal and generalized dys- Unclassified phenotypes tonia phenotypes. A number of scattered pedigrees not carrying the Cervical dystonia is the most common among DYT1 mutation have been described. In some of these forms. Various abnormal head positions can these families recently discovered dystonia loci (e.g. occur, including horizontal head rotation DYT6) have not been excluded. Linkage studies (torticollis), head tilting (laterocollis), head flexion have not been performed or have not been inform- (anterocollis), or head extension (retrocollis). These ative, leaving these pedigrees unmapped. postures can be combined variably depending on A non-Jewish American family presented with the neck muscles involved. Pain occurs in 75% of adult-onset DYT1-negative PD [96]. The disease patients with cervical dystonia [100]. Cranial started in the neck in 6 cases and in a leg in 1. All dystonias are less prevalent than cervical forms.

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(a) (b) (c) (d)

(e)

(f)

(g)

Figure 8.2 Representation of different forms of dystonia: (a) Meige syndrome (still frame from [150]); (b) cervical dystonia (still frame from [88]); (c) axial dystonia; (d) hemidystonia; (e) upper limb dystonia (writer’s cramp); (f) lower limbs dystonia in a DYT1 patient; (g) generalized (Oppenheim’s) dystonia in a DYT1 patient (reproduced from [28] with permission from Wiley-Blackwell).

Spasmodic dysphonia affects the vocal folds and sometimes called Meige syndrome. In cranial- may result in abnormal adduction, which causes a cervical dystonia, another type of segmental strained, strangled voice, or, less frequently, it may dystonia, the cranial districts are involved together result in vocal cord abduction, in which the voice with the neck muscles. sounds whispery and breathy. Patients with blepharospasm have abnormal contraction of the orbicularis oculi; mild cases are Pathophysiology characterized by a simple increase of blink rate and occasional flurries of blinking; in more severe cases The pathophysiology of dystonia has been reviewed forceful eye closure can interfere with vision in Chapter 2. The core feature is an abnormal co- leading to functional blindness. In oromandibular contraction of agonists, and antagonists muscles dystonia there is abnormal activity in lower facial, worsened by certain task-specific actions and are tongue, jaw, and pharyngeal muscles that can sometimes relieved by some sensory tricks. The interfere with speaking or swallowing. Brachial abnormal co-contraction is thought to be caused dystonia is a form of focal dystonia that can be by a dysfunction either at the spinal or cortical primarily, or exclusively, present with writing level or both [101]. Reciprocal inhibition is the (writer’s cramp). central nervous system process in which a muscle Segmental dystonia can affect the upper and is inhibited when its antagonist is activated. lower cranial muscles, as in the combination of A decreased reciprocal inhibition at different levels blepharospasm with oromandibular dystonia, of the central nervous system might contribute to

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the excessive movement seen in dystonia. Another Treatment research area suggests that dystonic patients may have faulty processing within the inhibitory inter- There is no etiologic or neuroprotective treatment actions between antagonist muscles at the sensory- for primary pure dystonia syndromes. Etiologic motor cortex level. remedies are instead available for some dystonia An emerging line of evidence indicates that dysto- plus syndromes of metabolic origin, such as DRD, nia could be a disorder of neuroplasticity. In some or non-primary forms, such as Wilson disease. susceptible individuals, during the acquisition of new Symptomatic treatments aim to relieve involuntary motor skills, the mechanisms of neuroplasticity are movements, correct abnormal posture, prevent subtly abnormal. In the presence of such predisposi- contractures, reduce pain and embarrassment, tion, several environmental factors, such as repeti- and improve function [115]. Botulinum toxin is tive training or peripheral nervous system injury, can the first choice treatment for most types of focal trigger an abnormal maladaptive plasticity, which dystonia. Neurosurgical treatments have a growing can lead to an overt dystonia particularly in patients role in the symptomatic treatment plan. Evidence- with a predisposing genetic background [101]. based guidelines have been recently published Although primary dystonias are traditionally con- by the European Federation of Neurological sidered not to be associated with morphological brain Sciences [14]. abnormalities, voxel-based morphometry studies have shown increase in gray matter density or vol- Etiologic treatments ume in various areas, including cerebellum, basal In metabolic disorders the knowledge of the bio- ganglia, and primary somatosensory cortex, which chemistry and metabolic pathway involved in the might represent plastic changes secondary to overuse pathogenesis can help to identify etiologic treat- [102–106]. Diffusion MRI studies have found signal ments, such as enzyme-replacement therapy to res- abnormalities in various brain areas (including cor- cue cellular function or systemic delivery of a pus callosum, basal ganglia, pontine, brainstem, and missing metabolite. A growing number of genes are prefrontal cortical areas) in cervical dystonia, writer’s being found to cause familial forms of dystonia and, cramp and primary generalized dystonia, but not consequently, the molecular diagnosis of these dis- blepharospam [107–110]. It is difficult to reconcile orders is becoming increasingly important. these morphological evidences that may pick up An etiologic treatment is available for DRD. some epiphenomena related to prolonged functional Reduced activity of GCH1, TH, or SPR is thought to changes in the brain motor systems. cause symptoms by depleting dopamine, consist- Data on genetically defined forms also provides ently with the pronounced therapeutic effect of insights on the neuropathology of primary dysto- levodopa, even in patients who have been severely nia. It has been observed that symptomatic DYT1 incapacitated for several years [116]. mutation carriers have a smaller basal ganglia size Patients with DRD typically experience a marked compared to non-carriers or asymptomatic carriers, long-term benefit with low doses of levodopa and the severity of dystonia correlates negatively [117]. The optimal regimen varies among patients; with basal ganglia size in DYT1 carriers [111]. A sig- while some respond magnificently to small doses, nificant reduction in caudate and putamen D2 others require higher dosages. In the largest receptor availability and reduced [11C] raclopride available series, clinical benefit was observed at a binding has also been described in the ventrolateral mean dose of 343.8 mg daily for patients who thalamus of DYT1 and DYT6 carriers [112]. Other developed dyskinesias, and 189.1 mg daily for studies failed to observe neuropathological changes patients without dyskinesias [117]. The overall in the basal ganglia of DYT1 patients [113], but per- long-term responsiveness to levodopa was inuclear inclusion bodies have been detected in the excellent in GCH1-DRD and the prescribed doses midbrain reticular formation and periaqueductal had to be increased only in a minority of patients. gray matter of DYT1 patients [114]. Long-term observations have shown that side

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effects such as dyskinesias or motor fluctuations Systemic treatments are unlikely to occur [52]. In contrast to patients Little evidence-based information is available for with GCH1 mutations, TH-DRD patients may show other medical treatments of primary dystonia. a delayed and incomplete levodopa response with Anticholinergic drugs at high dosage are reported occurrence of dyskinesias [59]. to be effective in the treatment of childhood-onset primary or secondary generalized dystonias [126, Botulinum toxins 127]. This therapy is generally well tolerated when Botulinum neurotoxins (BoNTs) inhibit the vesic- the dose is started low and increased slowly. ular release of acetylcholine at the neuromuscu- Trihexyphenidyl should be titrated up to a dosage lar junction, resulting in a transient, localized of 30–40 mg per day but some patients might impairment of neurotransmission. Different type require up to 60–100 mg per day, although dose- A and one type B BoNT are available for clinical related side effects (e.g. drowsiness, memory diffi- use [118]. culty, and urinary retention) might limit its In properly adjusted doses, BoNTs are effective usefulness, especially in adults. and safe treatments of cranial and cervical dystonia Non-controlled trials are available on the effects [119]. According to one systematic review, no con- of antidopaminergic drugs. Tetrabenazine was ini- clusions can be drawn on the efficacy of BoNTs for tially found to be effective in a small double-blind different types of spasmodic dysphonia [120], randomized cross-over study [128]. The positive although uncontrolled studies have found this treat- effect of this treatment on dystonia was confirmed ment efficacious. BoNT/A has also been proven effi- in a large series of patients with different types of cacious for the treatment of writing dystonia [121]. movement disorders, including dystonia, followed BoNT injections can be performed by direct up retrospectively for a mean duration of 3.0 inspection, EMG- or ultrasound-guided targeting years [129]. and there is no consensus on which is the most appropriate practice. In recent years long-term Deep brain stimulation studies on the efficacy and safety of BoNT/A have Long-term electrical stimulation of the globus pal- become available, new formulations of BoNT/A lidum internum (GPi) is now established as an have been marketed, and new studies on BoNT/B effective treatment for primary generalized or seg- have been performed. mental (mainly cervical) dystonia [130, 131]. The efficacy and safety profile of BoNT treat- Surgery is indicated after medications or BoNT ments has been evaluated in long-term observa- have failed to provide adequate improvement. tional studies. BoNT/A was found to be effective There is limited experience on targets different and safe in treating blepharospasm, with long-last- from the GPi [132] such as the thalamus, the sub- ing efficacy up to 15 years of follow up [122]. In thalamic nucleus [133], and the cerebral cortex patients with different dystonia types followed for [134]. Chronic stimulation in dystonia uses both over 12 years there was no decline of efficacy and higher pulse width and voltage than in PD result- the main side effects consisted in muscle weakness ing in earlier battery depletion: replacement may in or around the injected region [123]. Onabot- be needed sometimes every 2 years or less. GPi ulinumtoxin A immunogenicity was found to be DBS, in general, is less effective in secondary dysto- low in long-term use [124]. A meta-analysis found nia. This procedure requires a specialized expertise that adverse events are more frequent among chil- and a multidisciplinary team, and is not without dren with cerebral palsy than in individuals with side effects. Other indications are still being other conditions [125]. BoNTs are safe when explored, such as status dystonicus, task-specific repeated treatments are performed over many dystonias, camptocormia, secondary hemidystonia, years, but doctors and patients should be aware pantothenate kinase-associated neurodegene- that excessive cumulative doses may be dangerous, ration, Lesch-Nyhan and cerebral palsy-related particularly in children. dystonia-choreoathetosis.

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According to a National Institute for Clinical References Excellence (NICE) guideline [135], GPi DBS provides marked benefit with improvement of dysto- 1 Oppenheim H. Über eine eigenartige Krampfkrankheit nia motor scores, ranging between 34 and 88%, des kindlichen und jugendlichen Alters (Dysbasia lor- and disability scores, between 40 and 50%. dotica progressiva, Dystonia musculorum deformans). A meta-analysis using a regression analysis pub- Neurologische Centralblatt 1911; 30:1090–107. lished in 2006 revealed that longer duration of 2 Flatau E, Sterling W. Progressiver Torsionspasm bie Kindern. Z ges Neurol Psychiat 1911; 7:586–612. dystonia correlated negatively with surgical out- 3 Denny-Brown D. The nature of dystonia. Bull N Y come [136]. Improvement of dystonia after DBS Acad Med 1965; 41:858–69. commonly follows a specific pattern, with phasic 4 Marsden CD, Harrison MJ. Idiopathic torsion dystonia (clonic or tremulous) elements improving earlier (dystonia musculorum deformans). A review of forty- than tonic features, the latter often with a delay of two patients. Brain 1974; 97:793–810. weeks or months [137–139]. Overall, the most 5 Fahn S, Eldridge R. Definition of dystonia and beneficial results with pallidal DBS were reported classification of the dystonic states. Adv Neurol 1976; in children with primary generalized dystonia, par- 14:1–5. ticularly in DYT1 dystonia, which improves in the 6 Marsden CD. Dystonia: the spectrum of the disease. range of 40 to 90% [140–142]. Long-term efficacy Res Publ Assoc Res Nerv Ment Dis 1976; 55:351–67. was reported to be sustained after more than 7 Marsden CD. Blepharospasm-oromandibular dystonia syndrome (Brueghel’s syndrome). A variant of adult- 5 years of follow-up [143]. In patients with cervical onset torsion dystonia? J Neurol Neurosurg Psychiatry dystonia, GPi DBS has so far been used primarily in 1976; 39:1204–9. those who were thought not to be ideal candidates 8 Marsden CD, Sheehy MP. Spastic dysphonia, Meige for peripheral denervation, including patients with disease, and torsion dystonia. Neurology 1982; 32: head tremor and myoclonus, or marked phasic 1202–3. movements [144]. 9 Sheehy MP, Marsden CD. Writers’ cramp: a focal Safety aspects which have to be considered dystonia. Brain 1982; 105:461–80. include surgery-related complications, stimula- 10 Fahn S, Marsden CD, Calne DB. Classification and tion-induced side effects and hardware-related investigation of dystonia. In: Marsden CD, Fahn S, problems. Recently, it was noted that GPi DBS in editors. Movement disorders 2. London: Butterworths; patients with segmental dystonia may induce a 1987. pp. 332–58. 11 Fahn S. Concept and classification of dystonia. Adv parkinsonian gait or bradykinesia in extremities Neurol 1988; 50:1–8. which were not affected by dystonia at chronic 12 Albanese A. The clinical expression of primary stimulation with high voltage [145, 146]. Bilateral dystonia. J Neurol 2003; 250:1145–51. pallidal stimulation does not impair cognitive 13 Fahn S, Bressman SB, Marsden CD. Classification of performance [147]. dystonia. Adv Neurol 1998; 78:1–10. 14 Albanese A, Asmus F, Bhatia KP, Elia AE, Elibol B, Filippini G, et al. EFNS guidelines on diagnosis and Other neurosurgical procedures treatment of primary dystonias. Eur J Neurol 2011; According to NICE guideline for selective periph- 18:5–18. eral denervation in cervical dystonia [148], this 15 Defazio G, Abbruzzese G, Livrea P, Berardelli A. procedure requires a specialized expertise, it is safe Epidemiology of primary dystonia. Lancet Neurol 2004; 3:673–8. with infrequent and minimal side effects and is 16 Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; indicated exclusively in cervical dystonia. Intrath- 24:1725–31. ecal baclofen has been used in patients with severe 17 Lalli S, Albanese A. The diagnostic challenge of generalized dystonia. Since this treatment is primary dystonia: evidence from misdiagnosis. Mov burdened by medication-related side effects, it is Disord 2010; 25:1619–26. currently indicated only in patients where second- 18 Elia AE, Lalli S, Albanese A. Differential diagnosis of ary dystonia is combined with spasticity [149]. dystonia. Eur J Neurol 2010; 17(Suppl 1):1–8.

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19 Wissel J, Muller J, Ebersbach G, Poewe W. Trick primary torsion dystonia without family history. Arch maneuvers in cervical dystonia: investigation of Neurol 2000; 57:333–5. movement- and touch-related changes in polymyo- 33 Gatto EM, Pardal MM, Micheli FE. Unusual pheno- graphic activity. Mov Disord 1999; 14:994–9. typic expression of the DYT1 mutation. Parkinsonism 20 Sitburana O, Jankovic J. Focal hand dystonia, mirror Relat Disord 2003; 9:277–9. dystonia and motor overflow. J Neurol Sci 2008; 34 Chinnery PF, Reading PJ, McCarthy EL, Curtis A, Burn 266:31–3. DJ. Late-onset axial jerky dystonia due to the DYT1 21 Jedynak PC, Tranchant C, de Beyl DZ. Prospective deletion. Mov Disord 2002; 17:196–8. clinical study of writer’s cramp. Mov Disord 2001; 35 Edwards M, Wood N, Bhatia K. Unusual phenotypes 16:494–9. in DYT1 dystonia: a report of five cases and a review of 22 Muller U. The monogenic primary dystonias. Brain the literature. Mov Disord 2003; 18:706–11. 2009; 132:2005–25. 36 Bressman SB, Sabatti C, Raymond D, de Leon D, Klein 23 Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer C, Kramer PL, et al. The DYT1 phenotype and PL, Shalish C, et al. The early-onset torsion dystonia guidelines for diagnostic testing. Neurology 2000; gene (DYT1) encodes an ATP-binding protein. Nat 54:1746–52. Genet 1997; 17:40–8. 37 Ikeuchi T, Shimohata T, Nakano R, Koide R, Takano 24 Bressman SB, de Leon D, Brin MF, Risch N, Burke RE, H, Tsuji S. A case of primary torsion dystonia in Japan Greene PE, et al. Idiopathic dystonia among Ashkenazi with the 3-bp (GAG) deletion in the DYT1 gene with a Jews: evidence for autosomal dominant inheritance. unique clinical presentation. Neurogenetics 1999; Ann Neurol 1989; 26:612–20. 2:189–90. 25 Valente EM, Warner TT, Jarman PR, Mathen D, 38 Asanuma K, Ma Y, Okulski J, Dhawan V, Chaly Fletcher NA, Marsden CD, et al. The role of DYT1 in T, Carbon M, et al. Decreased striatal D2 receptor primary torsion dystonia in Europe. Brain 1998; binding in non-manifesting carriers of the DYT1 dys- 121:2335–9. tonia mutation. Neurology 2005; 64:347–9. 26 Fasano A, Nardocci N, Elia AE, Zorzi G, Bentivoglio AR, 39 Fiorio M, Gambarin M, Valente EM, Liberini P, Loi M, Albanese A. Non-DYT1 early-onset primary torsion Cossu G, et al. Defective temporal processing of sen- dystonia: comparison with DYT1 phenotype and review sory stimuli in DYT1 mutation carriers: a new endo- of the literature. Mov Disord 2006; 21:1411–18. phenotype of dystonia? Brain 2007; 130:134–42. 27 Opal P, Tintner R, Jankovic J, Leung J, Breakefield XO, 40 Valente EM, Povey S, Warner TT, Wood NW, Davis Friedman J, et al. Intrafamilial phenotypic variability MB. Detailed haplotype analysis in Ashkenazi Jewish of the DYT1 dystonia: from asymptomatic TOR1A and non-Jewish British dystonic patients carrying the gene carrier status to dystonic storm. Mov Disord GAG deletion in the DYT1 gene: evidence for a limited 2002; 17:339–45. number of founder mutations. Ann Hum Genet 1999; 28 Bentivoglio AR, Loi M, Valente EM, Ialongo T, Tonali 63:1–8. P, Albanese A. Phenotypic variability of DYT1-PTD: 41 Doheny D, Danisi F, Smith C, Morrison C, Velickovic does the clinical spectrum include psychogenic M, de Leon D, et al. Clinical findings of a myoclonus- dystonia? Mov Disord 2002; 17:1058–63. dystonia family with two distinct mutations. 29 Gambarin M, Valente EM, Liberini P, Barrano G, Bonizzato Neurology 2002; 59:1244–6. A, Padovani A, et al. Atypical phenotypes and clinical 42 Hewett J, Gonzalez-Agosti C, Slater D, Ziefer P, Li S, variability in a large Italian family with DYT1-primary Bergeron D, et al. Mutant torsinA, responsible for torsion dystonia. Mov Disord 2006; 21:1782–4. early-onset torsion dystonia, forms membrane 30 Kostic VS, Svetel M, Kabakci K, Ristic A, Petrovic I, inclusions in cultured neural cells. Hum Mol Genet Schule B, et al. Intrafamilial phenotypic and genetic 2000; 9:1403–13. heterogeneity of dystonia. J Neurol Sci 2006; 250: 43 Kustedjo K, Bracey MH, Cravatt BF. Torsin A and its 92–6. torsion dystonia-associated mutant forms are lumenal 31 Fasano A, Elia A, Albanese A. Early onset primary glycoproteins that exhibit distinct subcellular localiza- torsion dystonia. In: Fernández-Alvarez E, Arzimanoglou tions. J Biol Chem 2000; 275:27933–9. A, Tolosa E, editors. Paediatric movement disorders. 44 Shashidharan P, Good PF, Hsu A, Perl DP, Brin MF, Esher: John Libbey; 2005. pp. 31–55. Olanow CW. TorsinA accumulation in Lewy bodies in 32 Brassat D, Camuzat A, Vidailhet M, Feki I, Jedynak P, sporadic Parkinson’s disease. Brain Res 2000; 877: Klap P, et al. Frequency of the DYT1 mutation in 379–81.

Albanese_c08.indd 130 12/24/2011 6:56:27 AM Primary Dystonias 131

45 Almasy L, Bressman SB, Raymond D, Kramer PL, 58 Huang CC, Yen TC, Weng YH, Lu CS. Normal dopa- Greene PE, Heiman GA, et al. Idiopathic torsion mine transporter binding in dopa responsive dystonia. dystonia linked to chromosome 8 in two Mennonite J Neurol 2002; 249:1016–20. families. Ann Neurol 1997; 42:670–3. 59 Asmus F, Gasser T. Dystonia-plus syndromes. Eur 46 Fuchs T, Gavarini S, Saunders-Pullman R, Raymond J Neurol 2010; 17(Suppl. 1):37–45. D, Ehrlich ME, Bressman SB, et al. Mutations in the 60 Nygaard TG, Marsden CD, Fahn S. Dopa-responsive THAP1 gene are responsible for DYT6 primary torsion dystonia: long-term treatment response and prognosis. dystonia. Nat Genet 2009; 41:286–8. Neurology 1991; 41:174–81. 47 Bressman SB, Raymond D, Fuchs T, Heiman GA, 61 Zirn B, Steinberger D, Troidl C, Brockmann K, von der Ozelius LJ, Saunders-Pullman R. Mutations in THAP1 HM, Feiner C, et al. Frequency of GCH1 deletions in (DYT6) in early-onset dystonia: a genetic screening Dopa-responsive dystonia. J Neurol Neurosurg study. Lancet Neurol 2009; 8:441–6. Psychiatry 2008; 79:183–6. 48 Bonetti M, Barzaghi C, Brancati F, Ferraris A, 62 Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Bellacchio E, Giovanetti A, et al. Mutation screening Chabrol B, et al. Exhaustive analysis of BH4 and of the DYT6/THAP1 gene in Italy. Mov Disord 2009; dopamine biosynthesis genes in patients with Dopa- 24:2424–7. responsive dystonia. Brain 2009; 132:1753–63. 49 Houlden H, Schneider SA, Paudel R, Melchers A, 63 Schiller A, Wevers RA, Steenbergen GC, Blau N, Jung Schwingenschuh P, Edwards M, et al. THAP1 muta- HH. Long-term course of L-dopa-responsive dystonia tions (DYT6) are an additional cause of early-onset caused by tyrosine hydroxylase deficiency. Neurology dystonia. Neurology 2010; 74:846–50. 2004; 63:1524–6. 50 Gavarini S, Cayrol C, Fuchs T, Lyons N, Ehrlich ME, 64 Hoffmann GF, Assmann B, Brautigam C, Dionisi-Vici C, Girard JP, et al. Direct interaction between causative Haussler M, de Klerk JB, et al. Tyrosine hydroxylase genes of DYT1 and DYT6 primary dystonia. Ann deficiency causes progressive encephalopathy and Neurol 2010; 68:549–53. dopa-nonresponsive dystonia. Ann Neurol 2003, 51 Kaiser FJ, Osmanoric A, Rakovic A, Erogullari A, 54(Suppl. 6):S56-S65. Uflacker N, Braunholz D, et al. The dystonia gene 65 Robinson R, McCarthy GT, Bandmann O, Dobbie M, DYT1 is repressed by the transcription factor THAP1 Surtees R, Wood NW. GTP cyclohydrolase deficiency; (DYT6). Ann Neurol 2010; 68:554–9. intrafamilial variation in clinical phenotype, including 52 Trender-Gerhard I, Sweeney MG, Schwingenschuh levodopa responsiveness. J Neurol Neurosurg P, Mir P, Edwards MJ, Gerhard A, et al. Autosomal- Psychiatry 1999; 66:86–9. dominant GTPCH1-deficient DRD: clinical 66 Bandmann O, Goertz M, Zschocke J, Deuschl G, Jost characteristics and long-term outcome of 34 W, Hefter H, et al. The phenylalanine loading test in patients. J Neurol Neurosurg Psychiatry 2009; 80: the differential diagnosis of dystonia. Neurology 2003; 839–45. 60:700–2. 53 Furukawa Y. Update on dopa-responsive dystonia: 67 Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli locus heterogeneity and biochemical features. Adv D, Roze E. Myoclonus-dystonia: an update. Mov Neurol 2004; 94:127–38. Disord 2009; 24:479–89. 54 Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai 68 Koukouni V, Valente EM, Cordivari C, Bhatia KP, H. Hereditary progressive dystonia with marked diur- Quinn NP. Unusual familial presentation of epsilon- nal fluctuation. Adv Neurol 1976; 14:215–33. sarcoglycan gene mutation with falls and writer’s 55 Bandmann O, Wood NW. Dopa-responsive dystonia. cramp. Mov Disord 2008; 2313:1913–5. The story so far. Neuropediatrics 2002; 33:1–5. 69 Asmus F, Zimprich A, Tezenas du MS, Kabus C, 56 Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Deuschl G, Kupsch A, et al. Myoclonus-dystonia Lucking CB, et al. Levodopa-responsive dystonia. GTP syndrome: epsilon-sarcoglycan mutations and pheno- cyclohydrolase I or parkin mutations? Brain 2000; type. Ann Neurol 2002; 52:489–92. 123:1112–21. 70 Schule B, Kock N, Svetel M, Dragasevic N, Hedrich K, 57 Jeon BS, Jeong JM, Park SS, Kim JM, Chang YS, Song de Carvalho AP, et al. Genetic heterogeneity in ten HC, et al. Dopamine transporter density measured by families with myoclonus-dystonia. J Neurol Neurosurg [123I]beta-CIT single-photon emission computed Psychiatry 2004; 758:1181–5. tomography is normal in dopa-responsive dystonia. 71 Roze E, Apartis E, Clot F, Dorison N, Thobois S, Ann Neurol 1998; 43:792–800. Guyant-Marechal L, et al. Myoclonus-dystonia: clinical

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and electrophysiologic pattern related to SGCE muta- 84 Camargos S, Scholz S, Simon-Sanchez J, Paisan-Ruiz tions. Neurology 2008; 70:1010–6. C, Lewis P, Hernandez D, et al. DYT16, a novel young- 72 Asmus F, Hjermind LE, Dupont E, Wagenstaller onset dystonia-parkinsonism disorder: identification J, Haberlandt E, Munz M, et al. Genomic deletion size of a segregating mutation in the stress-response at the epsilon-sarcoglycan locus determines the protein PRKRA. Lancet Neurol 2008; 7:207–15. clinical phenotype. Brain 2007; 130:2736–45. 85 Leube B, Rudnicki D, Ratzlaff T, Kessler KR, Benecke 73 Vidailhet M, Tassin J, Durif F, Nivelon-Chevallier R, Auburger G. Idiopathic torsion dystonia: assign- A, Agid Y, Brice A, et al. A major locus for several ment of a gene to chromosome 18p in a German phenotypes of myoclonus-dystonia on chromosome family with adult onset, autosomal dominant inherit- 7q. Neurology 2001; 56:1213–6. ance and purely focal distribution. Hum Mol Genet 74 Saunders-Pullman R, Shriberg J, Heiman G, Raymond D, 1996; 5:1673–7. Wendt K, Kramer P, et al. Myoclonus dystonia: possible 86 Bentivoglio AR, Del Grosso N, Albanese A, Cassetta association with obsessive-compulsive disorder and E, Tonali P, Frontali M. Non-DYT1 dystonia in a large alcohol dependence. Neurology 2002; 58:242–5. Italian family. J Neurol Neurosurg Psychiatry 1997; 75 Hess CW, Raymond D, de Carvalho Aguiar P, Frucht S, 62:357–60. Shriberg J, Heiman GA, et al. Myoclonus-dystonia, 87 Valente EM, Bentivoglio AR, Cassetta E, Dixon PH, obsessive-compulsive disorder, and alcohol depend- Davis MB, Ferraris A, et al. DYT13, a novel primary ence in SGCE mutation carriers. Neurology 2007; torsion dystonia locus, maps to chromosome 1p36. 68:522–4. 13–36.32 in an Italian family with cranial-cervical or 76 Doheny DO, Brin MF, Morrison CE, Smith CJ, Walker upper limb onset. Ann Neurol 2001; 49:362–6. RH, Abbasi S, et al. Phenotypic features of myoclonus- 88 Bentivoglio AR, Ialongo T, Contarino MF, Valente EM, dystonia in three kindreds. Neurology 2002; 59: Albanese A. Phenotypic characterization of DYT13 1187–96. primary torsion dystonia. Mov Disord 2004; 19: 77 Valente EM, Edwards MJ, Mir P, Digiorgio A, Salvi S, 200–6. Davis M, et al. The epsilon-sarcoglycan gene in myo- 89 Chouery E, Kfoury J, Delague V, Jalkh N, Bejjani P, clonic syndromes. Neurology 2005; 64:737–9. Serre JL, et al. A novel locus for autosomal recessive 78 Klein C, Schilling K, Saunders-Pullman RJ, Garrels J, primary torsion dystonia (DYT17) maps to 20p11. Breakefield XO, Brin MF, et al. A major locus for 22–q13.12. Neurogenetics 2008; 9:287–93. myoclonus-dystonia maps to chromosome 7q in eight 90 Gimenez-Roldan S, Delgado G, Marin M, Villanueva families. Am J Hum Genet 2000; 67:1314–9. JA, Mateo D. Hereditary torsion dystonia in gypsies. 79 Leung JC, Klein C, Friedman J, Vieregge P, Adv Neurol 1988; 50:73–81. Jacobs H, Doheny D, et al. Novel mutation in the 91 Gimenez-Roldan S, Lopez-Fraile IP, Esteban A. TOR1A (DYT1) gene in atypical early onset dystonia Dystonia in Spain: study of a Gypsy family and general and polymorphisms in dystonia and early onset survey. Adv Neurol 1976; 14:125–36. parkinsonism. Neurogenetics 2001; 3:133–43. 92 Khan NL, Wood NW, Bhatia KP. Autosomal recessive, 80 Han F, Lang AE, Racacho L, Bulman DE, Grimes DA. DYT2-like primary torsion dystonia: a new family. Mutations in the epsilon-sarcoglycan gene found to be Neurology 2003; 61:1801–3. uncommon in seven myoclonus-dystonia families. 93 Moretti P, Hedera P, Wald J, Fink J. Autosomal recessive Neurology 2003; 612:244–6. primary generalized dystonia in two siblings from a 81 Grimes DA, Han F, Lang AE, George-Hyssop P, Racacho consanguineous family. Mov Disord 2005; 20:245–7. L, Bulman DE. A novel locus for inherited myoclonus- 94 Parker N. Hereditary whispering dysphonia. J Neurol dystonia on 18p11. Neurology 2002; 59:1183–6. Neurosurg Psychiatry 1985; 48:218–24. 82 Dobyns WB, Ozelius LJ, Kramer PL, Brashear A, 95 Ahmad F, Davis MB, Waddy HM, Oley CA, Marsden Farlow MR, Perry TR, et al. Rapid-onset dystonia- CD, Harding AE. Evidence for locus heterogeneity in parkinsonism. Neurology 1993; 43:2596–602. autosomal dominant torsion dystonia. Genomics 83 Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg 1993; 15:9–12. M, Frijns CJ, Gollamudi S, et al. The phenotypic 96 Bressman SB, Heiman GA, Nygaard TG, Ozelius LJ, spectrum of rapid-onset dystonia-parkinsonism (RDP) Hunt AL, Brin MF, et al. A study of idiopathic torsion and mutations in the ATP1A3 gene. Brain 2007; dystonia in a non-Jewish family: evidence for genetic 130:828–35. heterogeneity. Neurology 1994; 44:283–7.

Albanese_c08.indd 132 12/24/2011 6:56:27 AM Primary Dystonias 133

97 Holmgren G, Ozelius L, Forsgren L, Almay BG, 110 Bonilha L, de Vries PM, Vincent DJ, Rorden C, Holmberg M, Kramer P, et al. Adult onset idiopathic Morgan PS, Hurd MW, et al. Structural white matter torsion dystonia is excluded from the DYT 1 region abnormalities in patients with idiopathic dystonia. (9q34) in a Swedish family. J Neurol Neurosurg Mov Disord 2007; 22:1110–16. Psychiatry 1995; 59:178–81. 111 Draganski B, Schneider SA, Fiorio M, Kloppel S, 98 Klein C, Pramstaller PP, Castellan CC, Breakefield XO, Gambarin M, Tinazzi M, et al. Genotype-phenotype Kramer PL, Ozelius LJ. Clinical and genetic evalua- interactions in primary dystonias revealed by differ- tion of a family with a mixed dystonia phenotype ential changes in brain structure. Neuroimage 2009; from South Tyrol. Ann Neurol 1998; 44:394–8. 47:1141–7. 99 Albanese A, Bentivoglio AR, Del Grosso N, Cassetta E, 112 Carbon M, Niethammer M, Peng S, Raymond D, Frontali M, Valente EM, et al. Phenotype variability Dhawan V, Chaly T, et al. Abnormal striatal and tha- of dystonia in monozygotic twins. J Neurol 2000; lamic dopamine neurotransmission: Genotype-related 247:148–50. features of dystonia. Neurology 2009; 72:2097–103. 100 Chan J, Brin MF, Fahn S. Idiopathic cervical dysto- 113 Walker RH, Brin MF, Sandu D, Good PF, Shashidharan nia: clinical characteristics. Mov Disord 1991; P. TorsinA immunoreactivity in brains of patients 6:119–26. with DYT1 and non-DYT1 dystonia. Neurology 2002; 101 Quartarone A, Rizzo V, Morgante F. Clinical features 58:120–4. of dystonia: a pathophysiological revisitation. Curr 114 Holton JL, Schneider SA, Ganesharajah T, Gandhi S, Opin Neurol 2008; 21:484–90. Strand C, Shashidharan P, et al. Neuropathology 102 Obermann M, Yaldizli O, De GA, Lachenmayer ML, of primary adult-onset dystonia. Neurology 2008; Buhl AR, Tumczak F, et al. Morphometric changes of 70:695–9. sensorimotor structures in focal dystonia. Mov 115 Jankovic J. Treatment of hyperkinetic movement Disord 2007; 22:1117–23. disorders. Lancet Neurol 2009; 8:844–56. 103 Draganski B, Thun-Hohenstein C, Bogdahn U, 116 Nemeth AH. The genetics of primary dystonias and Winkler J, May A. “Motor circuit” gray matter related disorders. Brain 2002; 125:695–721. changes in idiopathic cervical dystonia. Neurology 117 Hwang WJ, Calne DB, Tsui JK, Fuente-Fernandez R. 2003; 61:1228–31. The long-term response to levodopa in dopa-responsive 104 Garraux G, Bauer A, Hanakawa T, Wu T, Kansaku K, dystonia. Parkinsonism Relat Disord 2001; 8:1–5. Hallett M. Changes in brain anatomy in focal hand 118 Albanese A. Terminology for preparations of botuli- dystonia. Ann Neurol 2004; 55:736–9. num toxins. What a difference a name makes. JAMA 105 Egger K, Mueller J, Schocke M, Brenneis C, 2011; 305: 89–90. Rinnerthaler M, Seppi K, et al. Voxel based morpho- 119 Albanese A, Barnes MP, Bhatia KP, Fernandez- metry reveals specific gray matter changes in primary Alvarez E, Filippini G, Gasser T, et al. A systematic dystonia. Mov Disord 2007; 22:1538–42. review on the diagnosis and treatment of primary 106 Delmaire C, Vidailhet M, Elbaz A, Bourdain F, Bleton (idiopathic) dystonia and dystonia plus syndromes: JP, Sangla S, et al. Structural abnormalities in the cer- report of an EFNS/MDS-ES Task Force. Eur J Neurol ebellum and sensorimotor circuit in writer’s cramp. 2006; 13:433–44. Neurology 2007; 69:376–80. 120 Watts CC, Whurr R, Nye C. Botulinum toxin injec- 107 Fabbrini G, Pantano P, Totaro P, Calistri V, Colosimo tions for the treatment of spasmodic dysphonia. C, Carmellini M, et al. Diffusion tensor imaging in Cochrane Database Syst Rev 2004, CD004327. patients with primary cervical dystonia and in 121 Balash Y, Giladi N. Efficacy of pharmacological patients with blepharospasm. Eur J Neurol 2008; treatment of dystonia: evidence-based review 15:185–9. including meta-analysis of the effect of botulinum 108 Carbon M, Kingsley PB, Tang C, Bressman S, Eidelberg toxin and other cure options. Eur J Neurol 2004; D. Microstructural white matter changes in primary 11:361–70. torsion dystonia. Mov Disord 2008; 23:234–9. 122 Bentivoglio AR, Fasano A, Ialongo T, Soleti F, 109 Delmaire C, Vidailhet M, Wassermann D, Descoteaux Lo Fermo S, Albanese A. Fifteen-year experience M, Valabregue R, Bourdain F, et al. Diffusion abnor- in treating blepharospasm with Botox or Dysport: malities in the primary sensorimotor pathways in same toxin, two drugs. Neurotox Res 2009; writer’s cramp. Arch Neurol 2009; 66:502–8. 153:224–31.

Albanese_c08.indd 133 12/24/2011 6:56:27 AM 134 Chapter 8

123 Mejia NI, Vuong KD, Jankovic J. Long-term botuli- pallidus internus in patients with primary general- num toxin efficacy, safety, and immunogenicity. Mov ized dystonia: long-term results. J Neurosurg 2004; Disord 2005; 20:592–7. 101:189–94. 124 Brin MF, Comella CL, Jankovic J, Lai F, Naumann M. 138 Krause M, Fogel W, Kloss M, Rasche D, Volkmann Long-term treatment with botulinum toxin type A in J, Tronnier V. Pallidal stimulation for dystonia. cervical dystonia has low immunogenicity by mouse Neurosurgery 2004; 55:1361–70. protection assay. Mov Disord 2008; 23:1353–60. 139 Krauss JK, Pohle T, Weber S, Ozdoba C, Burgunder 125 Albavera-Hernandez C, Rodriguez JM, Idrovo AJ. JM. Bilateral stimulation of globus pallidus internus Safety of botulinum toxin type A among children for treatment of cervical dystonia. Lancet 1999; 354: with spasticity secondary to cerebral palsy: a system- 837–8. atic review of randomized clinical trials. Clin Rehabil 140 Coubes P, Roubertie A, Vayssiere N, Hemm S, 2009; 23:394–407. Echenne B. Treatment of DYT1-generalised dystonia 126 Burke RE, Fahn S. Double-blind evaluation of by stimulation of the internal globus pallidus. Lancet trihexyphenidyl in dystonia. Adv Neurol 1983; 2000; 355:2220–1. 37:189–92. 141 Egidi M, Franzini A, Marras C, Cavallo M, Mondani M, 127 Burke RE, Fahn S, Marsden CD. Torsion dystonia: a Lavano A, et al. A survey of Italian cases of dystonia double blind, prospective trial of high-dosage treated by deep brain stimulation. J Neurosurg Sci trihexyphenidil. Neurology 1986; 36:160–4. 2007; 51:153–8. 128 Jankovic J. Treatment of hyperkinetic movement 142 Borggraefe I, Mehrkens JH, Telegravciska M, disorders with tetrabenazine: a double-blind crosso- Berweck S, Botzel K, Heinen F. Bilateral pallidal ver study. Ann Neurol 1982; 11:41–7. stimulation in children and adolescents with primary 129 Kenney C, Hunter C, Jankovic J. Long-term tolerability generalized dystonia - Report of six patients and of tetrabenazine in the treatment of hyperkinetic move- literature-based analysis of predictive outcomes ment disorders. Mov Disord 2007; 22:193–7. variables. Brain Dev 2010; 32:223–8. 130 Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain 143 Isaias IU, Alterman RL, Tagliati M. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004; stimulation for primary generalized dystonia: long- 21:18–30. term outcomes. Arch Neurol 2009; 66:465–70. 131 Kupsch A, Benecke R, Muller J, Trottenberg T, 144 Krauss JK. Deep brain stimulation for cervical dysto- Schneider GH, Poewe W, et al. Pallidal deep-brain nia. J Neurol Neurosurg Psychiatry 2003; 74:1598. stimulation in primary generalized or segmental 145 Ostrem JL, Marks WJ, Jr., Volz MM, Heath SL, Starr dystonia. N Engl J Med 2006; 355:1978–90. PA. Pallidal deep brain stimulation in patients with 132 Capelle HH, Krauss JK. Neuromodulation in cranial-cervical dystonia (Meige syndrome). Mov Dystonia: Current Aspects of Deep Brain Stimulation. Disord 2007; 22:1885–91. Neuromodulation 2009; 12:8–21. 146 Berman BD, Starr PA, Marks WJ, Ostrem JL. 133 Lyons MK, Birch BD, Hillman RA, Boucher OK, Induction of bradykinesia with pallidal deep brain Evidente VG. Long-term follow-up of deep brain stimulation in patients with cranial-cervical dystonia. stimulation for Meige syndrome. Neurosurg Focus Stereotact Funct Neurosurg 2009; 87:37–44. 2010; 29:E5. 147 Pillon B, Ardouin C, Dujardin K, Vittini P, Pelissolo 134 Romito LM, Franzini A, Perani D, Carella F, Marras A, Cottencin O, et al. Preservation of cognitive func- C, Capus L, et al. Fixed dystonia unresponsive to pal- tion in dystonia treated by pallidal stimulation. lidal stimulation improved by motor cortex stimula- Neurology 2006; 66:1556–8. tion. Neurology 2007; 68:875–6. 148 The National Institute for Clinical Excellence. Selective 135 National Institute for Health and Clinical Excellence. peripheral denervation of cervical dystonia. 2004. Deep brain stimulation for tremor and dystonia 149 Albright AL, Barry MJ, Shafton DH, Ferson SS. (excluding Parkinson’s disease). http://www nice org Intrathecal baclofen for generalized dystonia. Dev uk/guidance/IPG188 2006. Med Child Neurol 2001; 43:652–7. 136 Holloway KL, Baron MS, Brown R, Cifu DX, Carne W, 150 Romito LM, Elia AE, Franzini A, Bugiani O, Albanese Ramakrishnan V. Deep brain stimulation for dystonia: A. Low-voltage bilateral pallidal stimulation for a meta-analysis. Neuromodulation 2006; 9:253–61. severe Meige syndrome in a patient with primary 137 Coubes P, Cif L, El Fertit H, Hemm S, Vayssiere N, segmental dystonia: case report. Neurosurgery 2010 Serrat S, et al. Electrical stimulation of the globus Sep; 67(3 Suppl Operative):E308.

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Historical background neuronal networks associated with dystonia. However, because making a diagnosis can be Dystonia is a hyperkinetic movement disorder challenging, clinical red flags are an important defined by involuntary twisting and repetitive aid to the clinician. Examples of clinical clues movements resulting in abnormal postures [1]. pointing towards a secondary etiology are sum- Historically, one of the first descriptions of the marized in the following (see also Box 9.1) and condition may be that by Destarac from 1901 who syndromic associations will be discussed in the reported generalized dystonia affecting the neck, following. arm, pelvis muscles, and feet in a teenage girl. Soon after, in 1908, Schwalbe described several patients, some of whom had a suggestion of Box 9.1 Clinical features suggestive hereditability. The term “dystonia” itself was of secondary dystonia coined by Oppenheim. Much was written following this, documenting the details of the clinical • Sudden onset and/or rapid progression phenotype and the disease course, the underlying • Unusual distribution such as: different etiologies and pathophysiology, and Hemidystonia outcome. Cranial onset in childhood Dystonia syndromes can be classified by onset Adult-onset of leg dystonia age, distribution of symptoms, and the underly- • Unusual disease course such as: ing etiology. With respect to the latter, dystonic Restriction to focal or segmental dystonia in patients with childhood-onset syndrome’s primary and secondary forms can be Progression to generalized dystonia of adult-onset broadly distinguished. Secondary forms may be dystonia due to strategic brain lesions, metabolic disease, • Prominent orobulbar involvement neurodegenerative conditions, or following expo- • Absence of “sensory tricks” sure to drugs (in particular dopamine antagonists) or toxins [2–4]. In particular, postmortem • Other neurological or systemic signs (except tremor) studies gave insight into which brain areas and

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Phenomenology and other Dystonia with prominent orobulbar clinical features involvement While some primary dystonias may have laryngeal Sudden onset of symptoms involvement, prominent orolingualbuccal dystonia In primary dystonia onset is usually slow (with is uncommon in primary dystonia and a secondary the exception of the genetic form of “Rapid or heredodegenerative form should be considered Onset Dystonia Parkinsonism”, DYT 12). When [6], particularly when severe. symptoms develop acutely, a secondary cause, such Primary dystonias with prominent orobulbar as a vascular event or a metabolic disequilibrium, involvement include DYT4 (“whispering dysto- should be investigated for. Psychogenic dystonia nia,” the underlying gene remains unkown), can also have a sudden onset. DYT6 (due to mutations in the THAP1 gene, as recently identified), DYT12 (“rapid-onset dystonia An unusual distribution parkinsonism”) due to mutations in the ATP1A3 The group of primary dystonias has been reviewed gene and DYT17 (recessively inherited, linked to in the preceding chapter [5]. In recent years there the chromosome 20, gene not yet identified) have been advances in neurogenetics and the dystonia [7–10]. clinical phenotypes of the genetic dystonia forms Among the group of secondary dystonias, particu- have been delineated, for example of DYT1 dystonia larly previous neuroleptic intake should be thought where symptoms usually begin in childhood in of; but also certain genetic disorders such as thelower limbs and later become generalized [5]. pantothenate kinase-associated neurodegenera- Indeed, being aware of the classic phenotypes is tion (PKAN, also known as Hallervorden–Spatz important to recognize patients in whom the disease) due to mutations of the PANK2 gene, neuro- distribution either fits the patterns associated with acanthocytosis, neuroferritinopathy, and Lesch– genetic forms and who should thus be considered Nyhan syndrome can produce dystonia with marked for genetic testing, or patients in whom the distri- orobulbar involvement [6]. With the exception of bution is atypical and who should be thoroughly neuroferritinopathy (autosomal dominant inherit- investigated for a secondary cause. An example for ance) these latter genetic diseases follow autosomal the latter may be the onset of leg dystonia in an recessive inheritance and family history may thus adult, or hemidystonia. The latter may be a hint be negative for a similar disorder, but there may be toward a brain lesion. (See Video 9.1.) a history of consanguinity (see Video 9.2).

Video 9.1 Hemidystonia following basal Ocular motor signs and fundus oculi ganglia lesion We expect patients with primary dystonia to have This man has a past medical history of a trauma causing a normal eye movements and the presence of an eye left basal ganglia lesion. The video shows a hemidystonia of the right arm when the arms are outstretched and movement disorder may hint toward a secondary with the elbow flexed. Unilateral symptoms should raise form of dystonia. Ocular motor dysfunction can, for the clinical suspicion of a structural lesion. [Video example, manifest as supranuclear gaze palsy and courtesy of Kailash Bhatia, MD, London, UK] this has been observed in Niemann–Pick type C and PKAN, both inherited autosomal recessively. In the neurovisceral lipid storage disorder Niemann–Pick type C supranuclear gaze palsy was in fact present in 75% of adult-onset cases and a presenting sign in 8% of cases [11]. The presence of retinitis pigmentosa is another useful sign to narrow down the list of differential http://bit.ly/s5Z1sa diagnoses in patients with dystonia. Most importantly,

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Video 9.2 Dystonia in PKAN This 38-year-old woman has generalized dystonia with a retrocollis and arm dystonia (left more than right) when walking. Note the prominent sialorrhoea and oromandibular-lingual dystonia. The differential diagnosis of prominent oromandibular dystonia includes pantothenate kinase-associated neurodegeneration (PKAN) (see main text). On work-up the MRI of the patient showed the eye-of-the-tiger sign and genetic testing revealed compound heterozygous PANK2 mutations. (see Aggarwal et al. Indian- subcontinent NBIA: Unusual phenotypes, novel PANK2 mutations and undetermined genetic forms. Mov. Disord. 2010;25:1424-31 for more details.

http://bit.ly/uX1z2i

Figure 9.1 Woodhouse Sakati syndrome is a rare autosomal recessive multisystemic neuroendocrine PKAN (or the allelic disorder referred to as HARP h disorder characterized by fronto-parietal alopecia, syndrome – characterized by ypoprebetalipopro- diabetes mellitus, hypogonadism, deafness, mental a r teinemia, canthocytosis, etinitis pigmentosa, retardation, and extrapyramidal features. Note the and pallidal degeneration), GM2 gangliosidosis, characteristic pattern of hair loss in this patient. (See and metachromatic leukodystrophy should be Steindl et al. [16] for further details of this patient.) considered. mental retardation, and extrapyramidal features Hearing loss (Figure 9.1) [15, 16]. However, there is phenotypic The combination of “dystonia and deafness” is and genetic variability. characteristic of the mitochondrial disorder Mohr– Tranebjaerg syndrome associated with mutations in Dystonia and peripheral neuropathy the DDP1 gene [12]. Other mitochondrial diseases The presence of neuropathy is not a feature of may produce a complex phenotype consistent of primary dystonia, although the pathophysiological neurological features with movement disorders, role of the sensory system is being discussed. visual problems (blindness), hearing impairment Hallett has suggested that dystonia may be a and heart problems [13]. sensory disorder [17] and others are investigating Another complex disorder with phenotypic the presence of subclinical impairment of sensory similarities to mitochondrial disease is the discrimination as a possible endophenotype of autosomal recessively inherited disorder with dystonia [18]. the name of Woodhouse–Sakati syndrome for Neuropathy may be secondary to diabetes melli- which the underlying cause was recently identified. tus and the combination of dystonia and diabetes is The full function of the associated gene, C2orf 37, seen in acerulpla sminemia (a rare genetic disorder and the encoded nucleolar protein remain with autosomal recessive inheritance due to muta- unknown [14]. The phenotype is characterized tions of the ceruloplasmin gene which is character- by hypogonadism, alopecia, diabetes mellitus, ized by movement disorders, dementia, and diabetes

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mellitus), mitochondrial disease and the Video 9.3 Complex regional pain syndrome Woodhouse–Sakati syndrome (for these see above). Once diabetes has been excluded, but ataxia is This patient is 47 years old. At age 46, she noticed rigidity and tension in the right hand and gradually additionally present, there are also a number of developed a clenched fist over the following week. differentials to consider. This includes the common Local skin changes mainly consisted in swelling and recessive forms of ataxia, such as Friedreich’s ataxia dyschromia. A clinical diagnosis of complex regional [19] and ataxia telangiectasia [20, 21] and their pain syndrome was made. The videotape shows the differential diagnoses [22]. In all these ataxia, clenched fist due to fixed dystonia of the right hand. The patient is asked to open her fingers and raise her dystonia and peripheral neuropathy may be arms. Then, the patient is asked to lay down the fingers present. For example, in a study of 70 ataxia and open her hands. There is no impairment in the left telangiectasia patients, dystonia was present in 55 hand, whereas on the right hand side the patient can and peripheral neuropathy 50 of them [20]. A less only move the thumb. No overflow or mirroring are common cause of this combination is the young- detected during hand movements. [Video courtesy of Alberto Albanese, MD, Milan, Italy] onset variant of Niemann–Pick type C disease [11]. Because the presence of vertical gaze palsy is also characteristic (see above) in Niemann–Pick type C, which is present in 75–80% of patients, this should also be looked for. A further clue toward this diagnosis may be hepato- or splenomegaly which are present in about 30 to 90% of cases [11, 23]. Notably, the combination of dystonia, neuropathy http://bit.ly/v17UZg and ataxia has also been reported for some of the autosomal dominant spinocerebellar ataxias [24], e.g. SCA 3 [25]. Dystonia and parkinsonism Furthermore, the combination of peripheral In addition to pure dystonic and pure parkinsonian neuropathy, progressive dystonia and ataxia, as syndromes, there are conditions with an overlapping well as a cognitive decline is seen in metachro- phenotype of these symptoms. First, dystonic matic leukodystrophy caused by mutations in the conditions may have superimposed parkinsonism, arylsulfatase A gene [26]. as seen in dopa-responsive dystonia or Wilson Finally, patients with complex regional pain disease. Second dystonia may be a seen in (or even syndrome (CRPS) may have additional dystonia. be the presenting feature of) various parkinsonian CRPS, formerly referred to as reflex sympathetic disorders. Dystonia in a drug-naive patient with dystrophy is defined as regional, post-traumatic, features of idiopathic parkinsonism would however neuropathic pain problem affecting one or more be atypical. Its presence may, on one hand, be a red limbs [27] and patients may experience hyper- flag toward an atypical parkinsonian syndrome esthesia, hyperalgesia or allodynia, temperature like progressive supranuclear palsy (PSP), multiple asymmetry, or abnormal sudomotor (sweating) system atrophy (MSA), or corticobasal degeneration activity. In addition there may be local edema, (CBD) [31]. Dystonia may then manifest as axial changes of skin color, hair, or nails. Particularly in dystonia and blepharospasm (levator inhibition) type 1 CRPS, motor dysfunction including dystonia, causing the starring expression associated with PSP; often fixed, may occur [28, 29] (see Video 9.3). The antecollis and facial dystonia in MSA; or the dystonic pathogenesis of CRPS and the relation to dystonia arm posture seen in CBD. On the other hand, remain poorly understood. An association with parkinsonism associated with dystonia may be seen small fibre neuropathy has been discussed [30]; in some of the genetic disorders. For example, in however, there is also an ongoing debate regarding early-onset parkinsonism, including the parkin- a possible psychogenic nature of dystonia in associated variant, dystonia may intermittently be CRPS [28]. present as so-called exercise-induced paroxysmal

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foot dystonia, and this may precede signs of characterized by rapidly progressive dementia, parkinsonism by some years [32]. The combination mutism, ataxia, and extrapyramidal and pyramidal of young-onset dystonia and parkinsonism is involvement [35]. The movement disorder is typically also seen in other neurodegenerative diseases characterized by focal or generalized myoclonus like the rare autosomal recessive disorders (present in 80–100% of cases), but dystonia occurs with nigrostriatal-pallidal-pyramidal degeneration, and may rarely be a presenting sign [35–37] (see inclu ding Kufor Rakeb disease (PARK9) or PLA2G6- Video 9.4). Dystonia in Creutzfeldt–Jakob disease is associated neurodegeneration (PARK14) [33] (also then usually unilateral and distal but may become see review by Schneider et al. [34]). generalized in later stages of the disease [35]. Overall, Most frequent, however, is dystonia in the con- the course of the disease is progressive, which should text of parkinsonism as a complication of dopamin- alert the clinician to this diagnosis. Furthermore, HIV ergic treatment, for example as peak-dose dystonia, encephalopathy is a cause of dementia, and dystonia diphasic dystonia, and off-dystonia [31]. may be present [38]. Finally, dementia may also be a symptom in the Dystonia with progressive dementia complex autosomal recessive dystonia parkinso- Progressive dementia is not a feature of the nian syndromes mentioned above [34]. primary dystonias like the young-onset DYT1- related dystonia or the adult-onset sporadic forms. Progressive dementia is, however, one of the core Neuroimaging features features of Huntington disease and the Huntington disease-look like syndromes (including HDL4/ Investigations will confirm or exclude the suspected SCA17], as well as neuroacanthocytosis and PKAN. clinical diagnosis. Neuroimaging, for example, can Indeed, chorea is the main movement disorder in reveal patterns that are characteristic of certain these conditions, however, prominent dystonia can conditions. occur. A further condition to consider is Creutzfeldt– First, strategic lesions in the basal ganglia, Jakob disease, a rare neurodegenerative disease brainstem, cerebellum, or cortical areas (parietal and frontal) can result in dystonia [39–47] and should be looked for; however, not all basal ganglia lesions necessarily result in neurological Video 9.4 Creutzfeldt–Jakob disease symptoms or signs. If present, there may be a This woman presented cognitive impairment with relationship between the distribution of dystonia subacute onset at the age of 58. Few weeks later she and the localization of such lesion: for example, developed myoclonic dyskinesias with prevalent thalamic lesions are more likely to result in hand involvement of the right hand. A brain MRI showed hyperintensities in the frontal cortex, basal ganglia and dystonia, while brainstem lesions are associated insula. The EEG showed severe disorganization of the with cranial dystonias such as blepharospasm, and signal with evidence of widespread periodic activity. putaminal lesions, were found in patients with A diagnosis of Creutzfeldt-Jakob disease was made. The hemidy stonia or limb dystonia. As mentioned videotape shows myoclonus and dystonic posturing of above, in hemidystonia, lesions are often unilateral, the right hand. [Video courtesy of the Neurophysiology Unit, Carlo Besta Institute, Milan, Italy] contralaterally to the dystonia. The cause of strategic lesions is variable and includes vascular causes, space-occupying lesions, trauma, inflammation, atrophic changes in the context of neurodegeneration or accumulation of metals (such as iron, copper, manganese, etc.; see Box 9.2). In particular, metal deposition disorders have attracted interest in recent years. It is known that http://bit.ly/rMOQL6 the basal ganglia host high concentrations of metals

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Box 9.2 Differential diagnosis of basal ganglia metal deposition

Iron: - NBIA type 1 (pantothenate kinase- associated neurodegeneration, previously known as Hallervorden– Spatz disease) - NBIA type 2 (PLA2G6-associated neurodegeneration, PARK 14) - Kufor Rakeb disease (PARK 9) - Aceruloplasminemia - Neuroferritinopathy Copper: - Wilson disease Manganese: - Exposure to manganese as seen in mine workers or after illicit drug use - Chronic liver dysfunction Calcium: - Hypoparathyroidism - Infections (e.g. toxplasmosis, rubella, cytmomegaly, herpes, HIV) - Following carbon monoxide poisoning - Familial, Fahr disease (striopallidodentate calcinosis) Figure 9.2 Eye of the tiger sign on T2-weighted axial brain MRI in a genetically proven PKAN patient. including iron, copper, and manganese which act as cofactors for metabolic activity. In the case of excessive metal accumulation, however, this may cause hyperintensity (probably representing fluid dysfunction and disease. Such metal deposition can accumulation or edema). On axial slides, this radio- be detected by neuroimaging on CT (e.g. copper) or logical pattern resembles an eye-of-the-tiger [48] MRI (e.g. iron or manganese). In recent years, in (Figure 9.2) and there may be a high correlation particular, iron deposition disorders have received with the presence of PANK2 gene mutations [48, growing attention and a new term referring to 53]. NBIA type 2 is associated with mutations in the these disorders, “syndromes of neurodegeneration PLA2G6 gene on chromosome 22q13 encoding a with brain iron accumulation” (NBIA), has been calcium-independent phospholipase. The clinical coined. This group entails the condition of PKAN phenotype is heterogeneous and includes infantile (NBIA type 1, also known as Hallervorden–Spatz neuroaxonal dystrophy and adolescence/adult-onset disease), PLA2G6-associated neurodegeneration dystonia parkinsonism, and it is a key differential (NBIA type 2, PARK14) [33], neuroferritinopathy, diagnosis of PKAN. As in PKAN there is iron deposi- and aceruloplasminemia [48, 49]. In addition, there tion on MRI imaging, however there is no classical is recent evidence that Kufor Rakeb disease eye-of-the-tiger sign, but there is only a hypointen- (PARK9) and FA2H-associated neurodegeneration sity in the globus pallidus, whereas the central may also belong to this group of the NBIAs [50, 51]. hyperintensity is lacking. Notably, however, normal McNeill et al. [52] proposed that the different MRI imaging has also been reported in a gene-proven NBIA syndromes may be distinguished with gradi- case of PLA2G6-associated neurodegeneration and ent recalled echo (GRE) T2*-weighted and fast the disorder should thus also be considered when spin echo T2-weighted brain MRI. The authors find iron is absent [33]. T2*-weighted MRI scans of that in PKAN iron deposits are localized within the neuroferritinopathy fall into two groups [52]: first, globus pallidus interna and can be depicted as those with basal ganglia hypointensity; and, second, hypointense signal (representing iron) with a central those with confluent hyperintensity (probable

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cavitation) of the globi pallidi and the putamen their age, should be further investigated where with hypointensity of the substantia nigra and other basal ganglia or brain areas are affected. The dentate nuclei. In a recent study, a subset of patients differential diagnosis is wide and includes metabolic, had additional caudate or thalamus involvement. infectious, toxin-induced, and degenerative causes An eye-of-the-tiger sign indistinguishable from [63]. Among the metabolic disorders, idiopathic or that seen in PKAN has also been observed in gene- surgical hypoparathyroidism is probably the most proven neuroferritinopathy cases [52]. Finally, in common cause of symmetric basal ganglia calcifi- the case of Kufor Rakeb disease reported by cation, and dystonia as presenting feature may Schneider et al. [50], iron deposition affected the occur [64]. Infections (including congenital forms) putamen and caudate rather than the globus by toxplasmosis, rubella, cytmomegaly, herpes, and pallidus as seen in NBIA types 1 and 2. Thus, there HIV may result in basal ganglia damage with calcifi- is an overlap of features between the different cations and secondary dystonia [65, 66]. Following syndromes. Furthermore, there are other patients carbon monoxide poisoning, movement disorders with iron deposition on MRI who do not carry including dystonia may develop as a part of delayed mutations in any of the associated genes, suggesting encephalopathy [67] and imaging may reveal the existence of yet unrecognized NBIA disorders. basal ganglia calcifications [68]. Neurodegenerative Copper deposition also shows as hyperintense causes include Wilson disease [69]. signal on T2-weighted scans. Copper deposition Last, but not least, familial causes of basal ganglia in the putamen and globus pallidus, liver, and calcifications with autosomal dominant inheritance cornea are characteristic of Wilson disease, an have been recognized (and also referred to as important differential diagnosis of secondary striopallidodentate calcinosis or Fahr disease), and dystonia, particularly in young patients [54, 55]. dystonia has been observed [69]. This is known as the “face of the giant panda” sign (referring to the combination of high signal intensity in the tegmentum except for the red Prevalence and etiology nucleus, with preservation of signal intensity of the lateral portion of the pars reticulata of the How common is secondary dystonia? Prevalence substantia nigra, and hypointensity of the superior data on secondary dystonia are limited. A Brazilian colliculus) [56]. study of 122 patients with a dystonic syndrome, 46 Manganese accumulation has been associated (38%) were found to have a symptomatic form [70]. with secondary parkinsonism following mangan- Among these, the most frequent causes were tardive ese exposure (for example, in mineworkers or after dystonia (35%) and perinatal cerebral injury (30%). illicit drug use) [57] or with chronic liver failure Other causes included stroke (13%), encephalitis [58]. In the basal ganglia manganese accumulates (6.5%), and Wilson disease (4%). Causes were more symmetrically within the globus pallidum and is common in certain age groups: Younger patients depicted as hyperintensity on T1 sequences. tended to have had perinatal cerebral injury or Dystonia may also be prominent [59–62]. encephalitis preceding their dystonia. In older Calcium deposition can be easily detected by CT patients stroke and exposure to drugs (tardive imaging as high-intense lesions and incidental dystonia) were more common. In a recent study of a calcifications are relatively frequent (up to 1.5% of total of 706 patients studied by Wenning et al. [71] CT scans). Within the basal ganglia, calcium most of 16 elderly patients with dystonia, 10 (62.5%) commonly affects the globus pallidus and is usually were classified as having a secondary form. Of these, benign, in most cases idiopathic or age-related [63]. 8 were drug-induced dystonias, highlighting the In view of this, it has been proposed that presence importance of this etiology. This is in line with a of globus pallidus calcifications only requires large study of more than 3,000 dystonia patients, further elaboration when the patient is younger 29% of which had a secondary form: tardive than 40. In addition, all patients, irrespective of dystonia was the leading cause [72, 73].

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Treatment as a peripheral blood smear to screen for neuroacathocytosis, or neuroimaging, may help to Therapy depends on the underlying etiology. reach at the correct diagnosis. Space-occupying strategic lesions should be removed surgically, if possible. Infectious causes should be treated with antibiotic, antiviral, or anti- Acknowledgments fungal treatment as appropriate. Similarly, meta- SAS was supported by the Deutsche Forschung- bolic and hormonal imbalances should be addressed sgemeinschaft (German Research Foundation) and by resetting hemostasis. In secondary dystonia due a research grant from the University of Lübeck to drug or toxin exposure, the triggering factors (E48.2009). should be withdrawn. If symptoms remain, symptomatic treatment can be explored [74]. There are three main therapeutic References routes which include medication, surgical interventions, and supportive methods. The goal is to correct 1 Fahn S. Concept and classification of dystonia. Adv abnormal postures, prevent contractures, reduce Neurol 1988; 50:1–8. pain, and improve function and quality of life [75]. 2 Calne DB, Lang AE. Secondary dystonia. In: Fahn Anticholinergic agents (such as trihexyphenidyl) is S, Marsden CD, Calne DB, eds. Dystonia 2. New York: the drug of choice for generalized dystonias. On fail- Raven Press, 1988; pp 9–33. ure, muscle relaxants like baclofen can bring bene- 3 Hartmann A, Pogarell O, Oertel WH. Secondary fit. All young-onset patients should also have a trial dystonias. J Neurol 1998 Aug; 245(8):511–18. of levodopa to exclude dopa-responsive dystonia. 4 Sethi KD. Drug-induced Movement Disorders. New York, Basel: Marcel Dekker, 2006. For patients with focal dystonia botulinum toxin is 5 Bressman S. Genetics of dystonia. J Neural Transm the drug of choice, injected into the affected muscle Suppl 2006; 70:489–95. [76]. For severe or treatment-resistant cases, surgi- 6 Schneider SA, Aggarwal A, Bhatt M, et al. Severe cal interventions like deep brain stimulation can be tongue protrusion dystonia: clinical syndromes promising. Last, but not least, patients benefit from and possible treatment. Neurol 2006 Sep 26; additive supportive therapy such as physiotherapy 67(6):940–3. and speech therapy. 7 Djarmati A, Schneider SA, Lohmann K, et al. Mutations in THAP1 (DYT6) are associated with generalised dystonia with prominent spasmodic dysphonia – a genetic screening study. Lancet Neurol Conclusion 2009; 8(5):447–52. 8 Ahmad F, Davis MB, Waddy HM, et al. Evidence for While the presence of tremor is compatible with a locus heterogeneity in autosomal dominant torsion diagnosis of primary dystonia, there are other clini- dystonia. Genomics 1993 Jan; 15(1):9–12. cal features which point away from this diagnosis 9 Chouery E, Kfoury J, Delague V, et al. A novel locus but may be suggestive of a secondary or heredo- for autosomal recessive primary torsion dystonia degenerative etiology causing dystonia as a pre- (DYT17) maps to 20p11.22–q13.12. Neurogenet 2008 Oct; 9(4):287–93. dominant feature or as a part of a syndrome. 10 Fuchs T, Gavarini S, Saunders-Pullman R, et al. Clinical red flags include eye movement disorders, Mutations in the THAP1 gene are responsible for retinitis pigmentosa, or peripheral neuropathy, to DYT6 primary torsion dystonia. Nat Genet 2009 Mar; name a few. Syndromic associations, some of 41(3):286–288. which have been outlined in this chapter, can thus 11 Sevin M, Lesca G, Baumann N, et al. The adult form of be useful and help the clinician to narrow down Niemann-Pick disease type C. Brain 2007 Jan; 130 the list of differential diagnosis. Investigations such (Pt 1):120–33.

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12 Jin H, May M, Tranebjaerg L, et al. A novel X-linked 26 Yatziv S, Russell A. An unusual form of metachro- gene, DDP, shows mutations in families with deafness matic leukodystrophy in three siblings. Clin Genet (DFN-1], dystonia, mental deficiency and blindness. 1981 Apr; 19(4):222–7. Nat Genet 1996 Oct; 14(2):177–80. 27 Rho RH, Brewer RP, Lamer TJ, Wilson PR. Complex 13 Zeviani M, Di DS. Mitochondrial disorders. Brain 2004 regional pain syndrome. Mayo Clin Proc 2002; Oct; 127(Pt 10):2153–72. 77:174–80 Abs. 14 Alazami AM, Al-Saif A, Al-Semari A, et al. Mutations 28 Lang AE, Chen R. Dystonia in Complex Regional Pain in C2orf37, encoding a nucleolar protein, cause hypo- Syndrome Type 1. Ann Neurol 2010 (epub ahead of gonadism, alopecia, diabetes mellitus, mental retarda- print) Abs. tion, and extrapyramidal syndrome. Am J Hum Genet 29 Schrag A, Trimble M, Quinn N, Bhatia K. The syn- 2008 Dec; 83(6):684–91. drome of fixed dystonia: an evaluation of 103 patients. 15 Schneider SA, Bhatia KP. Dystonia in the Woodhouse Brain 2004 Oct; 127(Pt 10):2360–72. Sakati syndrome: A new family and literature review. 30 Oaklander AL, Fields HL. Is reflex sympathetic Mov Disord 2008; 23(4):592–6. dystrophy/complex rehional pain syndrome type 1 16 Steindl K, Alazami AM, Bhatia KP, et al. A novel C2orf37 a small fibre neuropathy? Ann Neurol 2009; 65: mutation causes the first Italian cases of Woodhouse 629–38 Abs. Sakati syndrome. Clin Genet 2010 Dec; 78(6):594–7. 31 Tolosa E, Compta Y. Dystonia in Parkinson’s disease. 17 Hallett M. Is dystonia a sensory disorder? Ann Neurol J Neurol 2006 Dec; 253(Suppl 7):7–13. 1995 Aug; 38(2):139–40. 32 Bozi M, Bhatia KP. Paroxysmal exercise-induced 18 Walsh R, O’Dwyer JP, Sheikh IH, et al. Sporadic dystonia as a presenting feature of young-onset adult onset dystonia: sensory abnormalities as an Parkinson’s disease. Mov Disord 2003 Dec; 18(12): endophenotype in unaffected relatives. J Neurol 1545–7. Neurosurg Psychiat 2007 Sep; 78(9):980–3. 33 Paisan-Ruiz C, Bhatia KP, Li A, et al. Characterization 19 Garcia Ruiz PJ, Mayo D, Hernandez J, et al. Movement of PLA2G6 as a locus for dystonia–parkinsonism. Ann disorders in hereditary ataxias. J Neurol Sci 2002 Oct Neurol 2009; 65(1):19–23. 15; 202(1–2):59–64. 34 Schneider SA, Bhatia KP, Hardy J. Complicated reces- 20 Woods CG, Taylor AM. Ataxia telangiectasia in the sive dystonia parkinsonism syndromes. Mov Disord British Isles: the clinical and laboratory features of 70 2009 Mar 15; 24(4):490–9. affected individuals. Q J Med 1992 Feb; 82(298): 35 Maltete D, Guyant-Marechal L, Mihout B, Hannequin 169–79. D. Movement disorders and Creutzfeldt–Jakob 21 Carrillo F, Schneider SA, Taylor AM, et al. Prominent disease: a review. Parkinsonism Relat Disord 2006 oromandibular dystonia and pharyngeal telangiectasia Mar; 12(2):65–71. in atypical ataxia telangiectasia. Cerebellum 2009; 36 Hellmann MA, Melamed E. Focal dystonia as the 8(1):22–7. presenting sign in Creutzfeldt–Jakob disease. 22 Le BI, Bouslam N, Rivaud-Pechoux S, et al. Frequency Mov Disord 2002 Sep; 17(5):1097–8. and phenotypic spectrum of ataxia with oculomotor 37 Sethi KD, Hess DC. Creutzfeldt–Jakob’s disease apraxia 2: a clinical and genetic study in 18 patients. presenting with ataxia and a movement disorder. Mov Brain 2004 Apr; 127(Pt 4):759–67. Disord 1991; 6(2):157–62. 23 Garver WS, Francis GA, Jelinek D, et al. The National 38 Wicki J, Germanier Y, Sztajzel R, Burkhard PR. Niemann-Pick C1 disease database: report of clinical Brueghel syndrome as a new manifestation of HIV features and health problems. Am J Med Genet A encephalopathy. Eur Neurol 2008; 60(2):107–8. 2007 Jun 1; 143(11):1204–11. 39 Tan EK, Chan LL, Auchus AP. Hemidystonia precipi- 24 Klockgether T. Hereditary Ataxias. In: Jankovic tated by acute pontine infarct. J Neurol Sci 2005 Jul J, Tolosa E, eds. Parkinson’s Disease and Movement 15; 234(1–2):109–11. Disorders, 5th edn. Philadelphia: Lippincott Williams & 40 Bhatia KP, Marsden CD. The behavioural and motor Wilkins, 2007; pp 421–35. consequences of focal lesions of the basal ganglia in 25 Klockgether T, Schols L, Abele M, et al. Age related man. Brain 1994 Aug; 117(Pt 4):859–76. axonal neuropathy in spinocerebellar ataxia type 41 Soland V, Evoy F, Rivest J. Cervical dystonia due to 3/Machado-Joseph disease (SCA3/MJD). J Neurol a frontal meningioma. Mov Disord 1996 May; Neurosurg Psychiat 1999 Feb; 66(2):222–4. 11(3):336–7.

Albanese_c09.indd 143 12/24/2011 6:57:48 AM 144 Chapter 9

42 LeDoux MS, Brady KA. Secondary cervical dystonia 57 de Bie RM, Gladstone RM, Strafella AP, Ko JH, Lang associated with structural lesions of the central AE. Manganese-induced Parkinsonism associated nervous system. Mov Disord 2003 Jan; 18(1):60–9. with methcathinone (Ephedrone) abuse. Arch Neurol 43 Kim JW, Lee PH. Dystonic head tremor associated 2007 Jun; 64(6):886–9. with a parietal lesion. Eur J Neurol 2007 Jan; 58 Park NH, Park JK, Choi Y, et al. Whole blood 14(1):e32–e33. manganese correlates with high signal intensities on 44 Khan AA, Sussman JD. Focal dystonia after removal T1-weighted MRI in patients with liver cirrhosis. of a parietal meningioma. Mov Disord 2004 Jun; Neurotoxicol 2003 Dec; 24(6):909–15. 19(6):714–16. 59 Kenangil G, Ertan S, Sayilir I, Ozekmekci S. Progressive 45 Burguera JA, Bataller L, Valero C. Action hand dysto- motor syndrome in a welder with pallidal T1 hyperin- nia after cortical parietal infarction. Mov Disord 2001 tensity on MRI: A two-year follow-up. Mov Disord Nov; 16(6):1183–5. 2006 Dec; 21(12):2197–2200. 46 Alarcon F, Tolosa E, Munoz E. Focal limb dystonia in a 60 Huang CC, Chu NS, Lu CS, et al. The natural history of patient with a cerebellar mass. Arch Neurol 2001 Jul; neurological manganism over 18 years. Parkinsonism 58(7):1125–7. Relat Disord 2007 Apr; 13(3):143–5. 47 Kostic VS, Stojanovic-Svetel M, Kacar A. Symptomatic 61 Huang CC, Chu NS, Lu CS, et al. Long-term progres- dystonias associated with structural brain lesions: sion in chronic manganism: ten years of follow-up. report of 16 cases. Can J Neurol Sci 1996 Feb; Neurol 1998 Mar; 50(3):698–700. 23(1):53–6. 62 Josephs KA, Ahlskog JE, Klos KJ, et al. Neurologic 48 Sethi KD, Adams RJ, Loring DW, et al. Hallervorden– manifestations in welders with pallidal MRI T1 Spatz syndrome: clinical and magnetic resonance imag- hyperintensity. Neurol 2005 Jun 28, 64(12):2033–9. ing correlations. Ann Neurol 1988 Nov; 24(5):692–4. 63 Anderson JC, Costantino MM, Stratford T. Basal 49 Chinnery PF, Crompton DE, Birchall D, et al. Clinical ganglia: anatomy, pathology, and imaging characteris- features and natural history of neuroferritinopathy tics. Curr Probl Diagn Radiol 2004 Jan; 33(1): caused by the FTL1 460InsA mutation. Brain 2007 28–41. Jan; 130(Pt 1):110–19. 64 Soffer D, Licht A, Yaar I, Abramsky O. Paroxysmal 50 Schneider S.A., Paisán-Ruiz C, Quinn N, et al. choreoathetosis as a presenting symptom in idiopathic ATP13A2 mutations (PARK9) cause Neurode- hypoparathyroidism. J Neurol Neurosurg Psychiat generation with Brain Iron Accumulation. Mov Disord 1977 Jul; 40(7):692–4. 2010 [Epub ahead of print]. 65 Abbruzzese G, Rizzo F, Dall’Agata D, et al. Generalized 51 Kruer MC, Paisán-Ruiz C, Boddaert N, et al. Defective dystonia with bilateral striatal computed-tomographic FA2H leads to a novel form of neurodegeneration lucencies in a patient with human immunodeficiency with brain iron accumulation (NBIA). Ann Neurol virus infection. Eur Neurol 1990; 30(5):271–3. 2010 Nov; 68(5):611–8. 66 Tolge CF, Factor SA. Focal dystonia secondary to cer- 52 McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSE ebral toxoplasmosis in a patient with acquired immune MRI distinguishes four subtypes of neurodegeneration deficiency syndrome. Mov Disord 1991; 6(1):69–72. with brain iron accumulation. Neurol 2008 Apr 29, 67 Choi IS, Cheon HY. Delayed movement disorders 70(18):1614–19. after carbon monoxide poisoning. Eur Neurol 1999; 53 Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, 42(3):141–4. clinical, and radiographic delineation of Hallervorden– 68 Illum F. Calcification of the basal ganglia following Spatz syndrome. N Engl J Med 2003 Jan 2; 348(1): carbon monoxide poisoning. Neuroradiol 1980; 33–40. 19(4):213–14. 54 Magalhaes AC, Caramelli P, Menezes JR, et al. Wilson’s 69 Manyam BV, Walters AS, Narla KR. Bilateral strio- disease: MRI with clinical correlation. Neuroradiol pallidodentate calcinosis: clinical characteristics of 1994; 36(2):97–100. patients seen in a registry. Mov Disord 2001 Mar; 55 Saatci I, Topcu M, Baltaoglu FF, et al. Cranial MR 16(2):258–64. findings in Wilson’s disease. Acta Radiol 1997 Mar; 70 Andrade LA, Ferraz HB. Idiopathic dystonia. Clinical 38(2):250–8. profile of 76 Brazilian patients. Arq Neuropsiquiat 56 Hitoshi S, Iwata M, Yoshikawa K. Mid-brain pathology 1992 Dec; 50(4):426–32. of Wilson’s disease: MRI analysis of three cases. 71 Wenning GK, Kiechl S, Seppi K, et al. Prevalence of J Neurol Neurosurg Psychiat 1991 Jul; 54(7):624–6. movement disorders in men and women aged 50–89

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years (Bruneck Study cohort): a population-based 75 Jankovic J. Treatment of dystonia. Lancet Neurol 2006 study. Lancet Neurol 2005 Dec; 4(12):815–20. Oct; 5(10):864–72. 72 Bressman S. Overview of dystonia. In: Adler CH, ed. 76 Simpson DM, Blitzer A, Brashear A, et al. Assessment: Clinical usefulness of Botulinum Toxin and Treatment Botulinum neurotoxin for the treatment of move- of Dystonia. Minneapolis, MN: American Academy of ment disorders (an evidence-based review): Report Neurology, 2002; pp 2–30. of the Therapeutics and Technology Assessment 73 Uc EY, Rodnitzky RL. Juvenile parkinsonism. Semin Subcommittee of the American Academy of Pediat Neurol 2003 Mar; 10(1):62–7. Neurology. Neurol 2008; 70:1699–1706 Abs. 74 Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2010 [Epub ahead of print] Abs.

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Albanese_p04.indd 147 12/24/2011 6:58:24 AM CHAPTER 10 Huntington Disease and Other Genetic Choreas Ainhi Ha and Joseph Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurol, Baylor College of Medicine, Houston, TX, USA

Historical background movements, classically choreic [1, 8]. The mean age at onset is approximately 40 years, but there The clinical syndrome of Huntington disease (HD), are descriptions of individuals who became symp- an autosomal dominant neurodegeneration [1], tomatic during infancy and as late as 9th decade of was first delineated in 1872 by George Huntington, life. Juvenile cases (less than 20 years of age at who reported: onset) constitute about 5.4 % of all cases of HD [9].

“Hereditary chorea … confined to certain and fortu- Premanifest HD nately a few families, and has been transmitted to Because of its serious implications, the diagnosis of them, an heirloom from generations away back in manifest HD is reserved for at-risk persons who the dim past. It is spoken of by those in whose veins have developed chorea or another movement the seeds of the disease are known to exist, with a disorder. A number of individuals, however, have kind of horror … There are three marked peculiari- prominent mood, thought, or personality disorders ties in this disease: 1. Its hereditary nature. 2. A that present in the years prior to onset of definitive tendency to insanity and suicide. 3. Its manifesting motor signs. Cognitive changes may also precede itself as a grave disease only in adult life” [2] onset of motor definitive symptoms [10]. The earliest cognitive indicator of HD is emotional recognition, The degeneration of the striatum was recognized which may be detected in gene-positive individuals as the essential neuropathologic feature around the more than 15 years from the pre dicted motor turn of the century [1, 3–5]. The gene for HD was diagnosis. Within 15 years of the predicted motor the first human gene to be localized by linkage diag nosis, a number of cognitive measures may analysis using restriction fragment length polymor- detect additional impairments, including time phisms [6], and the mutation was discovered to be production and speed of processing [11]. Mild an expansion of a trinucleotide repeat in a novel cognitive impairment may be present in nearly gene on the short arm of chromosome 4 [7]. 40 % of individuals with prediagnosed HD, with higher rates in individuals closer to the HD dia- Phenomenology and other gnosis [12]. One study examining prodromal HD clinical features patients who were estimated to be less than 9 years from their clinical dia gnosis found significantly HD is an autosomal dominant, neurodegenerative poorer performance scores on nearly all cognitive disease that causes disorders of motor control, tests compared with a control group [13]. emotional control, cognitive ability, and involuntary Individuals who had an estimated 9–15 years

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before their clinical diagnosis had poor performance Motor manifestations scores on about half of their cognitive tests. In one The appearance of a motor disorder in the presence study, prediagnostic CAG expanded individuals of a positive family history heralds the onset of appeared to demonstrate a more rapid decline in clinically manifest HD. This is confirmed by genetic some (but not all) neurocognitive and psychomotor testing. The prototypical movement disorder is measures, as they approached the estimated onset chorea, which interferes with voluntary motor of disease [14]. control and causes progressive physical disability Psychiatric symptoms may also be evident in [23]. Chorea, from the Greek word meaning, “to premanifest individuals. One study identified dance,” is an involuntary movement defined as specific psychiatric symptom dimensions (obses- a relatively continuous abnormal involuntary move- sive-compulsive, interpersonal sensitivity, anxiety, ment produced by jerk-like contractions of muscles paranoid ideation, and psychoticism) that differen- that move randomly from one part of the body to tiate non-mutation carriers from individuals in the early preclinical stages of HD who are either symptom free or have minor non-specific motor abnormalities [15]. Video 10.1 Mild generalized chorea Other signs that may portend onset of clinically in Huntington disease manifest HD include increased motor restlessness, This woman with Huntington’s disease is 35. She had slowing of saccadic eye movements, and slowing a positive family history with autosomal dominant or dysrhythmic production of rapid, repetitive transmission from her mother. Disease onset was at age 30. The videotape shows a florid choreatic disorder movements of the fingers or tongue [16, 17]. that is activated by speech and voluntary movements. Abnormalities in saccadic latency have been Chorea is also evident during walking, where it gives demonstrated in premanifest HD patients, with the appearance of a dance-like attitude. The involuntary significant changes seen from year to year [18]. movement causes disability in performing even simple Oculomotor defects may be seen in presympto- tasks, such as fastening and unfastening the watch belt. [Video courtesy of Alberto Albanese, MD, Milan, Italy] matic patients with a predicted time to clinical onset of up to 10 years [19]. Variability in speeded and metronome tapping tasks were also reported in manifest and premanifest HD in one cross-sectional study, and were more pronounced in the later stages [20]. The speeded tapping variability

in HD and premanifest HD correlated with the http://bit.ly/sHBlly UHDRS total motor score. In addition, tapping variables were associated with gray matter atrophy and cortical thinning. Such deficits may provide a possible outcome measure for use in future Video 10.2 Moderate chorea in Huntington preventative clinical trials [21]. disease Weight loss, which is a well-recognized mani- Young woman with HD and moderate generalized festation of established HD, has also been chorea. demonstrated in individuals in the early stages of HD, who do not yet have a clinically apparent movement disorder [1]. In addition, caloric intake may need to be increased to maintain body mass index in clinically unaffected gene carriers, suggesting increased energy expenditure due to subtle motor impairment or a hypermetabolic http://bit.ly/vr0xt8 state [22].

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another. Chorea also impairs the ability to produce Video 10.3 Chorea in Huntington disease sequences of movements and to rhythmically Patient with HD showing generalized, perioral and produce rapid repetitions of a single movement [24]. upper facial chorea, due to irregular, random, Apraxia, particularly ideomotor apraxia, is often asymmetrical, unpredictable frontalis contractions. present even at the onset [25], although language skills remain mostly intact. Patients are unable to learn complicated motor skills. Loss of voluntary motor control continues throughout the course of the illness until it causes complete inability to perform any purposeful motor act. Other motor signs include bradykinesia, dystonia, http://bit.ly/tG61vD imbalance, and speech disturbances. Bradykinesia generally coexists with chorea in the adult form of illness [26]. Juvenile cases and occasional young Video 10.4 Juvenile-onset Huntington adult cases can present with prominent parkinson- disease ism or rigidity-dystonia with little or no chorea 15 year old boy with juvenile HD (89 CAG repeats), (Table 10.1). diagnosed with mental retardation at age 6 years. A parkinsonian state with marked slowing of At age 9 years he began to have generalized seizures and developed involuntary jerk-like movements, eye movements is seen in the juvenile-onset problems with his balance and generalized slowness. cases (Westphal variant); seizures and myoclonus Subsequently developed dysarthria, myoclonus, and commonly complicate the course of juvenile-onset ataxia. Father committed suicide at age 41. MRI showed HD. Deep tendon reflexes are typically hyperactive, marked caudate and putamen atrophy. He also hung-up, and pendular [27]. Motor impersistence demonstrates marked blepharospasm and apraxia of eyelid opening as well as bradykinesia. Three years is another characteristic feature of HD, and may be later he has much more severe bradykinesia, postural demonstrated by the inability to maintain tongue instability, and spontaneous as well as stimulus-sensitive protrusion. myoclonus. The movement disorder in adult-onset HD changes with time. Chorea gradually decreases in amplitude and may be replaced by dystonia-rigidity in the end stages. Patients can develop fixed dystonic contraction of limb and axial muscles leading to contractures and immobility. Speech and swallowing dysfunction develop mid-stage of the illness http://bit.ly/voz4h4 and ultimately lead to inability to communicate

Table 10.1 Clinical features. Adult onset Juvenile onset

Age at onset 35–55 (mean age 40) Before 20 Initial Chorea, personality Personality changes, deterioration features changes. of school performance, rigidity, May have mild cognitive bradykineisa, dystonia. impairment. Late Dementia, abnormal eye Dementia, dysarthria, abnormal features movements, dystonia, eye movements, tremor, seizures, rigidity, bulbar dysfunction ataxia, myoclonus Duration 15–30 years 5–15 years

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14 seconds or more or if the Berg Balance Scale Video 10.5 Features associated with scores were 40 or less. Individuals with HD exhibit Huntington disease slower stepping response times, poorer dynamic This patient with HD has mild chorea, but marked balance, mobility and motor performance when inability to maintain tongue protrusion. She also demonstrated “hung-up” and “pendular” reflexes. compared with controls [31]. Subtle postural deficits in the setting of changing sensory conditions have also been reported in one study, involving not only manifest HD individuals, but also premanifest HD individuals up to 5 years before estimated disease onset [32]. The Tinetti Mobility Test has been examined in one study as a potential tool for assessment of balance and falls http://bit.ly/u74AEe risk in individuals in the ambulatory stages of symptomatic HD [33].

Psychiatric and behavioral Video 10.6 Progression of motor impairment manifestations in Huntington disease George Huntington described a “tendency to This patient with HD demonstrated typical chorea. insanity and sometimes that form of insanity that Eight years later she is in an end stage of the disease, markedly demented, dysarthric and having contracture leads to suicide, is marked.” Psychiatric disorders of the right hand. are prevalent in patients with HD. A variety of disturbances have been observed, including psychosis and hallucinations, delusional thought disorder, mood lability, anxiety, irritability, mania, obsessive behavior, or rigidity of thought. Severe psychiatric problems occur in one fifth of individuals. This includes suicidal ideation and attempts, and http://bit.ly/sldqUm irritability/aggression. Frank psychosis is relatively unusual, although delusions may occur. A study by the Huntington Study Group reported the probability of obsessive compulsive symptoms is approxi- and swallow. Autonomic dysfunction may also be mately three times greater in patients with clearly seen in patients with HD [28]. manifest disease than in those with no apparent Falls are common in patients with HD. In a study motor abnormalities [34]. Changes in tempera- of 45 early- to mid-stage HD patients, falls occurred ment or personality with irritability are common more commonly in patients with higher scores and often troublesome for family members. for chorea, bradykinesia, and aggression, as well as Disabling or overwhelming apathy from frontal lower cognitive scores [29]. In addition, HD lobe dysfunction is not unusual. Depression is the patients had decreased gait velocity and a decreased most common psychiatric manifestation of HD and stride length; fallers had increased stride length may be accompanied by emotional irritability with variability and a significantly greater trunk sway in outbursts of disruptive behavior. Health-related the mediolateral direction compared to non-fallers. quality of life in patients with HD appears to be Another study showed that over 50 % of HD determined by the depressive mood and greater patients had fallen more than twice in the previous functional incapacity, more so than by decreased 12 months [30]. They tended to have an increased motor and cognitive functions [35]. Suicide occurs risk of falls if the Timed “Up & Go” test scores were in 5 to 10 % of HD patients, and there is an increased

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risk of suicide for those at-risk for the disease [36]. expenditure also appears to increase with disease Paulsen and colleagues suggest that there are two duration [46]. critical periods for increased risk of suicide in HD. Weight loss, and alterations in sexual behavior The first is immediately before receiving a formal and wake–sleep cycle, frequently found in patients diagnosis of HD, and the second is in stage 2 of the with HD, have been attributed to involvement disease, when independence diminishes [37]. The of the hypothalamus even in early stages of depression subscale of the Hospital Anxiety and HD as demonstrated by PET and postmortem Depression Scale and the Depression Intensity studies [47]. Scale Circles have been found to be good screening measures for depression in the HD population in one study [38]. Epidemiology

Cognitive manifestations The prevalence of HD is geographically hetero- Cognitive decline occurs in all patients and may be geneous, probably related to the diaspora after the more, less, or equally as disabling as the motor founder mutation in the Middle Ages in southeast disorder in different patients [1, 39]. Decline in England. Thus, in certain regions of the world the cognitive ability most closely relates to the number prevalence is as high as 560 per 100,000 (Moray of years affected by HD [40]. Patients tend to be Firth, Scotland) and 700 per 100,000 (Lake disorganized and suffer from lack of initiative. Maracaibo, Venezuela) [27]. The prevalence of Some may show no awareness of their movement affected individuals in the United States has been or cognitive disorder. The cognitive profile is typi- estimated to be at 5 to 10 per 100,000 [48]. How- cally characterized by attention deficits, cognitive ever, there are concerns that the prevalence of HD slowing, impaired planning and problem solving, may actually be underestimated due to a variety of and visuoperceptual and construction deficits. In reasons, such as stigma associated with the disease contrast to the cognitive impairment seen in [49, 50], low expectations of medical interventions, Alzheimer disease, other cognitive deficits appear and potential discrimination from employers or to contribute to functional impairment in HD insurers [51]. The effect of the baby-boomer birth before the memory disturbance [41]. There is cohort, and the occurrence of new mutations may usually a more rapid decline in visuospatial function also play a contributory role [52]. The All Party as compared to verbal skills. Also, a more dramatic Parliamentary Group on Huntington’s disease, drop in performance IQ as opposed to verbal IQ aimed to promote HD research and care, also plans scores is seen [42]. One study demonstrated to investigate the true prevalence of HD”. of the evidence of impaired explicit motor sequence true prevalence of HD [53]. Approximately two to learning in premanifest and early HD, whereas four times as many individuals have inherited the implicit motor sequence learning was preserved mutation but are as yet asymptomatic. As an [43]. The Montreal Cognitive Assessment (MoCA) autosomal dominant disorder, there is no gender has been shown to achieve higher sensitivity with- predisposition and the disease is present world- out sacrificing specificity in many domains relative wide. Prevalence is correlated with European to the Folstein Mini Mental State Exam in mild to ancestry. HD is rare in Japan and China, and is seen moderate cognitive impairment in HD [44]. infrequently in African Americans. A nationwide population-based epidemiologic study in Taiwan Other manifestations found an average annual incidence rate of 0.1 per Progressive weight loss and muscle wasting is 100,000 [54]. Although the incidence rates and another feature of HD. Weight loss is likely to prevalence were much lower compared with result from a hypermetabolic state, and has estimates from Caucasian populations, the age been linked to CAG repeat length [45]. Energy distributions were similar.

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Etiopathogenesis At-Risk Observational Study (PHAROS) found that patients with intermediate repeat length expansions HD is an autosomal dominant disorder, and results overlapped on some behavioral measures of the from an expanded and unstable trinucleotide Unified Huntington’s Disease Rating Scale (UHDRS) repeat in the IT15 gene on the short arm of chro- with HD patients [60]. Kenney and colleagues mosome 4 [7]. There is a 50 % chance of inheriting reported a 65-year-old male with autopsy-proven the Huntingtin (HTT) gene from an affected parent. HD and 29 CAG repeats, suggesting that in rare Three nucleotides, cytosine—adenine–guanine cases, HD phenotype can occur in the normal CAG (CAG), normally form a trinucleotide and are repeat range [61]. Other cases of HD phenotype repeated in this gene. The gene produces a protein with intermediate CAG repeats have been reported called huntingtin (Htt). A normal person may have [62]. Motor and behavioral abnormalities have been as many as 35 repetitions of the CAG trinucleotide identified in individuals with intermediate length in the HTT gene. CAG repeats in the Cooperative Huntington’s Laboratory guidelines for HD Genetic Testing Observational Research Trial (COHORT) [63]. from the American College of Medical Genetics/ CAG repeat length is the major determinant of American Society of Human Genetics Huntington age at onset for HD with larger expansions respon- Disease Genetic Testing Working Group define the sible for earlier-onset disease [64, 65]. Individuals CAG repeat range of 40 or more to be consistent with shortest CAG expansions appear to have the with HD [55]. Individuals with 36–39 repeats are best prognosis [66]. Variability in age at onset categorized as HD allele with reduced penetrance, occurs after controlling for repeat length, especially and those with 27–35 are considered to have muta- in individuals with CAG repeat between 40 and 50, ble normal alleles. The HD allele with reduced where the repeat only determines 44 % of the penetrance range, with CAG repeats between 36 variability. In Venezuelan HD kindreds, the variance and −39, is considered abnormal. However, the HD in age of onset was attributable to genes other than phenotype is not always penetrant. A conservative the HTT gene and environmental factors [67]. estimate of penetrance in one observational study Genome-wide linkage analysis targets 2p25, 2q35, calculated that in this CAG repeat range, an 6q22 [68]. Other suggested regions are on chromo- individual has at least a 40 % chance of being some 5 (5p14 and 5q32). The Huntington disease asymptomatic at age 65 years and at least a 30 % MAPS study showed linkage for modifier of age at chance of being asymptomatic at age 75 years [56]. onset at 6q23–24. Evidence for linkage was also Such individuals may have offspring with clinical found at 18q22 [69]. HD who have a more expanded CAG repeat length The gender of the affected parent also modifies in the gene [57, 58]. The mutable normal allele age at onset with an earlier age at onset seen with (27–35 CAG repeats), otherwise referred to as paternal inheritance [65]. Children with juvenile intermediate alleles or high normal alleles, is onset have greater expansions typically between 60 defined as having a normal phenotype. Males with to 100 CAG repeats. Most juvenile-onset cases mutable normal alleles are at risk of transmitting an (90 %) have inherited HD from an affected father. HD allele with reduced or full penetrance (≥ 36) to It has been determined that marked expansion of offspring, even though they themselves will not the repeat length likely occurs in spermatogenesis, develop the disease [59]. Hendricks et al. estimated accounting for this sex-of-parent effect on the that the probability that a male with intermediate inheritance of juvenile-onset HD [70, 71]. or “high normal” (27–35) CAG repeats in one allele The pathogenic cause of the progressive will have an offspring with an expanded penetrant neurodegeneration in HD is not known, but studies allele ranges from 1/6,241 to 1/951. In recent years point to free radical toxicity [72], glutamate toxicity however, there has been some emerging evidence [73], and caspase activation [74–77] as potential of clinical disease in this group. Observations factors in pathogenesis. The neurodegeneration derived from the Prospective Huntington Disease affects the striatum prominently, but entire brain

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weight is decreased, and neuronal loss in cortex receptor-coactivator 1 (PGC–1α), a transcription and other nuclei has been documented. In the stri- cofactor that regulates mitochondrial biogenesis atum there is predominant loss of spiny projection and function, may provide a link between tran- neurons with preservation of the aspiny interneu- scription dysregulation and mitochondrial dysfunc- rons and large aspiny acetylcholinesterase positive tion in HD [85]. In addition, there is evidence that neurons [77]. This pattern has been produced in mutant Htt protein impairs intracellular trafficking animals by excitotoxic lesions and by the systemic of mitochondria, providing further evidence for a or local injection of mitochondrial toxins [79]. For possible pathogenic role of mitochondrial dysfunc- example, intrastriatal injections of quinolinic acid, tion in HD [86]. a glutamate agonist, into rat brain also reproduces Magnetic resonance spectroscopy (MRS) has closely the neurodegenerative changes found in documented an increase in brain lactate in patients HD [80] and serves as a model of an excitotoxic with HD as might be expected in the case of mito- lesion. Intraperitoneal administration of the mitochondrial dysfunction or increased excitatory stress chondrial toxin 3-nitropropionic acid also causes [87, 88]. The size of the HTT gene repeat has been progressive cell death in the striatum of rodent reported to affect mitochondrial function and may and non-human primates. Garcia and colleagues play as a disease modifier of other neurodegenera- describe activation of the c-Jun N-terminal kinase tive disorders. In the GenePD Study, there was no pathway during chronic 3-nitropropionic acid infu- effect on age at onset of familial Parkinson disease, sion leading to dorsolateral striatal cell death. In although 5.2 % of the sample had repeats in the addition, they found that the activation of c-Jun intermediate range (27 to 35 repeats), suggesting a N-terminal kinase pathway caused phosphoryla- relatively high prevalence of intermediate allele tion of c-Jun in vivo and in vitro models, which carriers in the general population [89]. In juvenile supports the role of phosphorylated c-Jun in HD patients, MRS has documented elevated gluta- causing selective striatal cell death [81]. The authors mate, mainly in the striatum but also in extrastri- postulate that similar activation of this pathway atal areas, and low striatal creatine [90]. In adults, may take place in HD brains by interactions with the glutamate elevations occur in preclinical and free radicals or glutamate toxicity. manifest patients, but low creatine levels were Mitochondrial dysfunction and abnormal energy found only in preclinical patients [91]. Evidence of metabolism is well documented in HD. However, mitochondrial dysfunction has also been demon- the precise cause and mechanism has not been strated in peripheral tissue. HD patients subjected clearly defined. Data from a number of studies to incremental cardiopulmonary exercise were suggest that the mutant huntingtin (Htt) protein found to have a lower anaerobic threshold on ven- impairs mitochondrial function directly as well as tilatory and cardiometabolic parameters associated and indirectly by dysregulation of transcriptional with an increase in plasma lactate, compared with processes [82]. The resulting defects include controls [92]. reduced Ca2+ uptake capacity, defects in the electron The mRNA for the HTT gene is widely expressed transport chain (ETC) activity, and increased in all tissues [93]. The mutated form of Htt protein sensitivity of mitochondria to Ca2+-induced perme- is found in both affected and unaffected regions of ability transition pore (mPTP) opening. Changes in the brain [94]. Thus, the regional specificity of the mitochondrial permeability can cause cytochrome c neuropathology is not explained by a differential release and subsequent caspase activation leading expression of the HTT gene in the brain. In a study to apoptotic cell death. Cell models have demon- using samples of caudate and whole blood from strated defects in mitochondrial complex II/III HD patients, it was shown that transcription is activity and to a lesser extent complex IV activity deregulated in large genomic regions in coordinated [83]. Evidence of mitochondrial respiratory fashion and that transcription in these regions is chain defects has also been identified in HD tissue associated with disease progression [95]. This [84]. The role of peroxisome proliferator-activated supports the notion of a common genome-wide

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1. Toxic gain Figure 10.1 Possible Abnormal protein- pathogenesis of HD. Folded wild type Misfolded mutant protein interaction protein protein (For example, binding with CBP)

Chaperones Abnormal Caspases accumulation of huntingtin fragments

2. Mitochondrial dysfunction 3. Dysregulation of neuronal signaling capabilities 4. Transcriptional dysregulation 5. Decreased neurotrophic support

mechanism of disruption of RNA transcription in containing Htt [102]. These inclusions are specific the brain and periphery of HD patients [96]. Indeed, to regions of the brain affected in HD. The microtu- there is growing evidence that HD is not merely a bular system of the cell may aid mutant Htt brain disease but a systemic disorder [97]. protein to gain access to the nucleus and help to Htt is a cytoplasmic protein. It is believed to play form inclusions [103, 104]. One laboratory study an important role in a number of biological demonstrated altered cell survival in response to processes, including synaptic transmission, intra- microtubule depolymerizing agents, with different cellular transport, and neuronal transcription [98]. responses depending on the presence or absence Using biochemical and live cell imaging, Marcora of mutant Htt [105]. The mutant Htt protein’s and Kennedy demonstrated that wild-type Htt also abnormal stretch of polyglutamines may confer stimulates the transport of nuclear factor k light- new properties to the protein and allow altered chain-enhancer of activated B cells (NF-kB) out of interactions with other proteins. For example, dendritic spines and supports active NF-kB in transglutaminase has been shown to crosslink neuronal nuclei. Also intriguing is the discovery with the pathologically expanded polyglutamine that normal Htt protein helps support brain-derived segment of Htt to help to form neuronal intranu- neurotrophic factor production in cortical neurons clear aggregates. Several other proteins have been that is then transported to striatal neurons. A recent described that interact with Htt [76, 106–111], and study also demonstrated a role of Htt in mitotic these interactions may possibly interfere with spindle orientation in Drosophila and mouse normal cell activity in select neurons (Figure 10.1). models [99]. Mutant Htt interferes with the function of the The proteolytic products of abnormal Htt cAMP responsive element binding protein (CBP), containing the expanded polyglutamine sequences which is required for neuronal health; its absence are sequestered in the nucleus where they interfere results in selective neuronal vulnerability and with gene regulation [98]. Neuronal intranuclear death [112]. CBP is an acetyltransferase enzyme inclusions occur in a mouse model transgenic for that activates transcription of important cell- the HD mutation [100]. These insoluble inclusions sustaining genes through acetylation of histones. contain a cleavage product of Htt formed only Mutant Htt binds with CBP and prevents its normal when polyglutamine stretches are pathologically function, thus interfering with gene transcription expanded [101]. Subsequent ultrastructural study of by reducing histone acetylation [113]. Further postmortem brain tissue from affected HD patients research in a Drosophila model of HD has shown revealed similar neuronal intranuclear inclusions that inhibiting histone deacetylase, thus increasing

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overall histone acetylation, can retard progression translated to clinical medicine. Autophagy, which of neuronal cell loss and improve survivability of enhances the clearance of misfolded protein, may the model [114]. Other examples of Htt disruption provide a potential treatment strategy in neuro- of transcriptional regulation are its action in degenerative proteinopathies [124]. Inducers of decreasing D2 receptor gene expression [115] and neuronal autophagy have been studied as potential mRNA data in transgenic mice that demonstrate therapeutic targets [125]. Inhibition of type 2 trans- alterations in several genes, including those for glutaminase, which is involved with apoptosis and neurotransmitter receptors and intracellular signal- autophagy regulation, may also provide an avenue ing systems [116]. Additionally, there is relative for future therapeutic studies [126]. McConoughey loss of brain-derived neurotrophic factor produc- and colleagues demonstrated that transglutaminase tion, thus neurotrophic support, due to down inhibition attenuated degeneration in a Drosophila regulation of transcription by mutant Htt, that may model of HD, and also protected mouse HD striatal lead to selective vulnerability in striatal neurons neurons from excitotoxicity [127]. Proteases [117]. The role of adenosine A(2A) receptors in belonging to the matrix metalloproteinase (MMP) modulating synaptic functions and maintaining family may play a role in the cleavage of mutant levels of brain-derived neurotrophic factor has also Htt, thus indicating a potentially important role been explored [118]. of MMPs in Htt proteolysis and toxicity [128]. Thus, mutant Htt protein potentially causes cell Inhibition of sirtuin 2 (SIRT2) may possibly alter death through pathways involving increased oxida- sterol biosynthesis and decrease mutant Htt toxicity tive stress, mitochondrial dysfunction, dysregula- in cellular and invertebrate models of HD [129]. tion of neuronal signaling capabilities, or gene In one study, nicotinamide was demonstrated to expression and decreased neurotrophic support. increase mRNA levels of brain-derived neuro- Interaction of the mutated Htt protein with trophic factor (BDNF) as well as peroxisome prolif- various other proteins, such as the small guanine erator-activated receptor gamma co-activator nucleotide-binding protein Rhes, localized to the 1-alpha (PGC–1α), and improve motor deficits in a striatum, leads to cytotoxicity and may contribute to mouse model [130]. One study using mouse mod- the localized neuropathology of HD [119]. els also demonstrated restoration of Htt function in The development of mouse models in HD has BDNF transport with the calcineurin inhibitor been tremendously exciting and has rapidly FK506 [131]. A recent study showed that Meclizine expanded our understanding of the disease process. suppressed apoptotic cell death in a murine cellular It has been discovered that the absence of Htt model of polyglutamine toxicity [132]. Hsp70 and causes embryonic death in mice [120], and that Hsp40, two major cytosolic molecular chaperones, deletions within chromosome 4 that involve the suppress mutant Htt toxicity in animal models HTT gene do not cause HD, suggesting that the [133]. One study demonstrated inhibition of mutant protein exerts its effect through a gain in polyglutamine (polyQ) protein aggregation by function rather than a loss of function [121]. human cytomegalovirus UL97 kinase in a cellular Transgenic mice expressing exon 1 of the mutant model of HD [134]. The role of type 1 cannabinoid human HTT gene develop a progressive neurologic receptors has also been studied. In mouse models, syndrome similar to that seen in humans [122]. receptor deletion aggravated the symptoms, This and other murine genetic models exhibit also neuropathology and molecular pathology of HD, some pathological changes seen in HD, making while pharmacological administration of the these mouse lines excellent models for preclinical cannabinoid Δ(9)-tetrahydrocannabinol amelio- evaluation of novel therapeutic approaches. rated those parameters [135]. A number of potential new therapeutic targets Recent studies have also provided further insights for HD have been investigated in animal and cellu- into possible mechanisms related to clinical mani- lar models of HD [123]. However, further studies festations of HD. Neuropathological studies have would be required before such findings can be shown loss of oxytocin- and vasopressin-expressing

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neurons, with increases in the number of cocaine- P, and calbindin [27]. The neurons containing and amphetamine-regulated transcript (CART)- enkephalin appear to be affected before those expressing neurons [136]. These alterations in containing substance P. On the other hand, the peptide expression of hypothalamic neurons may cholinergic and somatostatin-containing neurons influence the emotional and metabolic disturbances are spared (Figure 10.2). A particular class of striatal seen in HD. Studies of motor cortical plasticity in HD interneurons, characterized by immunoreactivity gene carriers (premanifest and very early manifest for the calcium-binding protein calretinin, was gene carriers) have revealed evidence of reduced found to be selectively increased in HD brains inhibition to continuous theta burst stimulation compared with controls [146]. It has been postu- [137]. Early cognitive deficits are probably related lated that the preferential loss of striatal neurons to synaptic and cellular dysfunction [138]. A post- projecting to the lateral globus pallidus gives rise to mortem neuropathological study found an associa- the clinical manifestation of chorea. The rigid- tion between motor dysfunction and cell loss in the akinetic symptoms, on the other hand, may be a primary motor cortex, as well as between major consequence of the additional loss of striatal mood symptomatology and cell loss in the anterior neurons projecting to the medial segment of the cingulate cortex [139]. A polymorphism in an pallidum [147]. Another possibility may be related autophagy-related gene (Atg7) was found to possibly to neuronal dysfunction, which occurs before cell modify age of disease onset in one study [140]. death [123]. A neuropathological classification system devised by Vonsattel and colleagues graded the severity of HD pathology based on microscopic Neuropathology and macroscopic criteria in the striatum [148]. The severity correlated with the degree of clinical HD affects both subcortical and cortical areas. The disability. The grades ranged from Grade 0, which striatum, particularly the medial region of the consisted of no gross or microscopic abnormalities, caudate followed by the putamen, is most severely and Grade 1, which involved mild to moderate affected [141, 142]. Other areas such as the globus microscopic evidence of gliosis in the putamen and pallidus, thalamus, and amygdala are involved to a caudate respectively without macroscopic changes, lesser extent [143, 144]. The hippocampus is to Grade 4 disease, with severe caudate, putamenal relatively spared [145]. The cell loss in the striatum and pallidal atrophy, with severe gliosis and preferentially affects the medium spiny GABAergic neuronal loss throughout the caudate and puta- neurons, which also contain enkephalin, substance men and moderate gliosis in accumbens.

Medium-sized spiny neurons (projecting GABA neurons) Substance P Interneurons (spared) Ach Striatum (caudate and GPe GPi putamen) Somatostatin GABA GABA Enkephalin GABA Tachykinin Tachykinin SNc SNr Figure 10.2 Pathology of Huntington disease.

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Subsequent studies revealed evidence of more and white matter loss in gene-positive patients widespread disease with cortical involvement without motor evidence of disease, indicating that [143–144, 149]. The degree of cortical atrophy is the pathological changes of HD begin before clinical less severe than in the striatum. There is an approx- onset [157]. Using volumetric measurements of imate 20–30 % reduction in cross-sectional area in caudate, putamen, total striatum, globus pallidus, the frontal, anterior parietal, anterior temporal, thalamus, total gray and white matter, one study and posterior temporal regions [145]. The large demonstrated that there were faster rates of atrophy pyramidal neurons in deeper cortical layers V and in striatum, total brain, and cerebral white matter VI are preferentially affected. Pathologically, there in prodromal individuals compared with controls is no significant astrocytosis involved in cortical [158]. Using the gray matter segment of MRI scans, degeneration, in contrast to the findings in the Klöppel and colleagues explored the usefulness of a striatum [148, 150]. The cortical volume loss has multivariate support vector machine to automati- been found to correlate with the neuropathological cally identify presymptomatic HD gene mutation grade of disease severity. In addition, the rates of carriers in the absence of any a priori information cortical and subcortical atrophy correlates with [159]. Presymptomatic HD gene mutation carriers CAG repeat length [151]. Intranuclear inclusion close to estimated diagnostic onset were success- bodies may also be found in the cortex and striatum fully separated from controls on the basis of single of patients with HD [152]. They may be seen in anatomic MRI scans. A study of 523 prodromal HD all cortical layers and in the medium-sized neurons subjects found evidence of volume decrement, of the striatum, but not in the neurons of the globus particularly affecting the posterior and superior cer- pallidus or cerebellum [102]. These inclusions ebral regions, even in the “midway to onset group” contain truncated, ubiquitinated Htt protein. The with an estimated proximity to clinical onset of frequency of the cortical intranuclear inclusions 9–15 years [160]. Paulsen and colleagues assessed correlated directly with the size of CAG expansion brain morphology by MRI in preclinical HD subjects but was inversely related to the age at onset and [161]. Preclinical participants had substantial mor- death [152]. Other CAG trinucleotide disorders phologic differences from controls throughout the such as dentatorubropallidoluysian atrophy may cerebrum. Volume of the cerebral cortex was sig- also demonstrate similar inclusions, consisting of nificantly increased in preclinical HD, whereas the polyglutamine protein [153]. The finding of basal ganglia and cerebral white matter volume dystrophic neurites has also been reported, were substantially decreased. In another study, not predominantly in cortical layers V and VI in HD only were the volumes of the caudate nucleus and brains [102]. DiFiglia and colleagues postulated putamen reduced in premanifest HD long before that these dystrophic neurites were distended axon predicted onset (>10.8 years), but atrophy of the terminals. Increased basal ganglia iron levels have accumbens nucleus and pallidum was also apparent also been identified on magnetic resonance imag- in premanifest HD [162]. In addition, the 12-month ing in HD, and its distribution may be related to the whole-brain atrophy rates were greater in early HD pattern of neurotoxicity observed in HD [154]. individuals as well as premanifest gene-positive carriers less than 10.8 years from predicted diagnosis compared with controls [163]. All gene-positive Imaging groups also showed faster rates of caudate and putamen atrophy over 12 months compared with Serial MRI scans to assess basal ganglia volume controls. The whole-brain and caudate atrophy [155] or specialized MRI scans to assess cortical rates were found to correlate with the UHDRS total thickness [156] may some day be useful to follow functional capacity score as well as with cognitive the progression of disease and effects of potential and quantitative motor measures. MRI changes in neuroprotective interventions. A report of voxel- the hypothalamic region have also been demon- based morphometry MRI revealed patterns of gray strated before clinical onset [164]. A study using

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magnetization transfer MR imaging demonstrated treatable symptoms and cannot be generalized to degeneration of the subcortical and cortical gray all patients or to an individual patient over all stages matter in HD gene carriers, with correlations of the illness (Figure 10.3). between regional magnetization transfer ratios and several clinical variables [165]. Nopoulos and col- Disease-modifying therapy leagues found evidence of reduced intracranial vol- For those who are gene-positive and asymptomatic umes in prodromal HD compared with controls, or early symptomatic, focus should be on treat- lending support to the theory of abnormal neu- ments that may potentially slow disease progres- rodevelopment in HD [166]. sion. CARE-HD, the first national trial exploring two of these interventions, showed that neither remacemide nor CoQ10 given alone or in Treatment combination had any significant effect on progressive functional decline [171]. However, Treatment of patients with HD requires a coordi- the CoQ10 treatment arm showed a trend nated effort on the part of a medical, psychiatric, toward slowing the disease, with participants social service, and physical or occupational therapy able to handle daily finances and domestic team [167–170]. Treatment is tailored to the chores longer. In addition, patients had improved

Clinical suspicion of HD

Positive gene test Negative gene test

Huntington’s disease HD phenocopy

Do symptoms interfere Consider other causes of chorea including with function? other genetic causes: SCA 1, 2, 3, 17, HD 1, 2, 3, PRNP, JPH3, JNK, VPS13A, XK, FTL1, NKX2-1 No. Yes. Consider coenzyme Consider symptomatic Q10 and creatine treatment

Depression, obsessive compulsive Rigidity, Myoclonus, Bruxism, Chorea behavior, irritability, bradykinesia epilespsy dystonia aggressiveness, dysphoria

Levodopa, Valproate, Botulinum SSRIs, tricyclic antidepressants, dopamine clonazepam toxin benzodiazepines agonists

Without With psychosis psychosis

Tetrabenazine, Tetrabenazine, quetiapine, Deep brain olanzapine, ziprasidone, clozapine, stimulation others

Figure 10.3 Treatment algorithm for Huntington disease.

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attention and were less distressed. A follow-up autopsy evidence for graft survival and integration study, 2CARE, aims to assess higher doses of CoQ10 in 1 patient who died 18 months postimplantation and will be the largest therapeutic clinical trial in [180]. Bachoud-Lévi and colleagues provided long- HD to date. A safety and tolerability study of higher term results of 5 patients with fetal neural trans- dosages found that CoQ10 was well tolerated, with plants [181]. They found that clinical improvement over 80 % of subjects achieving the target dosage plateaued after 2 years and then faded out between of 3,600 mg/day [172]. The most common adverse 4 and 6 years after surgery. Dystonia deteriorated events were gastrointestinal symptoms. A pilot consistently. Two patients who had no benefit from study conducted to study the effect of minocycline grafting at 2 years continued to decline in the in delaying disease progression showed that it was same way as non-grafted patients. This treatment well tolerated and had no serious adverse events approach remains experimental, with many of the [173]. Although minocycline at 200 mg/day was same concerns that have faced human fetal cell well tolerated and safe over 18 months of treat- transplantation in other neurologic conditions ment, there was no meaningful slowing of the rate [182]. Recently, graft overgrowth in a HD patient of functional decline [174]. A recent futility study receiving fetal neural transplantation resulting in a of minocycline showed that although futility was symptomatic mass was described [183]. not supported by the primary analysis, the data RNA interference and antisense technology has provided insufficient evidence to justify a larger shown efficacy in animal models for the silencing and longer trial of minocycline in HD [175]. The of molecular targets in HD and is being explored as PREQUEL study will evaluate CoQ10 in gene- a potential therapeutic strategy in HD [184]. positive, preclinical HD patients [176]. A 1-year, placebo-controlled clinical trial of creatine sup- Symptomatic therapy plementation (5 mg/day) in HD did not improve Psychiatric symptoms should be addressed as part functional, neuromuscular, or cognitive status in of the multidisciplinary approach to HD. Depression patients with early disorder [177]. A 2-year pilot often responds partially to treatment with standard study demonstrated that 10 g/day of creatine is antidepressants. Carbamazepine or valproate may safe and tolerated but whether it stabilized symp- improve patients with a manic disorder. Delusions toms is unclear [178]. In a randomized, double- and paranoia often respond to neuroleptics. Neuro- blind, placebo-controlled study in subjects with leptics also decrease chorea, but care is needed not HD, 8 g/day of creatine administered for 16 weeks to increase to doses that impair the individual’s was well tolerated and safe. Serum and brain functional level. Low doses of neuroleptics are creatine concentrations increased during creatine often well tolerated, whereas high doses are rarely treatment. Serum 8-hydroxy–2’-deoxyguanosine helpful and may impair motor function, such as levels, an indicator of oxidative injury to DNA, swallowing, and cognitive function. Irritability and were markedly elevated in HD and reduced by emotional dyscontrol are common in patients with creatine treatment [179]. The CREST-E trial is HD and can cause great disturbance in their families designed to assess whether high doses of pharma- or living situation. Behavioral modification on the ceutical grade creatine monohydrate can slow the part of the patient and caregiver can alleviate such functional decline. stressful situations. Carbamazepine, selective serotonin reuptake inhibitors, clonazepam, propranolol, Cell-based therapy valproate, and clomipramine are just some of Cell-based therapy has been considered in HD for the medications that may be helpful. Risperidone some time, but no grafting procedures have been may be useful for the management of psychiatric shown to provide meaningful disease-modifying or disorders in patients with HD [185]. symptomatic benefits. Hauser and colleagues have Chorea in HD may be treated with neuroleptics reported their early findings after bilateral fetal effectively. Other agents used include tetrabenazine, striatal transplantation in 7 HD patients, including benzodiazepines, and propranolol. In a prospective

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open-label study, high dose olanzapine (30 mg/day) to be withdrawn in a double-blind, staggered fash- was found to be useful in chorea [186]. In another ion [191]. The chorea scores of subjects withdrawn randomized trial, amantadine hydrochloride treat- from tetrabenazine treatment increased by 5.3, ment at doses of 300 mg/day had no effect whereas the scores of the group with partial or no on Huntington chorea, although most patients withdrawal of tetrabenazine treatment increased felt subjectively better [187]. An open-label pilot by 3.0 units (P = 0.0773). A post hoc analysis of the study suggested that levetiracetam may be effica- linear trend was positive for re-emergent chorea cious in reducing HD chorea in doses up to (P = 0.0486). No serious adverse events were 3,000 mg/day [188]. reported after abrupt withdrawal of tetrabenazine In August 2008, tetrabenazine was approved by treatment. The trend for the re-emergence of the Food and Drug Administration (FDA) for the chorea supports the effectiveness of tetrabenazine treatment of chorea in HD patients. Tetrabenazine’s in reducing chorea. Another publication by Kenney exact mechanism of the antichorea effects is and colleagues also outlines its efficacy in treatment unknown but is believed to be related to its effect as of hyperkinetic disorders including HD chorea a depletor of monoamines by reversibly binding [192]. In a small study of 6 HD patients, aripipra- to the type 2 vesicular monoamine transporter zole was compared to tetrabenazine [193]. Both (VMAT2) [189]. Tetrabenazine has more than 75 % had similar effects on UHDRS chorea scores, but bioavailability and is 82 to 85 % protein-bound. It is aripiprazole was associated with less sedation and metabolized hepatically by the CYP 450 enzymes. was better tolerated. There was a slight trend for In the pivotal clinical trial, 84 patients were rand- improvement in depression with the aripiprazole- omized to either tetrabenazine up to 100 mg/day or treated patients, but this was not significant. In a placebo for 12 weeks [189]. Tetrabenazine effec- multicenter, placebo- controlled trial, riluzole tively lessened chorea in ambulatory patients. The 200 mg/day decreased the intensity of chorea with- treatment effect was 3.5 UHDRS points, with 69 % out improving functional capacity [194]. It caused having at least a 3-point decline in total chorea reversible liver transaminase abnormalities that score and 19 % having at least a 10-point decline required long-term monitoring. Deep brain stimu- (28-point maximum). The clinical global improve- lation of the bilateral globus pallidus may have the ment scores showed 44 % of active treatment and potential to optimize motor response in HD, 7 % of placebo were very much improved or much improving chorea without worsening bradykinesia improved. Serious adverse events included suicide [195]. In a small report of 2 HD patients who and restlessness. When using strong CYP2D6 inhib- underwent pallidal DBS, sustained improvement in itors, the dose of tetrabenazine should be halved. chorea was seen after 2 years follow-up. However, The FDA suggests CYP2D6 genotyping when one patient had returned to his pre-operative level considering doses of more than 50 mg/day. Also, of functioning due to progressive deterioration in tetrabenazine has a risk evaluation and mitigation gait, bradykinesia and dystonia. In addition, both strategy with goals of minimizing the risk of patients experienced further decline in neurocogni- drug-associated depression and suicide, promoting tive functioning [196]. Dystonia and rigidity may informed prescribing, titration, and dosing, and complicate end-stage disease and if it is uncomfort- minimizing the risk of interactions with other able, or if there is interference with hygiene or care drugs. In another trial, 68 patients were treated of the patient, then excessive tone can be treated with tetrabenazine for a mean period of 34.4 with local injections of botulinum toxin type A months [190]. Tetrabenazine was well tolerated [168–170]. and produced long-term clinical benefit, but the Frequent awakening during sleep may become magnitude was reduced, despite a progressive problematic and sleep cycles may reverse. Disturbed increase of the doses. In a withdrawal study, 30 night-time sleep and a delayed sleep phase can patients treated with tetrabenazine were assigned occur in HD, and these may be associated with

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depression and lower cognitive and functional Box 10.1 Phenocopies of HD performance [197]. Avoidance of daytime sleeping and other basic good sleep hygiene practices as well • HDL1 – AD (prion protein, PRNP; 20p12) as medications, such as clonazepam, trazodone, or • HDL2 – AD (junctophilin, JPH3; 16q24.3) amitriptyline at bedtime can help to modify this • HDL3 – AR (4p16.3) problem. Because of impulsivity and excessive • DRPLA – AD (c-Jun NH-terminal kinase, JNK, 12p) movements some patients will need to be placed in • Neuroacanthocytosis – AR (VPS13A, 9q21) modified floor beds at night and may need special • McLeod syndrome – X-linked (HK, Xp21) chairs (e.g. Broda chair) for daytime seating. • Mitochondrial encephalomyopathies Juvenile cases of HD are often treated with • Benign hereditary chorea – AD (TITF–1, 14q13.1–q21.1) carbidopa and levodopa to reduce prominent • Ataxia-Chorea: bradykinesia, posture abnormalities, rigidity, and SCA2 (ataxin–2, 12q24.1), SCA1, SCA3, SCA12 dystonia. One case report cites success in such a case SCA17 – AD (HDL4) (TATA-Box binding protein, 6q27) using the dopamine agonist, pramipexole [197]. Friedreich’s ataxia (GAA repeat expansion in Nutrition is important in HD patients as their frataxin, 9p13) caloric requirements may be increased. At the Ataxia telangiectasia (ATM gene, 11q22–23) end stage, patients are bed-bound, mute, and • Neurodegeneration with brain iron accumulation (NBIA) rigid. Eventually dysphagia and aspiration become Pantothenate-kinase-associated neurodegeneration problematic. Changing the shape of cups and (PKAN) stable posture, in consultation with a speech Neuroferritinopathy therapist, may lessen the chance of aspiration • Psychogenic chorea [199]. The patient’s wishes regarding gastric tube • Wilson disease feeding should be ascertained in preparation for this stage of illness. Longer CAG repeat lengths are associated with earlier age at nursing home Video 10.7 Chorea in ataxia telangectasia placement as well as earlier age at percutaneous This 10-year-old patient had a normal birth. She had endoscopic gastrostomy placement, but the inter- normal early development milestones, except walking, val from the onset of HD symptoms to either of that started at the age 2. At 18 months she developed mild choreiform movements involving limbs and trunk. these endpoints is similar regardless of CAG She remained stable until the age 9, when she started to repeat length [200]. present gait ataxia. She also developed recurrent infections of the upper and lower respiratory tract. Immunodeficency with lymphopenia was detected. Telangiectasias on the Other genetic causes of chorea bulbar conjunctiva appeared bilaterally. A brain MRI showed cerebellar atrophy. Chromosomal instability was then detected, leading to a diagnosis of ataxia A number of genetic causes of chorea may mimic telangectasia. The videotape shows small jerks of the the HD phenotype, and may be clinically indistin- hands and feet that look like fidgeting. Lower limbs are guishable from HD. HD phenocopies should be held unstably against gravity. Instability and hyperkinetic considered in the setting of a compatible clinical features are visible while standing, walking and running. [Video courtesy of Nardo Nardocci, MD, Milan, Italy] picture with negative HD gene testing (Box 10.1).

Dentatorubral-pallidoluysian atrophy (DRPLA) DRPLA is an autosomal dominant neurodegenerative condition, caused by an unstable CAG expansion on chromosome 12 [201]. The unstable CAG repeats also exhibit the phenomenon of http://bit.ly/tSH9Iu

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anticipation. DRPLA is particularly prevalent in ataxia, dementia, psychosis, dystonia, chorea, Japan, although cases have also been identified parkinsonism, pyramidal signs, and seizures [209]. in European and African-American families [202, 203]. Similar to HD, the age of onset is correlated Neuroacanthocytosis with CAG repeat length, accounting for 62 % of the This autosomal recessive disorder is caused by observed variation in age at onset [204]. The mean mutations in the VPS13A gene on chromosome age of onset is in the fourth decade, and the condi- 9q21 [199]. It typically presents in the third and tion manifests as cerebellar ataxia, choreoathetosis, fourth decades of life, although its age of onset may dystonia, rest and postural tremor, parkinsonism, range from 8 to 62 years. Clinical features include and dementia [203]. Early-onset DRPLA, typically orolingual (eating) dystonia, chorea, tics, stereo- presenting before 20 years of age, may manifest typies, as well as cognitive and personality distur- with variable features of myoclonus, epilepsy, and bances, seizures, dysphagia, dysarthria, vertical mental retardation. ophthalmoparesis, parkinsonism, amyotrophy, areflexia, and elevated serum creatine kinase [203]. Huntington-like diseases (HDLs) Eating dystonia, involving tongue protrusion The mutation causing Huntington disease-like 1 during eating, was present in 16 % of individuals in (HDL1) has been mapped to the prion protein one series [210]. The presence of this uncommon (PRNP) gene on chromosome 20 [205]. The mean symptom is highly suggestive of the diagnosis age of onset is 20 to 45 years [206]. Clinical features [199]. McLeod syndrome is an X-linked recessive include involuntary movements, incoordination, from of acanthocytosis. It may cause depression, dementia and psychiatric symptoms [207]. Seizures bipolar disorder and personality disorders, in have also been described in this condition [208]. addition to chorea, involuntary vocalizations, sei- Huntington disease-like 2 (HDL2) is another zures, liver disease, hemolysis, motor axonopathy, autosomal dominant condition with similar clinical and elevated creatine kinase levels [211–213]. features to HD. It is caused by a CTG/CAG trinucleotide repeat expansion within the junctophilin–3 (JPH3/HDL2) gene [203]. The disorder occurs Video 10.8 Chorea in Neuroacanthocytosis predominantly in individuals of African origin. It This patient is 39 years old. At age 29 she developed classically presents in the fourth decade, and generalized choreic movements with prevalent cranial involvement that progressed mildly. A brain MRI consists of abnormalities of movements such as showed mild atrophy of cerebellum and caudate, chorea, dystonia, bradykinesia, rigidity, tremor, laboratory investigations showed increased level of gait abnormalities, as well as dysarthria, hyper- creatine phosphokinase and acanthocytosis (with 10% reflexia, psychiatric symptoms, and dementia. of acanthocytes). Her parents were consanguineous Huntington disease-like 3 (HDL3) is an autosomal and she had a brother and a sister with mild adult-onset dyskinesias and increased creatine kinase recessive disorder that has been described in one levels. A chorein deficiency was identified by Western family. The symptoms typically begin at age 3–4 blot leading to the diagnosis of neuroacanthocytosis. years. Clinical manifestations include chorea, dys- The videotape shows mild choreic movements which tonia, gait disorder, spasticity, seizures, mutism, are observed at rest. An occasional negative intellectual impairment, and bilateral frontal and myoclonus of the lower limbs is present when standing or walking. [Video courtesy of Alberto caudate atrophy. Spinocerebellar ataxia type 17 Albanese, MD, Milan, Italy] (SCA 17), also referred to as Huntington disease- like 4 (HDL4), is an autosomal dominant disorder. It is caused by a mutation of the TATA box-binding protein (TBP) gene on chromosome 6, resulting in abnormal CAG triplet repeats. Similar to HD, the age of onset is inversely correlated to the CAG repeat length. The mean age of onset is between http://bit.ly/tu2daa 19 and 48 years [208]. Clinical features include

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Neurodegeneration with brain further investigation. The identification of the iron accumulation locus for BHC on chromosome 14 [227, 228], and Pantothenate-kinase-associated neurodegenera- the subsequent finding of mutations in the TITF1 tion (PKAN) and neuroferritinopathy, two other gene [229] have allowed for a more accurate conditions that may present similarly to HD, have characterization of the disease. The TITF1 gene, characteristic features on brain MRI. PKAN, also which is involved in the organogenesis of the lung, referred to as neurodegeneration with brain iron thyroid, and the basal ganglia, is inherited in an accumulation type 1, or NBIA1, is an autosomal autosomal dominant manner. The neurological recessive condition caused by mutations in the symptoms typically begin in childhood, but usually pantothenate kinase (PANK2) gene. It typically become less severe or even disappear in adulthood. presents in childhood, with dystonia, dysarthria There has been limited success with pharmacologi- and rigidity. Atypical cases involving late-onset and cal treatments, although symptomatic improve- slowly progressive symptoms have also been ment with levodopa therapy has been reported in described [214]. MRI appearances in PKAN consist 2 siblings [230]. Mutations in the TITF–1 gene have of global pallidal hypointensity with a central also been found in individuals with chorea, region of hyperintensity, and are often referred to congenital hypothyroidism, and pulmonary dys- as the “eye of the tiger” sign. Neuroferritinopathy, function [231]. The term “Brain-Thyroid-Lung caused by mutations in the FTL gene, has a mean syndrome” was coined in reference to the multi- age of onset of 40 years. MRI findings include system involvement that may be seen with TITF1 symmetrical cystic degeneration of the globus mutations, distinct from the classic presentation of pallidus and putamen, and abnormal iron deposi- BHC [232, 233]. tion [215, 216]. NBIA is covered in greater detail in Chapter 8. Psychogenic chorea Rarely, chorea can be a component of a psychogenic movement disorder or can be seen in patients who Benign hereditary chorea (BHC) have family history of HD and become convinced The earliest report of hereditary non-progressive that they are developing early stages of HD, even in chorea of early onset described two brothers who the setting of negative DNA test for HTT mutation developed a non-progressive syndrome of inher- [234]. ited childhood-onset chorea [217]. Subsequent descriptions were heterogeneous in their clinical manifestations [218]. In some cases there was Conclusion delayed motor development, with one report of child who was wheelchair-bound until the age Huntington disease is an autosomal dominant of 9 [219, 220]. Intellectual impairment was also neurodegenerative condition that causes disorders reported in some cases [221]. Associated symp- of motor control, behavioral and cognitive func- toms of intention tremor [222] and sensorimotor tion, and involuntary movements. Cognitive and hearing loss [223] have also been described. The behavioral changes may occur years prior to the diagnostic accuracy of the syndrome has been onset of definitive motor signs. The management of reviewed critically in several reports [218, HD involves a multidisciplinary approach, taking 224–226]. In a follow-up study on 11 families into account cognitive impairment, psychiatric originally diagnosed with benign hereditary disturbances, motor symptoms, sleep disturbances, chorea, the diagnoses were subsequently changed and nutrition, in addition to genetic and social in 9 [218]. These alternate diagnoses included HD, issues. Treatment of HD currently remains sympto- myoclonus dystonia, idiopathic torsion dystonia, matic, chiefly directed against chorea, but treat- and ataxia-telengiectasia. This raised the concern ment of various comorbidities, including anxiety that benign hereditary chorea may not be an etio- and depression, is also often required. In the setting logical diagnosis, but rather a syndrome requiring of a compatible clinical picture and a negative

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gene test, HD phenocopies should be considered, 13 Stout JC, Paulsen JS, Queller S, et al. Neurocognitive although these account for only a small proportion signs in prodromal huntington disease. Neuropsycol of cases. 2011 Jan; 25(1):1–14. 14 Rupp J, Blekher T, Jackson J, et al. Progression in prediagnostic Huntington disease. J Neurol Neurosurg Psychiat 2010 Apr; 81(4):379–84. Epub 2009 Sep 1. References 15 Marshall J, White K, Weaver M, et al. Specific psychiatric manifestations among preclinical 1 Ha A. Huntington Disease. In: Gilman S, editor- Huntington disease mutation carriers. Arch Neurol in-chief. MedLink Neurol. San Diego: MedLink 2007; 64(1):116–21. Corporation. Available at www.medlink.com. 16 Folstein SE, Leigh RJ, Parhad IM, Folstein M. The Accessed December 5 2010. Reprinted with diagnosis of Huntington’s disease. Neurol 1986; permission. 36:1279–83. 2 Huntington G. On chorea. Medical and Surgical 17 Penney JB, Young AB, Shoulson I, et al. Huntington’s Reporter 1872; 26:317–21. disease in Venezuela: 7 years of follow-up on sympto- 3 Anton G. Uber die Beteiligung der grossen basalen matic and asymptomatic individuals. Mov Disord Gehirnganglien bei Bewegungsstorungen und insbe- 1990; 5:93–9. sondere bei Chorea. Jahrbucher Psychiat Neurol (Lpz) 18 Antoniades CA, Xu Z, Mason SL, et al. Huntington’s 1896; 14:141–81. disease: changes in saccades and hand-tapping over 3 4 Lanois M, Paviot J. Deux cas de chorée hereditaire years. J Neurol 2010 Nov; 257(11):1890–8. avec autopsies. Arch Neurol (Paris) 1897; 4:333–4. 19 Hicks S, Rosas HD, Berna C, et al. Oculomotor deficits 5 Alzheimer A. Uber die anatomische Grundlage der in presymptomatic and early Huntington’s disease and Huntingtonischen Chorea und der choreatischen their structural brain correlates. J Neurol Neurosurg Bewegungen uberhaupt. Neurol Cbl 1911; Psychiat 2010 Nov; 81(11):e33. 30:891–2. 20 Bechtel N, Scahill RI, Rosas HD, Acharya T, van den 6 Gusella JF, Wexler NS, Conneally PM, et al. A Bogaard SJ, Jauffret C, Say MJ, Sturrock A, Johnson H, polymorphic DNA marker genetically linked to Onorato CE, Salat DH, Durr A, Leavitt BR, Roos RA, Huntington’s disease. Nature 1983; 306:234–7. Landwehrmeyer GB, Langbehn DR, Stout JC, 7 Anonymous. A novel gene containing a trinucleotide Tabrizi SJ, Reilmann R. Tapping linked to function and repeat that is expanded and unstable on Huntington’s structure in premanifest and symptomatic Huntington disease chromosomes. The Huntington’s Disease disease. Neurol 2010 Dec 14; 75(24):2150–60. Collaborative Research Group. Cell 1993; 72: 21 Biglan KM. Tapping in Huntington disease: A path 971–83. forward to preventive therapies? Neurol 2010 Dec 14; 8 Koroshetz WJ, Myers R, Martin JB. Huntington’s 75(24):2142–3. disease. In: Rosenberg R, Pruisner SB, DiMauro S, 22 Marder K, Zhao H, Eberly S, Tanner CM, Oakes D, Barchi RL, Kunkel LM, editors. The molecular and Shoulson I; Huntington Study Group. Dietary intake genetic basis of neurologic disease. Boston: in adults at risk for Huntington disease: analysis of Butterworth-Heinemann, 1993:737–52. PHAROS research participants. Neurol 2009; 73(5): 9 Nance MA. Genetic testing of children at risk for 385–92. Huntington’s disease. Neurol 1997; 49:1048–53. 23 Folstein SE, Leigh RJ, Parhad IM, Folstein M. The 10 Paulsen JS, Zhao H, Stout JC, et al. Clinical markers of diagnosis of Huntington’s disease. Neurol 1986; early disease in persons near onset of Huntington’s 36:1279–83. disease. Neurol 2001; 57:658–62. 24 Willingham DB, Koroshetz WJ. Evidence for dissocia- 11 Paulsen JS. Cognitive impairment in huntington ble motor skills in Huntington’s disease patients. disease: diagnosis and treatment. Curr Neurol Psychobiology 1993; 21:173–82. Neurosci Rep. 2011 Oct; 11(5):474–83. 25 Shelton PA, Knopman DS. Ideomotor apraxia in 12 Duff K, Paulsen J, Mills J, et al. PREDICT-HD Huntington’s disease. Arch Neurol 1991; 48:35–41. Investigators and Coordinators of the Huntington 26 Thompson PD, Berardelli A, Rothwell JC. The coexist- Study Group. Mild cognitive impairment in prediag- ence of bradykinesia and chorea in Huntington’s nosed Huntington disease. Neurol 2010 Aug 10; 75(6): disease and its implications for theories of basal ganglia 500–7. Epub 2010 Jul 7. control of movement. Brain 1988; 111:223–44.

Albanese_c10.indd 166 12/24/2011 6:59:52 AM Huntington Disease and Other Genetic Choreas 167

27 Huntington Disease. In Fahn S, Jankovic J relation to genetic structure and clinical onset. Arch (ed):Principles and Practice of Movement Disorders. Neurol 1997; 54:1081–8. Philadelphia. Churchill Livingstone Elsevier, 2007, 41 Peavy GM, Jacobson MW, Goldstein JL, et al. Cognitive pp 369–392 and functional decline in Huntington’s disease: 28 Aziz NA, Anguelova GV, Marinus J, et al. Autonomic dementia criteria revisited. Mov Disord 2010 Jul 15; symptoms in patients and pre-manifest mutation 25(9):1163–9. carriers of Huntington’s disease. Eur J Neurol 2010 42 Zakzanis KK. The subcortical dementia of Aug; 17(8):1068–74. Epub 2010 Feb 24. Huntington’s disease. J Clin Exp Neuropsychol 1998; 29 Grimbergen YA, Knol MJ, Bloem BR, Kremer BP, 20:565–78. Roos RA, Munneke M. Falls and gait disturbances in 43 Schneider SA, Wilkinson L, Bhatia KP, et al. Abnormal Huntington’s disease. Mov Disord 2008; 23(7):970–6. explicit but normal implicit sequence learning in 30 Busse ME, Wiles CM, Rosser AE. Mobility and falls in premanifest and early Huntington’s disease. Mov people with Huntington’s disease. J Neurol Neurosurg Disord 2010 Jul 30; 25(10):1343–9. Psychiat 2009; 80(1):88–90. 44 Mickes L, Jacobson M, Peavy G, et al. A comparison of 31 Goldberg A, Schepens SL, Feely SM, et al. Deficits in two brief screening measures of cognitive impairment stepping response time are associated with impair- in Huntington’s disease. Mov Disord 2010 Oct 15; ments in balance and mobility in people with 25(13):2229–33. Huntington disease. J Neurol Sci 2010 Nov 15; 45 Aziz NA, van der Burg JM, Landwehrmeyer GB, 298(1–2):91–5. Brundin P, Stijnen T; EHDI Study Group, Roos RA. 32 Salomonczyk D, Panzera R, Pirogovosky E, et al. Weight loss in Huntington disease increases with higher Impaired postural stability as a marker of premanifest CAG repeat number. Neurol 2008; 71(19):1506–13. Huntington’s disease. Mov Disord 2010 Oct 30; 46 Aziz NA, Pijl H, Frölich M, et al. Systemic energy 25(14):2428–33. homeostasis in Huntington’s disease patients. J 33 Kloos AD, Kegelmeyer DA, Young GS, et al. Fall risk Neurol Neurosurg Psychiat 2010 Nov; 81(11):1233–7. assessment using the Tinetti mobility test in individuals 47 Politis M, Pavese N, Tai YF, et al. Hypothalamic with Huntington’s disease. Mov Disord 2010 Dec 15; involvement in Huntington’s disease: an in vivo PET 25(16):2838–44. study. Brain 2008; 131:2860–9. 34 Begnger LJ, Langbehn DR, Duff K, Stierman L. 48 Conneally PM. Huntington’s disease: genetics and Probability of obsessive and compulsive symptoms in epidemiology. Am J Hum Genet 1984; 36:506–26. Huntington’s disease. Biol Psychiat 2007; 49 Rawlins M. Huntington’s disease out of the closet? 61(3):415–8. Lancet 2010 Oct 23; 376(9750):1372–3. Epub 2010 35 Ho AK, Gilbert AS, Mason SL, Goodman AO, Jun 30. Barker RA. Health-related quality of life in 50 Wexler A. Stigma, history, and Huntington’s disease. Huntington’s disease: Which factors matter most? Lancet. 2010 Jul 3; 376(9734):18–9. Mov Disord 2009; 24(4):574–8. 51 Morrison PJ. Accurate prevalence and uptake of 36 Sorensen S, Fenger K. Causes of death in patients with testing for Huntington’s disease. Lancet Neurol 2010 Huntington’s disease and in unaffected first degree Dec; 9(12):1147. relatives. J Med Genetics 1992; 29:911–4. 52 Loy CT, Lownie A, McCusker E. Huntington’s disease. 37 Paulsen JS, Hoth KF, Nehl C, Stierman L. Critical Lancet. 2010 Oct 30; 376(9751):1463. periods of suicide risk in Huntington’s disease. Am J 53 Spinney L. Uncovering the true prevalence of Psychiat 2005; 162(4):725–31. Huntington’s disease. Lancet Neurol 2010 Aug; 38 De Souza J, Jones LA, Rickards H. Validation of 9(8):760–1. Epub 2010 Jun 30. self-report depression rating scales in Huntington’s 54 Chen YY, Lai CH. Nationwide Population-Based disease. Mov Disord 2010 Jan 15; 25(1):91–6. Epidemiologic Study of Huntington’s Disease in 39 White FR, Vasterling JJ, Koroshetz WJ, Myers R. Taiwan. Neuroepidemiology 2010; 35(4):250–4. Neuropsychology of Huntington’s disease. In: 55 ACMG/ASHG statement. Laboratory guidelines for White R, editor. Clinical syndromes in adult neuropsy- Huntington disease genetic testing. The American chology; the practitioner’s handbook. Amsterdam: College of Medical Genetics/American Society of Elsevier, 1992:213–48. Human Genetics Huntington Disease Genetic Testing 40 Jason GW, Suchowersky O, Pajurkova EM, et al. Working Group. Am J Hum Genet. 1998 May; Cognitive manifestations of Huntington disease in 62(5):1243–7.

Albanese_c10.indd 167 12/24/2011 6:59:52 AM 168 Chapter 10

56 Quarrell OW, Rigby AS, Barron L et al. Reduced 69 Li JL, Hayden MR, Warby SC, et al. Genome-wide penetrance alleles for Huntington’s disease: a multi- significance for a modifier of age at neurological onset centre direct observational study. J Med Genet. 2007 in Huntington’s disease at 6q23–24: the HD MAPS Mar; 44(3):e68. study. BMC Med Genet 2006; 17:7:71. 57 Myers RH, MacDonald ME, Koroshetz WJ, et al. De 70 Duyao M, Ambrose C, Myers R, et al. Trinucleotide novo expansion of a (CAG)n repeat in sporadic repeat length instability and age of onset in Huntington’s disease. Nat Genet 1993; 5:168–73. Huntington’s disease. Nature Genet 1993; 4:387–92. 58 Sanchez A, Mila M, Castellvi-Bel S, et al. Maternal 71 Kremer B, Almqvist E, Theilmann J, et al. Sex- transmission in sporadic Huntington’s disease. J dependent mechanisms for expansions and contrac- Neurol Neurosurg Psychiat 1997; 62:535–7. tions of the CAG repeat on affected Huntington’s 59 Hendricks AE, Latourelle JC, Lunetta KL, et al. disease chromosomes. Am J Hum Genet 1995; Estimating the probability of de novo HD cases from 57:343–50. transmissions of expanded penetrant CAG alleles in 72 Browne S, Bowling A, MacGarvey U, et al. Oxidative the Huntington disease gene from male carriers of damage and metabolic dysfunction in Huntington’s high normal alleles (27–35 CAG). Am J Med Genet disease: selective vulnerability of the basal ganglia. 2009; 149A:1375–1381. Ann Neurol 1997; 41:646–53. 60 Biglan KM, Jankovic J, Eberly S, et al. Longitudinal 73 Tabrizi SJ, Cleeter MW, Xuereb J, Taanman JW, Analysis of Intermediate CAGn Repeat Length Cooper JM, Shapira AH. Biochemical abnormalities Expansion in the Prospective Huntington Disease and excitotoxicity in Huntington’s disease brain. Ann At-Risk Observational Study (PHAROS). Mov Disord Neurol 1999; 45:25–32. 2010(Suppl 2):S270 (abstract). 74 Wellington C, Ellerby L, Hackam A, et al. Caspase 61 Kenney C, Powell S, Jankovic J. Autopsy-proven cleavage of gene products associated with triplet Huntington’s disease with 29 trinucleotide repeats. expansion disorders generates truncated fragments Mov Disord 2007; 22(1):127–30. containing the polyglutamine tract. J Biol Chem 1998; 62 Ha AD, Jankovic J. Exploring the correlates of 273:9158–67. intermediate CAG repeats in Huntington disease. 75 Ona V, Li M, Vonsattel J, et al. Inhibition of caspase–1 Postgrad Med 2011; 123:116–21. slows disease progression in a mouse model of 63 Ha A, Davidson A, Jankovic J. Intermediate CAG Huntington’s disease. Nature 1999; 399:263–7. repeats: Analysis of the Cooperative Huntington’s 76 Gervais FG, Singaraja R, Xanthoudakis S, et al. Observational Research Trial (abstract). Neuro- Recruitment and activation of caspase –8 by the therapeutics 2011; 8:145. Huntingtin-interacting protein Hip–1 and a novel 64 Brinkman RR, Mezei MM, Theilmann J, Almqvist E, partner Hippi. Nat Cell Biol 2002; 4:95–105. Hayden MR. The likelihood of being affected with 77 Kiechle T, Dedeoglu A, Kubilus J, et al. Cytochrome Huntington’s disease by a particular age, for a specific C and caspase–9 expression in Huntington’s disease. CAG size. Am J Hum Genet 1997; 60:1202–10. Neuromol Med 2002; 1:183–95. 65 Maat-Kievit A, Losekoot M, Zwinderman K, et al. 78 Kowall NW, Ferrante RJ, Martin JB. Patterns of cell Predictability of age of onset in Huntington’s disease in loss in Huntington’s disease. Trends Neurosci 1987; the Dutch population. Medicine 2002; 81:251. 10:24–9. 66 Rosenblatt A, Liang KY, Zhou H, et al. The association 79 Beal MF, Brouillet E, Jenkins BG, et al. Neurochemical of CAG repeat length with clinical progression in and histologic characterization of striatal excitotoxic Huntington disease. Neurol 2006; 11; 66(7):1016–20. lesions produced by the mitochondrial toxin 67 Wexler NS, Lorimer J, Porter J, et al. U.S.-Venezuela 3- nitropropionic acid. J Neurosci 1993; 13:4181–92. Collaborative Research Project. Venezuelan kindreds 80 Beal MF, Ferrante R, Swartz K, Kowall N. Chronic reveal that genetic and environmental factors modu- quinolinic acid lesions in rats closely resemble late Huntington’s disease age of onset. Proc Natl Acad Huntington’s disease. J Neurosci 1991; 11:1649–59. Sci U S A 2004; 101(10):3498–503. 81 Garcia M, Vanhoutte P, Pages C, et al. The mitochon- 68 Gayán J, Brocklebank D, Andresen JM, et al. drial toxin 3-nitropropionic aid induces striatal Genomewide linkage scan reveals novel loci modify- neurodegeneration via c-Jun N-terminal kinase/c-Jun ing age of onset of Huntington’s disease in the module. J Neurosci 2002; 22:2174–84. Venezuelan HD kindreds. Genet Epidemiol 2008; 82 Jin YN, Johnson GV. The interrelationship between 32(5):445–53. mitochondrial dysfunction and transcriptional dys-

Albanese_c10.indd 168 12/24/2011 6:59:52 AM Huntington Disease and Other Genetic Choreas 169

regulation in Huntington disease. J Bioenerg expression in Huntington’s disease. Brain 2008; Biomembr 2010 Jun; 42(3):199–205. 131(Pt 2):381–8. 83 Fukui H, Moraes CT. Extended polyglutamine repeats 96 Cha JH. Transcriptional dysregulation in Huntington’s trigger a feedback loop involving the mitochondrial disease. Trends Neurosci 2000; 23:387–92. complex III, the proteasome and huntingtin 97 van der Burg JM, Björkqvist M, Brundin P. Beyond aggregates. Hum Mol Genet 2007 Apr 1; 16(7):783– the brain: widespread pathology in Huntington’s 97. Epub 2007 Mar 13. disease. Lancet Neurol 2009; 8:765–74. 84 Turner C, Schapira AH. Mitochondrial matters of the 98 Marcora E, Kennedy MB. The Huntington’s disease brain: the role in Huntington’s disease. J Bioenerg mutation impairs Huntingtin’s role in the transport Biomembr 2010 Jun; 42(3):193–8. of NF-{kappa}B from the synapse to the nucleus. 85 Oliveira JM. Nature and cause of mitochondrial Hum Mol Genet 2010 Nov 15; 19(22):4373–84. dysfunction in Huntington’s disease: focusing on 99 Godin JD, Colombo K, Molina-Calavita M, et al. huntingtin and the striatum. J Neurochem 2010 Jul; Huntingtin is required for mitotic spindle orientation 114(1):1–12. Epub 2010 Apr 9. Review. and mammalian neurogenesis. Neuron 2010 Aug 12; 86 Li XJ, Orr AL, Li S. Impaired mitochondrial trafficking 67(3):392–406. in Huntington’s disease. Biochim Biophys Acta 2010 100 Davies SW, Turmaine M, Cozens B, et al. Formation Jan; 1802(1):62–5. Epub 2009 Jul 8. of neuronal intranuclear inclusions underlies the 87 Jenkins B, Koroshetz WJ, Beal MF, Rosen BR. neurological dysfunction in mice transgenic for the Evidence for impairment of metabolism in vivo in HD muatation. Cell 1997; 90:537–48. Huntington’s disease using localized 1H NMR 101 Scherzinger E, Lurz R, Turmaine M, et al. Huntingtin- spectroscopy. Neurol 1993; 43:2689–95. encoded polyglutamine expansions form amyloid- 88 Harms L, Meierkord H, Timm G, Pfeiffer L, Ludolph AC. like protein aggregates in vitro and in vivo. Cell Decreased N-acetyl-aspartate/choline ratio and 1997; 90:549–58. increased lactate in the frontal lobe of patients with 102 DiFiglia M, Sapp E, Chase KO, Davies S, Bates G, Huntington’s disease: a proton magnetic resonance Vonsattel J. Aggregation of huntingtin in neuronal spectroscopy study. J Neurol Neurosurg Psychiat 1997; intranuclear inclusions and dystrophic neurites in 62:27–30. brain. Science 1997; 277:1990–3. 89 McNicoll CF, Latourelle JC, MacDonald ME, et al. 103 Hoffner G, Kahlem P, Djian P. Perinuclear localization Huntington CAG repeat size does not modify onset of huntingtin as a consequence of its binding to age in familial Parkinson’s disease: the GenePD study. microtubules through an interaction with beta-tubu- Mov Disord 2008; 23(11):1596–601. lin: relevance to Huntington’s disease. J Cell Sci 90 Reynolds NC, Prost RW, Mark LP, Joseph SA. 2002; 115:941–8. MR-spectroscopic findings in juvenile-onset Hunting- 104 Muchowski PJ, Ning K, D’Souza-Schorey C, Fields S. ton’s disease. Mov Disord 2008; 23(13):1931–5. Requirement of an intact microtubule cytoskeleton 91 Reynolds NC Jr, Prost RW, Mark LP. Heterogeneity in for aggregation and inclusion body formation by a 1H-MRS profiles of presymptomatic and early manifest mutant huntingtin fragment. Proc Natl Acad Sci Huntington’s disease. Brain Res 2005; 1031(1):82–9. U S A 2002; 99:727–32. 92 Ciammola A, Sassone J, Sciacco M, et al. Low anaero- 105 Varma H, Yamamoto A, Sarantos MR, et al. Mutant bic threshold and increased skeletal muscle lactate huntingtin alters cell fate in response to microtubule production in subjects with Huntington’s disease. Mov depolymerization via gef-h1-rhoa-erk pathway. Disord 2011 Jan; 26(1):130–7. J Biol Chem 2010 Nov 26; 285(48):37445–57. 93 Strong TV, Tagle DA, Valdes JM, et al. Widespread 106 Li XJ, Li SH, Sharp AH, et al. A huntingtin-associated expression of the human and rat Huntington’s disease protein enriched in brain with implications for gene in brain and non-neural tissues. Nat Genet 1993; pathology. Nature 1995; 378:398–402. 5:259–65. 107 Bao J, Sharp A, Wagster M, et al. Expansion of poly- 94 Gourfinkel-An I, Cancel G, Trottier Y, et al. Differential glutamine repeat in huntingtin leads to abnormal distribution of the normal and mutated forms of protein interactions involving calmodulin. Proc Natl huntingtin in the human brain. Ann Neurol 1997; Acad Sci U S A 1996; 93:5037–42. 42:712–9. 108 Burke JR, Enghild JJ, Martin ME, et al. DRPLA 95 Anderson AN, Roncaroli F, Hodges A, Deprez M, proteins selectively interact with the enzyme Turkheimer FE. Chromosomal profiles of gene GAPDH. Nature Med 1996; 2:347–50.

Albanese_c10.indd 169 12/24/2011 6:59:52 AM 170 Chapter 10

109 Wanker EE, Rovira C, Scherzinger E, et al. HIP–1: a 123 Ross CA, Tabrizi SJ. Huntington’s disease: from huntingtin interacting protein isolated by the yeast molecular pathogenesis to clinical treatment. Lancet two-hybrid system. Hum Mol Genet 1997; 6: Neurol 2011; 10:83–98. 487–95. 124 Pan T, Kondo S, Le W, Jankovic J. The role of 110 Boutell J, Wood J, Harper P, Jones A. Huntingtin autophagy-lysosome pathway in neurodegeneration interacts with cystathionine beta-synthase. Hum Mol associated with Parkinson’s disease. Brain 2008; Genet 1998; 7:371–8. 131:1969–1978. 111 Faber P, Barnes G, Srinidhi J, Chen J, Gusella J, 125 Tsvetkov AS, Miller J, Arrasate M, et al. A small-mol- MacDonald M. Huntingtin interacts with a family of ecule scaffold induces autophagy in primary neurons WW domain proteins. Hum Mol Genet 1998; 7: and protects against toxicity in a Huntington disease 1463–74. model. Proc Natl Acad Sci U S A 2010 Sep 28; 112 Mantamadiotis T, Lemberger T, Bleckmann SC, et al. 107(39):16982–7. Epub 2010 Sep 10. Disruption of CREB function in brain leads to neuro- 126 Mastroberardino PG, Piacentini M. Type 2 transglu- degeneration. Nat Genet 2002; 31:47–54. taminase in Huntington’s disease: a double-edged 113 Nucifora FC, Sasaki M, Peters MF, et al. Interference sword with clinical potential. J Intern Med 2010 by huntingtin and atrophin 1 with CBP-mediated Nov; 268(5):419–31. transcription leading to cellular toxicity. Science 127 McConoughey SJ, Basso M, Niatsetskaya ZV, et al. 2001; 2423–8. Inhibition of transglutaminase 2 mitigates transcrip- 114 Steffan JS, Bodai L, Pallos J, et al. Histone deacety- tional dysregulation in models of Huntington disease. lase inhibitors arrest polyglutamine-dependent EMBO Mol Med 2010 Sep; 2(9):349–70. neurodegeneration in Drosophila. Nature 2001; 128 Miller JP, Holcomb J, Al-Ramahi I, et al. Matrix 413:739–43. metalloproteinases are modifiers of huntingtin prote- 115 Dunah AW, Jeong H, Griffin A, et al. Sp1 and olysis and toxicity in Huntington’s disease. Neuron TAFII130 transcriptional activity disrupted in early 2010 Jul 29; 67(2):199–212. Huntington’s disease. Science 2002; 296:2238–43. 129 Luthi-Carter R, Taylor DM, Pallos J, et al. SIRT2 inhi- 116 Luthi-Carter R, Strand A, Peters NL, et al. Decreased bition achieves neuroprotection by decreasing sterol expression of striatal signaling genes in a mouse biosynthesis. Proc Natl Acad Sci U S A 2010 Apr 27; model of Huntington’s disease. Hum Mol Genet 107(17):7927–32. Epub 2010 Apr 8. 2000; 9:1259–71. 130 Hathorn T, Snyder-Keller A, Messer A. Nicotinamide 117 Zuccato C, Ciammola A, Rigamonti D, et al. Loss of improves motor deficits and upregulates PGC–1α Huntingtin mediated BDNF gene transcription in and BDNF gene expression in a mouse model of Huntington’s disease. Science 2001; 293:493–8. Huntington’s disease. Neurobiol Dis 2011 Jan; 118 Tebano MT, Martire A, Chiodi V, et al. Role of 41(1):43–50. adenosine A(2A) receptors in modulating synaptic 131 Pineda JR, Pardo R, Zala D, et al. Genetic and functions and brain levels of BDNF: a possible key pharmacological inhibition of calcineurin corrects mechanism in the pathophysiology of Huntington’s the BDNF transport defect in Huntington’s disease. disease. ScientificWorldJournal 2010 Sep 1; 10: Mol Brain 2009 Oct 27; 2(1):33. 1768–82. 132 Gohil VM, Offner N, Walker JA, et al. Meclizine is 119 Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, neuroprotective in models of Huntington’s disease. a striatal specific protein, mediates mutant-huntingtin Hum Mol Genet 2011 Jan 15; 20(2):294–300. cytotoxicity. Science 2009; 324(5932):1327–30. 133 Lotz GP, Legleiter J, Aron R, et al. Hsp70 and Hsp40 120 Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, functionally interact with soluble mutant huntingtin Efstratiadis A. Increased apoptosis and early embry- oligomers in a classic ATP-dependent reaction cycle. onic lethality in mice nullizygous for the HD gene J Biol Chem 2010 Dec 3; 285(49):38183–93. homologue. Nat Genet 1995; 11:155–63. 134 Tower C, Fu L, Gill R, et al. Human cytomegalovirus 121 Albin R, Tagle D. Genetics and molecular biology of UL97 kinase prevents the deposition of mutant Huntington’s disease. Trends Neurosci 1995; 18:11–4. protein aggregates in cellular models of Huntington’s 122 Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of disease and Ataxia. Neurobiol Dis 2011 Jan; the HD gene with an expanded CAG repeat is sufficient 41(1):11–22. to cause a progressive neurological phenotype in 135 Blázquez C, Chiarlone A, Sagredo O, et al. Loss transgenic mice. Cell 1996; 87:493–506. of striatal type 1 cannabinoid receptors is a key

Albanese_c10.indd 170 12/24/2011 6:59:52 AM Huntington Disease and Other Genetic Choreas 171

pathogenic factor in Huntington’s disease. Brain rigid Huntington’s disease: implications for the func- 2011 Jan; 134(Pt 1):119–36. tional anatomy of chorea and rigidity-akinesia. Ann 136 Gabery S, Murphy K, Schultz K, et al. Changes in key Neurol. 1990 Apr; 27(4):357–65. hypothalamic neuropeptide populations in 148 Vonsattel, J., R. H. Myers, T. J. Stevens, M. S. Ferrante, Huntington disease revealed by neuropathological E. D. Bird, and E. P. Richardson 1985. Neuro- analyses. Acta Neuropathol 2010 Dec; 120(6): pathological classification of Huntington’s disease. 777–88. J. Neuropathol. Exp. Neurol. 44: 559–577. 137 Orth M, Schippling S, Schneider SA, et al. Abnormal 149 Sieradzan, K, DMA Mann, A Dodge. Clinical presen- motor cortex plasticity in premanifest and very early tation and patterns of cerebral atrophy related to the manifest Huntington disease. J Neurol Neurosurg length of trinucleotide repeat expansion in patients Psychiat 2010 Mar; 81(3):267–70. Epub 2009 Oct 13. with adult onset Huntington’s disease. Neurosci. Lett 138 Milnerwood AJ, Raymond LA. Early synaptic patho- 1997; 225: 45–48. physiology in neurodegeneration: insights from 150 Braak, H., and E. Braak 1992. Allocortical involve- Huntington’s disease. Trends Neurosci 2010 Nov; ment in Huntington’s disease. Neuropathol. Appl. 33(11):513–23. Neurobiol. 18: 539– 547. 139 Thu DC, Oorschot DE, Tippett LJ, et al. Cell loss in 151 Halliday GM, McRitchie DA, Macdonald V, et al. the motor and cingulate cortex correlates with symp- Regional specificity of brain atrophy in Huntington’s tomatology in Huntington’s disease. Brain 2010 Apr; disease. Exp Neurol 1998 Dec; 154(2):663–72. 133(Pt 4):1094–110. 152 Sieradzan KA, Mechan AO, Jones L, Wanker EE, 140 Metzger S, Saukko M, Van Che H, et al. Age at onset Nukina N, Mann DM. Huntington’s disease intranu- in Huntington’s disease is modified by the autophagy clear inclusions contain truncated, ubiquitinated hun- pathway: implication of the V471A polymorphism in tingtin protein. Exp Neurol. 1999 Mar; 156(1):92–9. Atg7. Hum Genet 2010 Oct; 128(4):453–9. Epub 153 Becher MW, Kotzuk JA, Sharp AH, et al. Intranuclear 2010 Aug 10. neuronal inclusions in Huntington’s disease and den- 141 Penney JB Jr, Vonsattel JP, MacDonald ME, tatorubral and pallidoluysian atrophy: correlation Gusella JF, Myers RH. CAG repeat number governs between the density of inclusions and IT15 CAG tri- the development rate of pathology in Huntington’s plet repeat length. Neurobiol Dis. 1998 Apr; 4(6): disease. Ann Neurol. 1997 May; 41(5):689–92. 387–97. 142 Myers RH, Vonsattel JP, Paskevich PA, Kiely DK, 154 Bartzokis G, Cummings J, Perlman S, et al. Increased Stevens TJ, Cupples LA, Richardson EP Jr, Bird ED. basal ganglia iron levels in Huntington disease. Arch Decreased neuronal and increased oligodendroglial Neurol. 1999 May; 56(5):569–74. densities in Huntington’s disease caudate nucleus. 155 Aylward EH, Li Q, Stine OC, et al. Longitudinal J Neuropathol Exp Neurol. 1991 Nov; 50(6):729–42. change in basal ganglia volume in patients with 143 De la Monte, S. M., J. P. Vonsattel, and E. P. Richardson Huntington’s disease. Neurol 1997; 48:394–9. 1988. Morphometric demonstration of atrophic 156 Rosas HD, Liu AK, Hersch S, et al. Regional and changes in the cerebral cortex, white matter and progressive thinning of the cortical ribbon in neostriatum in Huntington’s disease. J. Neuropathol. Huntington’s disease. Neurol 2002; 58:695–701. Exp. Neurol. 47: 516–525. 157 Thieben MJ, Duggins AJ, Good CD, et al. The distri- 144 Mann, D. M. A., R. Oliver, and J. S. Snowden 1993. bution of structural neuropathology in pre-clinical The topographic distribution of brain atrophy in Huntington’s disease. Brain 2002; 125:1815–28. Huntington’s disease and progressive supranuclear 158 Aylward EH, Nopoulos PC, Ross CA, et al. the palsy. Acta Neuropathol. 85: 553–559. PREDICT-HD Investigators and Coordinators of the 145 Sieradzan KA, Mann DM. The selective vulnerability Huntington Study Group. Longitudinal change in of nerve cells in Huntington’s disease. Neuropathol regional brain volumes in prodromal Huntington Appl Neurobiol. 2001 Feb; 27(1):1–21. disease. J Neurol Neurosurg Psychiat 2011 Apr; 146 Cicchetti F, Parent A. Striatal interneurons in 82(4):405–10. Huntington’s disease: selective increase in the density 159 Klöppel S, Chu C, Tan GC, et al. PREDICT-HD of calretinin-immunoreactive medium-sized neu- Investigators of the Huntington Study Group. rons. Mov Disord 1996 Nov; 11(6):619–26. Automatic detection of preclinical neurodegeneration: 147 Albin RL, Reiner A, Anderson KD, Penney JB, Young presymptomatic Huntington disease. Neurol 2009; AB. Striatal and nigral neuron subpopulations in 72(5):426–31.

Albanese_c10.indd 171 12/24/2011 6:59:52 AM 172 Chapter 10

160 Nopoulos PC, Aylward EH, Ross CA, et al. PREDICT-HD and healthy subjects. Mov Disord 2010 Sep 15; Investigators Coordinators of Huntington Study 25(12):1924–8. Group (HSG). Cerebral cortex structure in prodromal 173 Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington disease. Neurobiol Dis 2010 Dec; Huntington’s disease: a pilot study. Mov Disord 2004; 40(3):544–54. 19(6):692–5. 161 Paulsen JS, Zhao H, Stout JC, et al. Clinical markers 174 Huntington Study Group. DOMINO Results. of early disease in persons near onset of Huntington’s |{WebSite:Huntington Study Group website}{WebURL: disease. Neurol 2001; 57:658–62. http://www.huntington-study-group.org/Clinical 162 van den Bogaard SJ, Dumas EM, Acharya TP, et al. Research/CompletedClinicalTrials/DOMINOResults/ TRACK-HD Investigator Group. Early atrophy of tabid/104/Default.aspx}| 2009. Accessed October 21, pallidum and accumbens nucleus in Huntington’s 2009. disease. J Neurol 2011 Mar; 258(3):412–20. 175 Huntington Study Group DOMINO Investigators. A 163 Tabrizi SJ, Scahill RI, Durr A, et al. Biological and futility study of minocycline in Huntington’s disease. clinical changes in premanifest and early stage Mov Disord 2010 Oct 15; 25(13):2219–24. Huntington’s disease in the TRACK-HD study: the 176 Huntington Study Group. PREQUEL - Recruitment 12-month longitudinal analysis. Lancet Neurol 2011 for PREQUEL will begin in Fall 2009. |{WebSite: Jan; 10(1):31–42. Huntington Study Group website}{WebURL:http:// 164 Soneson C, Fontes M, Zhou Y, et al. Huntington Study www.huntington-study-group.org/ClinicalResearch/ Group PREDICT-HD investigators. Early changes in ClinicalTrialsObservationalStudiesinProgress/ the hypothalamic region in prodromal Huntington PREQUEL/tabid/107/Default.aspx}| 2009b. Accessed disease revealed by MRI analysis. Neurobiol Dis 2010 October 21, 2009. Dec; 40(3):531–43. Epub 2010 Aug 2. 177 Verbessem P, Lemiere J, Eijnde BO, et al. Creatine 165 Ginestroni A, Battaglini M, Diciotti S, et al. supplementation in Huntington’s disease: a placebo- Magnetization Transfer MR Imaging Demonstrates controlled pilot trial. Neurol 2003; 61(7):925–30. Degeneration of the Subcortical and Cortical Gray 178 Tabrizi SJ, Blamire AM, Manners DN, et al. High- Matter in Huntington Disease. AJNR Am J Neuro- dose creatine therapy for Huntington disease: a radiol 2010 Nov; 31(10):1807–12. 2-year clinical and MRS study. Neurol 2005; 64(9): 166 Nopoulos PC, Aylward EH, Ross CA, et al. the 1655–6. PREDICT-HD Investigators and Coordinators of 179 Hersch SM, Gevorkian S, Marder K, et al. Creatine in the Huntington Study Group. Smaller intracranial Huntington disease is safe, tolerable, bioavailable in volume in prodromal Huntington’s disease: evidence brain and reduces serum 8OH2’dG. Neurol 2006; for abnormal neurodevelopment. Brain 2011 Jan; 66(2):250–2. 134(Pt 1):137–42. 180 Hauser RA, Furtado S, Cimino CR, et al. Bilateral 167 Rosenblatt A, Ranen NG, Nance MA, Paulsen JS. A human fetal striatal transplantation in Huntington’s physician’s guide to the management of Huntington’s disease. Neurol 2002; 58:687–95. disease, 2nd ed. New York: Huntington’s Disease 181 Bachoud-Lévi AC, Gaura V, Brugieres P, et al. Effect Society of America 1999. of fetal neural transplants in patients with Hunting- 168 Frank S, Jankovic J. Advances in the pharmacologi- ton’s disease 6 years after surgery: a long term cal management of Huntington’s disease. Drugs follow-up study. Lancet Neurol 2006; 5(4):303–9. 2010; 70:561–71. 182 Bachoud-Lévi AC, Hantraye P, Peschanski M. Fetal 169 Adam OR, Jankovic J. Symptomatic treatment of neural grafts for Huntington’s disease: a prospective Huntington disease. Neurotherapeutics 2008; 5(2): view. Mov Disord 2002; 17:439–44. 181–97. 183 Keene CD, Chang RC, Leverenz JB, et al. A patient 170 Jankovic J. Treatment of hyperkinetic movement with Huntington’s disease and long-surviving fetal disorders. Lancet Neurol 2009; 8(9):844–56. neural transplants that developed mass lesions. Acta 171 Huntington Study Group. A randomized, placebo- Neuropathol 2009; 117(3):329–38. controlled trial of coenzyme Q10 and remacemide in 184 Sah DW. Therapeutic potential of RNA interference Huntington’s disease. Neurol 2001; 57:397–404. for neurological disorders. Life Sci 2006; 79(19): 172 Huntington Study Group Pre2CARE Investigators, 1773–80. Hyson HC, Kieburtz K, et al. Safety and tolerability of 185 DeVane CL, Mintzer J. Risperidone in the high-dosage coenzyme Q10 in Huntington’s disease management of psychiatric and neurodegenerative

Albanese_c10.indd 172 12/24/2011 6:59:52 AM Huntington Disease and Other Genetic Choreas 173

disease in the elderly: an update. Psychopharmacol 200 Marder K, Sandler S, Lechich A, et al. Relationship Bull 2003; 37(4):116–32. between CAG repeat length and late-stage outcomes 186 Bonelli RM, Mahnert FA, Niederwieser G. Olanzapine in Huntington’s disease. Neurol 2002; 59:1622–4. for Huntington’s disease: an open label study. Clin 201 Koide R, Ikeuchi T, Onodera O, et al. Unstable Neuropharmacol 2002; 25(5):263–5. expansion of CAG repeat in hereditary 187 O’Suilleabhain P, Dewey RB Jr. A randomized trial of dentatorubral-pallidoluysian atrophy (DRPLA). Nat amantadine in Huntington disease. Arch Neurol Genet. 1994 Jan; 6(1):9–13. 2003; 60(7):996–8. 202 Becher MW, Rubinsztein DC, Leggo J, Wagster MV, 188 Zesiewicz TA, Sullivan KL, Hauser RA, Sanchez- Stine OC, Ranen NG, Franz ML, Abbott MH, Ramos J. Open-label pilot study of levetiracetam Sherr M, MacMillan JC, Barron L, Porteous M, (Keppra) for the treatment of chorea in Huntington’s Harper PS, Ross CA. Dentatorubral and pallidoluysian disease. Mov Disord 2006; 21(11):1998–2001. atrophy (DRPLA). Clinical and neuropathological 189 Huntington Study Group. Tetrabenazine as anticho- findings in genetically confirmed North American rea therapy in Huntington disease: a randomized and European pedigrees. Mov Disord. 1997 Jul; controlled trial. Neurol 2006; 66(3):366–72. 12(4):519–30. 190 Fasano A, Cadeddu F, Guidubaldi A, et al. The long- 203 Chorea, Ballism, Athetosis. Phenomenolgy and term effect of tetrabenazine in the management of Etiology. In Fahn S, Jankovic J (ed). Principles and Huntington disease. Clin Neuropharmacol 2008; Practice of Movement Disorders. Philadelphia. 31(6):313–8. Churchill Livingstone Elsevier, 2007, pp 393–407. 191 Frank S, Ondo W, Fahn S, et al. A study of chorea 204 Wardle M, Morris HR, Robertson NP. Clinical and after tetrabenazine withdrawal in patients with genetic characteristics of non-Asian dentatorubral- Huntington disease. Clin Neuropharmacol 2008; pallidoluysian atrophy: A systematic review. Mov 31(3):127–33. Disord. 2009 Aug 15; 24(11):1636–40. 192 Kenney C, Jankovic J. Tetrabenazine in the treatment 205 Xiang F, Almqvist EW, Hug M, et al. Huntington of hyperkinetic movement disorders. Expert Rev disease-like neurodegenerative disorder maps to Neurother 2006; 6(1):7–17. chromosome 20p. Am J Hum Genet 1998; 63: 193 Brusa L, Orlacchio A, Moschella V, et al. Treatment of 1431–8. the symptoms of Huntington’s disease: preliminary 206 Schneider SA, Walker RH, Bhatia KP. The Huntington’s results comparing aripiprazole and tetrabenazine. disease-like syndromes: what to consider in patients Mov Disord 2009; 24(1):126–9. with a negative Huntington’s disease gene test. Nat 194 Huntington Study Group. Dosage effects of riluzole Clin Pract Neurol. 2007 Sep; 3(9):517–25. in Huntington’s disease: a multicenter placebo- 207 Laplanche JL et al. (1999) Prominent psychiatric fea- controlled study. Neurol 2003; 61(11):1551–6. tures and early onset in an inherited prion disease 195 Moro E, Lang AE, Strafella AP, et al. Bilateral globus with a new insertional mutation in the prion protein pallidus stimulation for Huntington’s disease. Ann gene. Brain 122: 2375–2386. Neurol 2004; 56(2):290–4. 208 Maltecca F, Filla A, Castaldo I, et al. Intergenerational 196 Kang GA, Heath S, Rothlind J, et al. Long-term instability and marked anticipation in SCA–17. follow-up of pallidal deep brain stimulation in two Neurol 2003; 61: 1441–4. cases of Huntington’s disease. J Neurol Neurosurg 209 Craig K, Keers SM, Walls TJ, et al. Minimum preva- Psychiat 2011 Mar; 82(3):272–7. lence of spinocerebellar ataxia 17 in the north east of 197 Aziz NA, Anguelova GV, Marinus J, et al. Sleep and England. J Neurol Sci. 2005 Dec 15; 239(1):105–9. circadian rhythm alterations correlate with depression Epub 2005 Oct 11. and cognitive impairment in Huntington’s disease. 210 Hardie RJ, Pullon HW, Harding AE, et al. Neuro- Parkinsonism Relat Disord 2010 Jun; 16(5):345–50. acanthocytosis. A clinical, haematological and patho- 198 Bonelli RM, Neiderwieser G, Diez J, et al. Pramipexole logical study of 19 cases. Brain. 1991 Feb; 114 ameliorates neurologic and psychiatric symptoms in (Pt 1A):13–49. a Westphal variant of Huntington’s disease. Clin 211 Witt TN, Danek A, Reiter M, et al. McLeod syndrome: Neuropharm 2002; 25:58–60. a distinct form of neuroacanthocytosis. Report of 199 Hamakawa S, Koda C, Umeno H, et al. Oropharyngeal two cases and literature review with emphasis on dysphagia in a case of Huntington’s disease. Auris neuromuscular manifestations. J Neurol. 1992 Jul; Nasus Larynx 2004; 31(2):171–6. 239(6):302–6.

Albanese_c10.indd 173 12/24/2011 6:59:52 AM 174 Chapter 10

212 Danek A, Rubio JP, Rampoldi L, et al. McLeod dystonia and hereditary essential myoclonus: an area neuroacanthocytosis: genotype and phenotype. Ann of confusion. Adv Neurol 1988; 50:391–401. Neurol 2001 Dec; 50(6):755–64. 225 Klein C, Wenning GK, Quinn NP, Marsden CD. 213 Danek A, Tison F, Rubio J, et al. The chorea of McLeod Ataxia without telangiectasia masquerading as syndrome. Mov Disord 2001 Sep; 16(5):882–9. benign hereditary chorea. Mov Disord 1996; 11: 214 Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, 217–220. clinical, and radiographic delineation of Hallervorden- 226 MacMillan JC, Morrison PJ, Nevin NC, et al. Spatz syndrome. N Engl J Med. 2003 Jan 2; Identification of an expanded CAG repeat in the 348(1):33–40. Huntington’s disease gene (IT15) in a family reported 215 Chinnery PF, Curtis AR, Fey C, et al. Neuro- to have benign hereditary chorea. J Med Genet 1993; ferritinopathy in a French family with late onset 30:1012–1013. dominant dystonia. J Med Genet. 2003 May; 227 de Vries BB, Arts WF, Breedveld GJ, et al. Benign 40(5):e69. hereditary chorea of early onset maps to chromo- 216 Ondo WG, Adam OR, Jankovic J, Chinnery PF. some 14q. Am. J. Hum. Genet 2000; 66:136–142. Dramatic response of facial stereotype/tic to 228 Fernandez M, Raskind W, Matsushita M, et al. tetrabenazine in the first reported cases of Hereditary benign chorea: clinical and genetic neuroferritinopathy in the United States. Mov Disord features of a distinct disease. Neurol 2001; 57: 2010; 25:2470–2. 106–110. 217 Haerer AF, Currier RD, Jackson JF. Hereditary 229 Breedveld GJ, van Dongen JW, Danesino C, et al. nonprogressive chorea of early onset. N Engl J Med. Mutations in TITF–1 are associated with benign 1967 Jun 1; 276(22):1220–4. hereditary chorea. Hum Mol Genet. 2002 Apr 15; 218 Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign 11(8):971–9. hereditary chorea–entity or syndrome? Mov Disord 230 Asmus F, Horber V, Pohlenz J, et al. A novel TITF–1 2000 Mar; 15(2):280–8. mutation causes benign hereditary chorea with 219 Robinson RO, Thornett CE. Benign hereditary response to levodopa. Neurol 2005; 64:1952–1954. chorea–response to steroids. Dev Med Child Neurol. 231 Krude H, Schutz B, Biebermann H, et al. 1985 Dec; 27(6):814–6. Choreoathetosis, hypothyroidism, and pulmonary 220 Wheeler PG, Weaver DD, Dobyns WB. Benign alterations due to human NKX2–1 haploinsuffi- hereditary chorea. Pediatr Neurol 1993 Sep-Oct; ciency. J Clin Invest 2002; 109:475–480. 9(5):337–40. Review. 232 Willemsen MA, Breedveld GJ, Wouda S, et al. Brain- 221 Leli DA, Furlow TW Jr, Falgout JC. Benign familial Thyroid- Lung syndrome: a patient with a severe chorea: an association with intellectual impairment. multi-system disorder due to a de novo mutation in J Neurol Neurosurg Psychiat. 1984 May; 47(5): the thyroid transcription factor 1 gene. Eur J Pediatr 471–4. 2005; 164:28–30. 222 Pincus JH, Chutorian A. Familial benign chorea with 233 Kleiner-Fisman G, Lang AE. Benign hereditary intention tremor: A clinical entity. J Pediatr 1967; chorea revisited: a journey to understanding. Mov 70:724–9. Disord. 2007 Dec; 22(16):2297–305; quiz 2452. 223 Damasio H, Antunes L, Damasio AR. Familial non- 234 Fekete R, Jankovic J. Psychogenic chorea associated progressive involuntary movements of childhood. with family history of Huntington disease. Mov Ann Neurol 1977; 1:602–3. Disord 2010; 25:503–4. 224 Quinn NP, Rothwell JC, Thompson PD, Marsden CD. Hereditary myoclonic dystonia, hereditary torsion

Albanese_c10.indd 174 12/24/2011 6:59:52 AM CHAPTER 11 Acquired Choreas Ruth H. Walker Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, and Mount Sinai School of Medicine, New York City, NY, USA

Historical background that these epidemics were due to ergotism appears unlikely as chorea is not a feature of ergot toxicity. The clinical phenomenon of chorea has been In the 17th century the English physician Thomas recognized for many centuries, and has been attrib- Sydenham noted the development of chorea in uted variously to psychological or organic causes [1]. children, and attributed this to a local epidemic of The term derives from the Greek word χορει′α dancing mania, hence the somewhat confusing which describes a type of traditional circle dance, term “St Vitus’ dance” [3]. This childhood disorder and suggests the rapid, jerk-like, albeit irregular was also known as chorea minor, to distinguish it and unpredictable quality of the movements. The from the wider epidemics of dancing mania in involuntary movements were first described as adults, chorea major. The connection with rheumatic dance-like by the physician and alchemist fever, and the use of the eponym “Sydenham’s Paracelsus in the 16th century. Paracelsus used the chorea” was only made later by Charcot in 1887 term “St Vitus’ dance” (Chorea Sancti Viti) to refer [1]. The hereditary nature of an adult-onset form primarily to epidemics of “dancing mania” which chorea in families on Long Island, New York, was occurred in Europe in medieval times. This dancing reported by George Huntington in 1872, although mania was also known in various locations as this was disputed by Charcot who believed that St John’s chorea, danse de St Guy (the French name most forms of chorea were variations of a similar of St Vitus), or the dancing procession of Echternach. inherited condition [1]. Clarification of different A form of this latter manifestion persists as an forms of hereditary and acquired chorea was made annual celebration in Luxembourg [2]. This attri- by William Osler in 1894 (On Chorea and bution of dancing mania to St Vitus may have been Choreiform Affections) [1]. because sufferers were cured after dancing in a chapel dedicated to St Vitus [3] (now known as the patron saint of dancers), although other explana- Phenomenology tions can be found. Several of these epidemics were described in various countries in the middle ages, Chorea refers to involuntary movements of limbs, and resulted in significant fatalities from exhaustion, trunk, neck, or face, which rapidly flit from region stroke, and heart attack. They clearly appear to to region without regular pattern. Mild chorea can have been psychogenic in origin [2,4]. The theory appear as subtle fidgetiness or restlessness, of which

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the patient may not even be aware. Involuntary writhing movement, and dystonia, in which movements may be disguised as purposeful abnormal movements are repeated, or there is a movements, such as scratching the ear or fiddling sustained abnormal posture. with clothing (parakinesia). Unlike dystonia, where Although it strictly means “abnormality of the same muscle groups are activated repetitively, movement,” the term “dyskinesia” usually refers body parts are involved in an irregular manner. more specifically to movements which are There is an inability to maintain a fixed posture, choreiform, most commonly “tardive dyskinesia” “motor impersistence,” which appears to be due to or “l-dopa-induced dyskinesia.” lapses in the ability to perform the task, as the converse of the intrusions of fragments of movements into voluntary tasks. This phenomenon results in Epidemiology the “milkmaid’s grip,” as if squeezing the udders of a cow, and the “trombonist’s tongue,” which moves The epidemiology of chorea reflects that of the back and forth in the mouth. underlying disorders. In addition to the ever- Chorea may occur with, but should be increasing list of relatively rare genetic disorders distinguished from, athetosis, which is a slower, which manifest with chorea, this movement

Table 11.1 Suggestive features in the evaluation of the patient with chorea.

Etiology Onset Progression Clinical features Diagnostic tests

Structural Acute (stroke) Stable, may resolve. Unilateral chorea; Neuroimaging Sub-acute Gradual worsening, localizing neurologic (space-occupying may stabilize features lesions) Metabolic Acute (e.g. DM) Resolves with Other metabolic Serum laboratory testing Subacute (e.g. treatment (usually) derangements; signs (glucose, electrolytes, hyperthryoidism, of related medical liver enzymes, thyroid, hyponatremia illness parathyroid hormones, B12, etc.) Autoimmune Acute/subacute Variable Signs of related Autoimmune evaluation medical illness (ASO titres, anti-DNase B, (autoimmune; antigliadin abs; erythrocyte carcinoma) sedimentation rate, lupus anticoagulant, antiphosholipid abs, antinuclear abs; paraneoplastic screen; imaging of thorax/ abdomen/pelvis; serum/CSF for antineuronal abs Drug-induced Acute/subacute Stable May be other signs Suggestive temporal of toxicity relationship with drug use Infectious/ Subacute Variable Signs of related HIV; RPR/FTA; mycoplasma post-infectious medical illness abs; EEG; lumbar puncture for 14–3–3 infection Psychogenic Acute, subacute Unexplained Inconsistent clinical fluctuations examination; other unexplained medical complaints

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Patient with chorea; genetic causes excluded

Streptococcal? Infant/child +ve Age of sore throat, rheumatic Sydenham’s chorea onset? heart disease ASO, anti-DNase Adult B titers Normal Delayed Tardive dyskinesia Structural lesion; Stroke, tumor, abscess, demyelination, +ve No Yes Time MRI Medication- Direct side effect arteriovenous malformation, related? course? Immediate or calcification, striatal necrosis, etc dose-related –ve Paraneoplastic syndrome +ve Metabolic, endocrine, infectious, etc; Hyper-, hypoglycemia, hyper-, hyponatremia, Anti-Hu, -Yo, Glucose, polycythemia rubra vera, -CRMP-5/CV2, Autoimmune electrolytes, hgb, Normal Normal Abnormal chorea gravidarum, -NMDA, -VGCC abs; work-up, pregnancy test acquired hepatocerebral degeneration, Structural evaluation anti-gliadin abs liver enzymes, TSH, PTH, RPR, HIV, hyperthyroidism, for tumor B12, Pb hyper-, hypoparathyroidism, neurosyphilis, HIV-related, B12 deficiency, Pb toxicity –ve +ve

Autoimmune disease; EEG-PLEDs SLE, Sjogren’s syndrome MRI findings anti-phospholipid ab syndrome, CSF 14-3-3 celiac disease.

+ve

Creutzfeldt-Jakob disease (confirmed by brain biopsy or pathology)

Figure 11.1 Flow chart for the evaluation of the patient HIV, human immunodeficiency virus; MRI, magnetic with acquired chorea. This algorithm assumes that resonance imaging; Pb, lead; PLEDs, periodic lateralizing genetic causes have been excluded, and should be used epileptiform discharges; PTH, parathyroid hormone; as a guide, taking clinical context into account, rather RPR, rapid plasma reagin; SLE, systemic lupus than strictly followed. erythematosus; TSH, thyroid-stimulating hormone. Abbreviations: ab, antibody; ASO, antistreptolysin O antibody; CSF, cerebrospinal fluid; hgb, hemoglobin;

disorder can be seen as an infrequent complication (Figure 11.1), and yet some patients invariably of many common disorders. The underlying remain undiagnosed. pathophysiology is likely to be an imbalance of the direct and indirect basal ganglia pathways. It is unclear why this happens in such a wide variety of Etiology clinical conditions, but also why it does not happen more often in common disorders, such as stroke Structural causes involving the basal ganglia. The causative diagnosis A large variety of structural causes have reported to may be suggested by features of the patient’s produce chorea in adults. In these cases chorea is history and examination (Table 11.1). The work-up typically unilateral, due to a focal lesion of the con- of the patient with chorea can be extensive tralateral basal ganglia. Vascular etiologies may

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Video 11.1 Hemichorea due to vascular hypoperfusion This 68-year-old man was referred for evaluation of hemichorea. There was no family history of movement disorders. He had multiple risk factors for vascular disease and had undergone right carotid endartectomy 10 years previously. Neuroimaging performed 3 years ago demonstrated complete occlusion of the right internal carotid artery. Involuntary movements affecting the left arm and leg developed 1–2 years prior to evaluation. Work-up for metabolic causes was negative. MRI of the brain showed no infarction, however, SPECT studies demonstrated right frontoparietal and basal ganglia hypoperfusion. Progressive compromise of collateral circulation was presumed to be the cause.

Figure 11.2 Single positron emission computerized http://bit.ly/rOQcye tomography (SPECT) study demonstrating right frontoparietal and basal ganglia hypoperfusion in a 68-year-old man with left hemichorea (see Video 11.1). anesthesia or neurosurgical procedure. Another con- MRI of the brain showed no infarction. Complete dition occasionally seen in children (and very rarely occlusion of the right internal carotid artery was in adults) is post-pump chorea which may occur documented 1 year prior to the development of following open-heart surgery on cardiopulmonary involuntary movements. bypass. This may be due to microemboli or a hyperviscosity syndrome, and appears to be reducing in include stroke, vasculitides, moya-moya disease, incidence with improvements in technology [7]. cavernous angioma, or arteriovenous malformation. Hypoperfusion may be demonstrated in the absence Metabolic of a structural lesion (Figure 11.2; Video 11.1). Space- The most commonly reported metabolic cause of occupying lesions due to tumor or infection may pre- chorea is in diabetic patients with non-ketotic sent with chorea. Multiple sclerosis is a rare cause [5]. hyperglycemia who may present acutely with Although it is usually accepted that chorea hemichorea. For unknown reasons this appears to originates in disruption of basal ganglia pathways, be common in older, Asian, female, patients, and is cases of reversible chorea associated with herniated typically unilateral. Neuroimaging demonstrates cervical discs have been reported [6]. hyperintensity of the contralateral putamen on T1- In children, cerebral palsy (CP) is a common cause and T2-weighted MRI [8], suggestive of breakdown of hyperkinetic movement disorders, including of the blood–brain barrier due to inflammation and dystonia and chorea. The history should be diagnos- edema [9], hyperviscosity [10], or ischemia [11]. tic, of neurological deficits due to pre- or perinatal The movement disorder should resolve with cor- lesions evolving from a spastic di- or quadriplegia to rection of the hyperglycemia, but has been reported a hyperkinetic disorder over several years. Chorea to persist for months [12]. Chorea has been reported may be acutely exacerbated in the setting of meta- in a non-diabetic patient following chronic sucrose bolic stress such as infection and fever, and may ingestion [13]. Hypoglycemia can occasionally require emergent intervention such as general result in chorea, which is usually bilateral.

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pregnancy. A similar pathophysiology, possibly sen- Video 11.2 Movement disorder of acquired sitization of dopamine receptors by estrogens, may hepatocerebral degeneration be responsible for chorea sometimes observed with This man has end-stage liver disease following viral the use of estrogens [24, 25]. hepatitis. He has prominent orofaciolingual and truncal chorea, dysarthric speech with cerebellar components, Vitamin B12 deficiency is reported as a reversible difficulty initiating saccadic gaze, bradykinesia of the cause of chorea [26, 27]. feet, and negative myoclonus (asterixis) with arms outstretched. [Video courtesy of John C. Morgan, MD, Autoimmune disorders PhD, and Kapil Sethi, MD, FRCP(UK), Augusta, Georgia] Certain components of neurons of the putamen appear to be especially susceptible targets for autoantibodies. As the chorea seen in various disorders due to autoantibodies is not associated with tissue destruction, it is likely that the autoantibodies interfere with neuronal signaling, perhaps by blocking specific receptors. http://bit.ly/umuCZp Sydenham chorea is a relatively common childhood chorea, occurring following a streptococcal throat infection. The recognition of basal ganglia Imbalance of most electrolytes has occasionally neurons by antistreptococcal antibodies appears to been reported to cause chorea, although this appears be the cause [28, 29]. As with other autoimmune to be relatively uncommon. These include hyper- etiologies, it is not known why the putamen is par- [14] and hyponatremia [15], hyper- [16] and ticularly vulnerable to autoantibodies. This disorder hypocalcemia [17], and hypomagnesemia. Chorea is usually self-limited and resolves within a few also been reported following correction of hypo- weeks, but may sometimes result in bizarre and natremia causing central pontine myelinolysis [18]. violent movements requiring medication. Disturbances of calcium levels as seen in hypo- A number of autoimmune disorders have been and hyperparathyroidism [19] and pseudo- reported to cause a range of movement disorders, hypoparathyroidism [20] are also reported to be both hypokinetic and hyperkinetic. These include associated with chorea, which may be paroxysmal. systemic lupus erythematosus [30, 31], Sjögren In addition, the deposition of calcium in the brain syndrome [32], and others. The association of known as Fahr disease may cause a variety of chorea with antiphospholipid antibodies (including movement disorders, including chorea, likely due anticardiolipin antibodies and lupus anticoagulant) to the structural lesion caused by calcium deposition is recognized, as part of an “antiphospholipid anti- in the putamen. The term “Fahr disease” describes body syndrome”. Polycythemia vera may present a number of different disorders, including those of with chorea [36, 37], although it is unclear whether calcium and mitochondrial metabolism. this is due to the presence of autoantibodies or to Patients with end-stage liver disease can develop hyperviscosity resulting in basal ganglia ischemia. acquired hepatocerebral degeneration (Video 11.2, Celiac disease has been associated with a number resulting in a mixed movement disorder, often with of neurologic complications, typically ataxia or prominent orofacial hyperkinesia, in addition to peripheral neuropathy, but occasionally chorea ataxia, parkinsonism, and tremor [21]. The (Video 11.3) which responds to a gluten-free pathophysiology is likely to be similar to that of diet [38]. Wilson disease. Manganese is deposited in the Paraneoplastic chorea has been reported in caudate–putamen, although this does not appear to patients with renal, small cell lung, breast, Hodgkins be a direct cause of the movement disorder [21]. and non-Hodgkins lymphoma [39–43], due to anti- Other endocrine causes of chorea include hyper- CRMP–5/CV2 [42, 44], anti-Hu [43], and anti-Yo thyroidism [22, 23], and chorea gravidarum, seen in [45] antineuronal autoantibodies.

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have been reported, and agents with a variety of Video 11.3 Celiac dyskinesia mechanisms of actions have been reported to This patient is 19. A few months before the video, reduce LIDs in animal models. Changes in gluta- he presented sudden onset of truncal chorea that mate NMDA receptors play a major role in the occurred while standing and resolved when sitting or lying down. No clinical progression was observed. development of LIDs [48], correlating with the fact Brain MRI was unremarkable. Investigations lead to a that NMDA-receptor antagonist amantadine diagnosis of celiac disease and a gluten-free diet was reduces LIDs. Loss of plasticity at glutamatergic started. The videotape shows orthostatic chorea that corticostriatal synapses plays a critical role [49], is visible while standing or walking. The involuntary and may lead to the loss of selection of signals via movements are greatly reduced during quiet sitting. Posture holding and hand movements increase the D1-stimulated direct pathway. The increase in chorea. Mirroring is observed in the left foot during activity of this (direct) pathway would lead to a repetitive movements of the right limb. [Video courtesy decrease in GPi activity [50, 51]. of Alberto Albanese, MD, Milan, Italy] Two different forms of LIDs are observed in PD patients. Peak dose dyskinesias are seen when l-dopa is at its highest blood level, and are choreiform in nature, involving the arms, trunk, and neck [52]. On–off dyskinesias tend to involve the legs, and have a dystonic component. One possible mechanism underlying the generation of these http://bit.ly/tg473Z dyskinesias may be imbalance in the dopaminergic levels of adjacent striatal regions. This would be seen particularly in advanced disease when loss of The syndrome associated with anti-NMDA- presynaptic dopamine terminals leads to reduced receptor antibodies involves encephalopathy and dopamine storage and, hence, impaired buffering complex, repetitive stereotypies with components of dopamine levels. of dystonia and chorea [46, 47]. In some cases a The term “tardive dyskinesia” (TD) is used to causative ovarian teratoma has been identified, refer to a movement disorder caused by exposure to although in others the etiology remains obscure. dopamine-receptor blocking drugs. It may manifest The outcome may be surprisingly good despite a as various forms of hyperkinesia, including chorea, prolonged disease course. although the typical orofacial-lingual dyskinesia, with coordinated, repetitive, patterned movements, Drug-induced choreas is best characterized as a stereotypy. Any dopamin- A form of chorea commonly seen in neurologic ergic antagonist may be responsible, including the practice is that induced by levo-dopa in Parkinson first, second, and third generation antipsychotics, disease (PD). This is mentioned here because an and some anti–emetics, such as metoclopromide understanding of the pathophysiology of l-dopa- [53]. Although promoted as having a lower risk of induced dyskinesias (LIDs), both in humans and TD, the atypical antipsychotics are increasingly in animal models of PD, may shed light upon reported to cause TD [54]. One form of drug- mechanisms in chorea of other etiologies. induced chorea is the withdrawal emergent The underlying cause of LIDs is a hyperdopamin- syndrome, typically seen in children treated with ergic state in the setting of underlying dopamine neurolepics [55]. Tardive chorea may be mixed depletion, as can be inferred from the relationship with tardive dystonia, which is often more to dosing with dopaminergic medications. However, debilitating. Other medications with different more complex changes occur at the neuronal level. mechanisms of action have been reported to cause Alterations of a large number of parameters relating TD, including selective serotonin reuptake inhibitors to different neurotransmitters within the striatum (SSRIs), lithium, and anticonvulsant medications.

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Stimulants, both those used therapeutically [56] this diagnosis should be made with caution. Rarely, and those used recreationally, such as amphetamine, patients with a strong family history of Huntington cocaine, and specifically crack, may result in chorea disease (HD) may present with psychogenic chorea (“crack-dancing”). The release of catecholamines is even though their genetic testing is negative [78]. probably the explanation for the appearance of the movement disorder. Anticonvulsants such as gabapentin [57, 58], Pathophysiology lamotrigine [59], and lithium [60], may cause chorea. The use of estrogens in the contracep- The model developed by Albin, Young, and Penny tive pill and as hormone replacement therapy [25] [79], despite its limitations [80, 81], can be used to may result in chorea, presumably by the same understand many of the pathophysiological aspects mechanism which causes chorea gravidarum of chorea. The direct pathway may be responsible However, contradictorily, suppression of estrogen for the activation of a motor program following an with LHRH may also result in chorea [61]. input from the motor cortex. The indirect pathway Methotrexate is recognized as a cause of chronic then focuses and selects the movements [82] neurotoxicity, but also can cause acute, reversible (Figure 11.3[A]). As a wide variety of pathophysi- chorea, especially after intrathecal administration ologies can cause chorea, it is likely that imbalance [62, 63]. of these pathways can occur at many levels, within the caudate–putamen, subthalamic nucleus (STN) Infectious and postinfectious (causing hemiballismus; Figure 11.3[B]), and the HIV infection may cause a variety of movement dis- globus pallidus internal (GPi) segment. orders [64] due to a mass lesion, such as lymphoma From the model, chorea is due to a decrease in or abscess, or as a direct effect of HIV encephalopathy activity of the indirect pathway from the caudate– [65, 66]. Syphilis should be considered as a very putamen to the external segment of the globus palli- rare but treatable cause of chorea [67]. Creutzfeldt– dus (GPe) (Figure 11.3[C]) [79, 83]. This results in Jakob disease, particularly the new variant related overactivity of this nucleus with increased inhibition, to bovine spongiform encephalopathy, should be and thus decreased activity of its projection targets, considered, especially if the course is of subacute the STN, the GPi, and the substantia nigra pars retic- deterioration over months [68,69]. ulata (SNr). This correlates with the fact that lesions In children, striatal necrosis may occur as a of the STN cause chorea (hemiballismus). A decrease complication of measles encephalitis [70] or in activity of the indirect pathway from the STN to following undefined febrile illness [71]. A similar the GPi results in a loss of selection of motor signals picture can be seen after mycoplasma pneumoniae that have arrived from the striatum via the direct infection [72], with a mixture of chorea and dysto- pathway [82]. The inhibited GPi/SNr consequently nia, hyperreflexia and encephalopathy. Chorea has has decreased inhibition of the motor thalamus, thus also been reported in the setting of encephalopathy there is an increase in thalamocortical signaling. due to parvovirus infection [73], and following herpes simplex encephalitis [74]. Treatment Psychogenic While mass psychogenic chorea, as a manifestation If possible, treatment should be directed at the of the “dancing mania,” was reported in medieval underlying disease process. If this is not possible, times [2, 4], and more recently [75], this seems at treatment is symptomatic, to the extent that present to be an uncommon occurrence. In general, movements are disabling or distressing (which may chorea is found in less than 10% of patients with not be the case). Reduction in chorea may not psychogenic movement disorders [76, 77], thus result in an improvement in function. Most

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(A) Normal Desired Figure 11.3 During normal movements Unwanted function of the basal ganglia, the selected movements direct pathway from the striatum not selected inhibits neurons of the GPi, disinhibiting the motor pattern generator, consisting of the Striatum + Motor motor thalamic nuclei and their thalamus projections to the cortex. Direct The neurons which select the pathway motor program are represented as being surrounded by a network, controlled by the GPe indirect pathway, which reduces Indirect STN the generation of unwanted SNc pathway GPi movements. [B] Damage to the + subthalamic nucleus results in decreased drive of the GPi, loss (B) Hemiballismus Desired of inhibition of the motor Involuntary movements thalamus, and the appearance movements selected of involuntary movements. generated STN lesions typically cause severe hemichorea, known as hemiballismus. The thickness of Striatum + Motor lines indicates the relative degree thalamus of activity. [C] Lesions affecting Direct the neurons of the indirect pathway pathway are a probable cause of chorea from striatal pathology. There is decreased surround GPe inhibition of the thalamus via Indirect STN the indirect pathway, with a SNc pathway GPi similar effect as in [B]. +

Striatum + Motor – thalamus Direct pathway

GPe

Indirect STN SNc pathway GPi +

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experience has been obtained with HD, and can be chorea of other etiologies. The mechanism of extrapolated to other choreiform conditions due to action is presumed to be similar to that in levodopa- the presumed similarity of pathophysiology. induced dyskinesias in PD, in which it appears to be Medical therapies aimed at decreasing beneficial, by reducing glutamatergic neurotrans- dopaminergic function are the main line of therapy mission, either in the caudate–putamen or in the at present. There is some evidence that drugs with GPi/SNr. Studies of the symptomatic (as opposed to other modes of action, such as NMDA-receptor neuroprotective) effects of riluzole in HD were antagonism, may be useful. A small number of positive [99], but sometimes not sustained [100], cases who underwent surgical therapies, specifically and the reduction in chorea did not necessarily deep brain stimulation (DBS) or lesioning, have result in improved function [101]. been reported, with mixed outcomes. Intrathecal baclofen Dopamine-blocking and In chorea due to cerebral palsy, intrathecal baclofen dopamine-depleting agents (ITB) has proven useful [102]; however, this may An excess of dopaminergic function is believed to be due to an upper motor neuron component of underlie the mechanism of chorea in many cases, the condition, as ITB is not of clear benefit in thus the first line of treatment is usually to reduce hyperkinetic disorders of other etiologies [103]. activity at dopamine receptors. The atypical antipsychotic agents are widely used, as there is less Immune modulators concern about the potential side effects of parkin- Chorea of autoimmune etiologies may respond sonism or tardive dyskinesia with these agents, specifically to immunosuppressive modalities, such which is felt to outweigh the possible metabolic as intravenous immunoglobulin, plasmapheresis, effects. Although, so far, there is little published or corticosteroids; however, symptomatic therapy data, clinical experience suggests that quetiapine, with dopamine-blocking agents, etc., is often olanzepine, and clozapine may be useful. adequate. Aripiprazole [84], ziprasidone [85], and tiapride [6, 89], may also be helpful in reducing chorea. Surgical therapies Tetrabenazine has been shown to be effective in DBS or lesioning of the STN or the GPi have been HD, and may be tried in other disorders. It depletes used to treat chorea of various etiologies in small monoamines from presynaptic terminals [86] and numbers of cases, usually of genetic etiologies. may be useful in a variety of hyperkinetic movement Results are often mixed and overall benefit to the disorders [87–89]; however, the side effects of patient is unclear. The motor thalamus has also been depression and parkinsonism may limit therapy. The proposed as a potentially promising site for DBS in use of reserpine carries the same caveats as tetra- “senile chorea” [104] and chorea from CP [105] and benazine, and it may occasionally play a role in the has been reported as being beneficial in a patient treatment of TD [90, 91]. with chorea-acanthocytosis [106]. The optimal site and frequency of stimulation for treatment of cho- Anticonvulsants rea remain to be identified, but this therapy may be Levetiracetam is reported to be beneficial in TD considered in intractable chorea from any cause. [92–94] and may be worth a therapeutic trial. Other anticonvulsants have been used with some Non-medical therapies positive results, possibly related to a membrane- In the absence of effective medical therapies to stabilizing effect. Sodium valproate and carbamaz- reverse or reduce the symptoms, adjunctive non- epine can be used in Sydenham chorea [95, 96]. medical therapies are invaluable. The pharyngeal musculature is often affected by hyperkinetic Glutamate NMDA-receptor antagonists movement disorders and thus an evaluation of Amantadine has been shown in some studies to swallowing is very important to avoid aspiration reduce chorea in HD [97, 98], and may be of use in and to maintain adequate oral intake. If the

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patient is at high risk for aspiration, placement of a 6 Tan EK, Lo YL, Chan LL, et al. (2002) Cervical disc feeding tube may be necessary. Dysarthria may also prolapse with cord compression presenting with be significant and patients may benefit from speech choreoathetosis and dystonia. Neurology 58:661–2. therapy. Physical therapy aimed at improving gait 7 Menache CC, du Plessis AJ, Wessel DL, et al. (2002) and balance may be useful to improve stability. Current incidence of acute neurologic complications after open-heart operations in children. Ann Thorac Assistive devices for walking, which provide a Surg 73:1752–8. wheeled frame in which the patient can stand or 8 Lee BC, Hwang SH, Chang GY. (1999) Hemiballismus- sit, are unwieldy but are very stable, and may hemichorea in older diabetic women: a clinical enable patients with a moderately advanced disease syndrome with MRI correlation. Neurol 52:646–8. to stay mobile. 9 Iwata A, Koike F, Arasaki K, et al. (1999) Blood brain barrier destruction in hyperglycemic chorea in a patient with poorly controlled diabetes. J Neurol Sci 163:90–3. Conclusion 10 Chu K, Kang DW, Kim DE, et al. (2002) Diffusion- weighted and gradient echo magnetic resonance Chorea is a commonly-seen movement disorder findings of hemichorea-hemiballismus associated with which may arise from a multiplicity of acquired diabetic hyperglycemia: a hyperviscosity syndrome? causes, with a wide variety of potential mechanisms. Arch Neurol 59:448–52. Details of the medical history and neurological 11 Chang KH, Tsou JC, Chen ST, et al. (2009) Temporal examination may be informative, yet a number of features of magnetic resonance imaging and spectros- patients typically remain undiagnosed. copy in non-ketotic hyperglycemic chorea-ballism Approaches to understanding the underlying patients. Eur J Neurol 2010 Apr; 17:589–93. 12 Ahlskog JE, Nishino H, Evidente VG, et al. (2001) pathophysiology focus primarily upon the caudate– Persistent chorea triggered by hyperglycemic crisis in putamen, yet the precise mechanism for the diabetics. Mov Disord 16:890–8. generation of involuntary movements remains 13 Jung S, Hwnag SH, Kang SY, et al. (2009) Bilateral obscure. Treatment is often challenging and is choreiform movements induced by excessive sucrose essentially based upon empiric observations, await- ingestion. Mov Disord 24:1247–9. ing further developments in our understanding of 14 Sparacio RR, Anziska B, Schutta HS. (1976) the etiology of this symptom. Hypernatremia and chorea. A report of two cases. Neurology 26:46–50. 15 Piccolo I, Defanti CA, Soliveri P, et al. (2003) Cause and course in a series of patients with sporadic chorea. References J Neurol 250:429–35. 16 Matsis PP, Fisher RA, Tasman-Jones C. (1989) Acute 1 Goetz CG, Chmura TA, Lanska DJ. (2001) History of lithium toxicity–chorea, hypercalcemia and hyperam- chorea: Part 3 of the MDS-sponsored history of move- ylasemia. Aust N Z J Med 19:718–20. ment disorders exhibit, Barcelona, June 2000. Mov 17 Topakian R, Stieglbauer K, Rotaru J, et al. (2006) Disord 16:331–3. Hypocalcemic choreoathetosis and tetany after 2 Krack P. (1999) Relicts of dancing mania: the dancing bisphosphonate treatment. Mov Disord 21:2026–7. procession of Echternach. Neurology 53:2169–72. 18 Tison FX, Ferrer X, Julien J. (1991) Delayed onset 3 Park RH, Park MP. (1990) Saint Vitus’ dance: vital movement disorders as a complication of central misconceptions by Sydenham and Bruegel. J R Soc pontine myelinolysis. Mov Disord 6:171–3. Med 83:512–15. 19 Hattori H, Yorifuji T. (2000) Infantile convulsions and 4 Aubert G. (2005) Charcot revisited: the case of Bruegel’s paroxysmal kinesigenic choreoathetosis in a patient chorea. Arch Neurol 62:155–61. with idiopathic hypoparathyroidism. Brain Dev 5 Roos RA, Wintzen AR, Vielvoye G, et al. (1991) 22:449–50. Paroxysmal kinesigenic choreoathetosis as presenting 20 Prashantha DK, Pal PK (2009) Pseudohypopar- symptom of multiple sclerosis. J Neurol Neurosurg athyroidism manifesting with paroxysmal dyskinesias Psychiat 54:657–8. and seizures. Mov Disord 24:623–4.

Albanese_c11.indd 184 12/24/2011 8:51:40 PM Acquired Choreas 185

21 Ferrara J, Jankovic J. (2009) Acquired hepatocerebral 36 Nazabal ER, Lopez JM, Perez PA, et al. (2000) Chorea degeneration. J Neurol 256:320–32. disclosing deterioration of polycythaemia vera. 22 Fischbeck KH, Layzer RB. (1979) Paroxysmal choreo- Postgrad Med J 76:658–9. athetosis associated with thyrotosicosis. Ann Neurol 37 Kumar H, Masiowski P, Jog M. (2009) Chorea in the 6:453–4. elderly with mutation positive polycythemia vera: 23 Lucantoni C, Grottoli S, Moretti A. (1994) Chorea due a case report. Can J Neurol Sci 36:370–2. to hyperthyroidism in old age. A case report. Acta 38 Pereira AC, Edwards MJ, Buttery PC, et al. (2004) Neurol 16:129–33. Choreic syndrome and coeliac disease: a hitherto 24 Nausieda PA, Koller WC, Weiner WJ, et al. (1979) unrecognised association. Mov Disord 19:478–82. Chorea induced by oral contraceptives. Neurology 39 Kujawa KA, Niemi VR, Tomasi MA, et al. (2001) 29:1605–9. Ballistic-choreic movements as the presenting feature 25 Suchowersky O, Muthipeedika J. (2005) A case of of renal cancer. Arch Neurol 58:1133–5. late-onset chorea. Nat Clin Pract Neurol 1:113–16. 40 Tani T, Piao Y, Mori S, et al. (2000) Chorea resulting 26 Shyambabu C, Sinha S, Taly AB, et al. (2008) Serum from paraneoplastic striatal encephalitis. J Neurol vitamin B12 deficiency and hyperhomocystinemia: a Neurosurg Psychiat 69:512–15. reversible cause of acute chorea, cerebellar ataxia in 41 Batchelor TT, Platten M, Palmer-Toy DE, et al. (1998) an adult with cerebral ischemia. J Neurol Sci Chorea as a paraneoplastic complication of Hodgkin’s 273:152–4. disease. J Neurooncol 36:185–90. 27 Pacchetti C, Cristina S, Nappi G. (2002) Reversible 42 Vernino S, Tuite P, Adler CH, et al. (2002) Paraneoplastic chorea and focal dystonia in vitamin B12 deficiency. chorea associated with CRMP-5 neuronal antibody N Engl J Med 347:295. and lung carcinoma. Ann Neurol 51:625–30. 28 Church AJ, Cardoso F, Dale RC, et al. (2002) Anti- 43 Dorban S, Gille M, Kessler R, et al. (2004) [Chorea- basal ganglia antibodies in acute and persistent athetosis in the anti-Hu syndrome]. Rev Neurol (Paris) Sydenham’s chorea. Neurol 59:227–31. 160:126–9. 29 Kirvan CA, Swedo SE, Heuser JS, et al. (2003) 44 Honnorat J, Cartalat-Carel S, Ricard D, et al. (2009) Mimicry and autoantibody-mediated neuronal cell Onco-neural antibodies and tumour type determine signaling in Sydenham chorea. Nat Med 9:914–20. survival and neurological symptoms in paraneoplastic 30 Font J, Cervera R, Espinosa G, et al. (1998) Systemic neurological syndromes with Hu or CV2/CRMP5 lupus erythematosus (SLE) in childhood: analysis of antibodies. J Neurol Neurosurg Psychiat 80:412–16. clinical and immunological findings in 34 patients and 45 Krolak-Salmon P, Androdias G, Meyronet D, et al. comparison with SLE characteristics in adults. Ann (2006) Slow evolution of cerebellar degeneration and Rheum Dis 57:456–9. chorea in a man with anti-Yo antibodies. Eur J Neurol 31 Watanabe T, Onda H. (2004) Hemichorea with 13:307–308. antiphospholipid antibodies in a patient with lupus 46 Vincent A, Bien CG. (2008) Anti-NMDA-receptor nephritis. Pediat Nephrol 19:451–3. encephalitis: a cause of psychiatric, seizure, and move- 32 Venegas FP, Sinning M, Miranda M. (2005) Primary ment disorders in young adults. Lancet Neurol Sjogren’s syndrome presenting as a generalized 7:1074–5. chorea. Parkinsonism Relat Disord 11:193–4. 47 Dalmau J, Tuzun E, Wu HY, et al. (2007) Paraneoplastic 33 Ciubotaru CR, Esfahani F, Benedict RH, et al. (2002) anti-N-methyl-D-aspartate receptor encephalitis Chorea and rapidly progressive subcortical dementia associated with ovarian teratoma. Ann Neurol in antiphospholipid syndrome. J Clin Rheumatol 61:25–36. 8:332–9. 48 Calon F, Rajput AH, Hornykiewicz O, et al. (2003) 34 Kiechl-Kohlendorfer U, Ellemunter H, Kiechl S. Levodopa-induced motor complications are associated (1999) Chorea as the presenting clinical feature of with alterations of glutamate receptors in Parkinson’s primary antiphospholipid syndrome in childhood. disease. Neurobiol Dis 14:404–16. Neuropediat 30:96–8. 49 Picconi B, Centonze D, Hakansson K, et al. (2003) 35 Sanna G, Bertolaccini ML, Cuadrado MJ, et al. (2003) Loss of bidirectional striatal synaptic plasticity in Neuropsychiatric manifestations in systemic lupus L-DOPA-induced dyskinesia. Nat Neurosci 6:501–6. erythematosus: prevalence and association with 50 Vitek JL, Giroux M. (2000) Physiology of hypokinetic antiphospholipid antibodies. J Rheumatol 30: and hyperkinetic movement disorders: model for 985–92. dyskinesia. Ann Neurol 47(4 Suppl 1):S131–S140.

Albanese_c11.indd 185 12/24/2011 8:51:40 PM 186 Chapter 11

51 Matsumura M, Tremblay L, Richard H, Filion M. 67 Ozben S, Erol C, Ozer F, et al. (2009) Chorea as the (1995) Activity of pallidal neurons in the monkey presenting feature of neurosyphilis. Neurol India during dyskinesia induced by injection of bicuculline 57:347–9. in the external pallidum. Neuroscience 65(1):59–70. 68 Bowen J, Mitchell T, Pearce R, et al. (2000) Chorea in 52 Del Sorbo F, Albanese A. (2008) Levodopa-induced new variant Creutzfeldt–Jacob disease. Mov Disord dyskinesias and their management. J Neurol 15:1284–5. 255(Suppl 4):32–41. 69 McKee D, Talbot P. (2003) Chorea as a presenting 53 Kenney C, Hunter C, Davidson A, et al. (2008) feature of variant Creutzfeldt–Jakob disease. Mov Metoclopramide, an increasingly recognized cause of Disord 18:837–8. tardive dyskinesia. J Clin Pharmacol 48:379–84. 70 Cambonie G, Houdon L, Rivier F, et al. (2000) Infantile 54 Pena MS, Yaltho TC, Jankovic J. (2010) Tardive dyski- bilateral striatal necrosis following measles. Brain Dev nesia and other movement disorders secondary to 22:221–3. aripiprazole. Mov Disord 2011Jan; 26:147–52. 71 Yamamoto K, Chiba HO, Ishitobi M, et al. (1997) 55 Mejia NI, Jankovic J. (2010) Tardive dyskinesia and Acute encephalopathy with bilateral striatal necrosis: withdrawal emergent syndrome in children. Expert favourable response to corticosteroid therapy. Eur J Rev Neurother 10:893–901. Paediat Neurol 1:41–5. 56 Weiner WJ, Nausieda PA, Klawans HL. (1978) 72 Zambrino CA, Zorzi G, Lanzi G, et al. (2000) Methylphenidate-induced chorea: case report and Bilateral striatal necrosis associated with Mycoplasma pharmacologic implications. Neurol 28:1041–4. pneumoniae infection in an adolescent: clinical 57 Lai MH, Wang TY, Chang CC, et al. (2008) Hemichorea and neuroradiologic follow up. Mov Disord 15: associated with gabapentin therapy with hypoperfu- 1023–6. sion in contralateral basal ganglion – a case of a para- 73 Fong CY, de Sousa C. (2006) Childhood chorea- plegic patient with neuropathic pain. J Clin Pharm encephalopathy associated with human parvovirus Ther 33:83–6. B19 infection. Dev Med Child Neurol 48:526–8. 58 Zesiewicz TA, Shimberg WR, Hauser RA, et al. (2008) 74 Kullnat MW, Morse RP (2008) Choreoathetosis after Chorea as a side effect of gabapentin (Neurontin) in a herpes simplex encephalitis with basal ganglia involve- patient with complex regional pain syndrome Type 1. ment on MRI. Pediatrics 121:e1003–7. Clin Rheumatol 27:389–90. 75 Gimenez-Roldan S, Aubert G. (2007) Hysterical 59 Miller MA, Levsky ME. (2008) Choreiform dyskinesia chorea: Report of an outbreak and movie documenta- following isolated lamotrigine overdose. J Child tion by Arthur Van Gehuchten (1861–1914). Mov Neurol 23:243. Disord 22:1071–6. 60 Stemper B, Thurauf N, Neundorfer B, et al. (2003) 76 Hinson VK, Cubo E, Comella CL, et al. (2005) Rating Choreoathetosis related to lithium intoxication. Eur scale for psychogenic movement disorders: scale J Neurol 10:743–4. development and clinimetric testing. Mov Disord 61 Gironell A, de Molina RM, Sancho G, et al. (2008) 20:1592–7. Chorea induced by a luteinizing hormone-releasing 77 Anderson KE, Gruber-Baldini AL, Vaughan CG, et al. hormone analog. J Neurol 2008 Aug; 255:1264–5. (2007) Impact of psychogenic movement disorders 62 Bota DA, Dafer RM. (2009) Acute methotrexate neuro- versus Parkinson’s on disability, quality of life, and toxicity with choreiform movements and focal neuro- psychopathology. Mov Disord 22:2204–9. logical deficits: a case report. South Med J 102:1071–4. 78 Fekete R, Jankovic J. (2010) Psychogenic chorea asso- 63 Necioglu OD, Yldrmak Y, Kenangil G, et al. (2009) ciated with family history of Huntington disease. Mov Intrathecal methotrexate-induced acute chorea. J Disord 25:503–4. Pediat Hematol Oncol 31:57–8. 79 Albin RL, Young AB, Penney JB. (1989) The func- 64 Tse W, Cersosimo MG, Gracies JM, et al. (2004) tional anatomy of basal ganglia disorders. Trends Movement disorders and AIDS: a review. Parkinsonism Neurosci 12:366–75. Relat Disord 10:323–34. 80 Chesselet MF, Delfs JM. (1996) Basal ganglia and 65 Passarin MG, Alessandrini F, Nicolini GG, et al. (2005) movement disorders: an update. Trends Neurosci 19: Reversible choreoathetosis as the early onset of 417–22. HIV-encephalopathy. Neurol Sci 26:55–6. 81 Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. 66 Sporer B, Linke R, Seelos K, et al. (2005) HIV-induced (2000) Pathophysiology of levodopa-induced chorea: evidence for basal ganglia dysregulation by dyskinesias in Parkinson’s disease: Problems with the SPECT. J Neurol 252:356–8. current model. Ann Neurol 47:S22–S34.

Albanese_c11.indd 186 12/24/2011 8:51:40 PM Acquired Choreas 187

82 Mink JW. (2003) The basal ganglia and involuntary efficacies of sodium valproate and carbamazepine movements – Impaired inhibition of competing motor regimens. Brain Dev 24:73–6. patterns. Arch Neurol 60:1365–8. 96 Harel L, Zecharia A, Straussberg R, et al. (2000) 83 Wichmann T, DeLong MR. (1998) Models of basal Successful treatment of rheumatic chorea with ganglia function and pathophysiology of movement carbamazepine. Pediat Neurol 23:147–51. disorders. Neurosurg Clin N Am 9:223–36. 97 Lucetti C, Del Dotto P, Gambaccini G, et al. (2003) IV 84 Brusa L, Orlacchio A, Moschella V, et al. (2009) amantadine improves chorea in Huntington’s dis- Treatment of the symptoms of Huntington’s disease: ease: an acute randomized, controlled study. Neurol preliminary results comparing aripiprazole and tetra- 60:1995–7. benazine. Mov Disord 24:126–9. 98 Verhagen ML, Morris MJ, Farmer C, et al. (2002) 85 Bonelli RM, Mayr BM, Niederwieser G, et al. (2003) Huntington’s disease: a randomized, controlled trial Ziprasidone in Huntington’s disease: the first case using the NMDA-antagonist amantadine. Neurol reports. J Psychopharmacol 17:459–60. 59:694–9. 86 Pearson SJ, Reynolds GP. (1988) Depletion of mono- 99 Rosas HD, Koroshetz WJ, Jenkins BG, et al. (1999) amine transmitters by tetrabenazine in brain tissue Riluzole therapy in Huntington’s disease (HD). Mov in Huntington’s disease. Neuropharmacology 27: Disord 14:326–30. 717–19. 100 Seppi K, Mueller J, Bodner T, et al. (2001) Riluzole in 87 Jankovic J. (2009) Treatment of hyperkinetic move- Huntington’s disease (HD): an open label study with ment disorders. Lancet Neurol 8:844–56. one year follow up. J Neurol 248:866–9. 88 Chatterjee A, Frucht SJ. (2003) Tetrabenazine in the 101 Huntington Study Group (2003) Dosage effects of treatment of severe pediatric chorea. Mov Disord riluzole in Huntington’s disease: a multicenter 18:703–6. placebo-controlled study. Neurol 61:1551–6. 89 Tetra-Hd Investigators HS. (2009) Tetrabenazine as 102 Albright AL (1996) Intrathecal baclofen in cerebral anti-chorea therapy in Huntington Disease: an open- palsy movement disorders. J Child Neurol 11(Suppl 1): label continuation study. BMC Neurol 9:62. S29–S35. 90 Markham CH, Clark WG, Winters WD. (1963) Effects 103 Walker RH, Danisi FO, Swope DM, et al. (2000) of Alpha-methyl dopa and reserpine in Huntington’s Intrathecal baclofen for dystonia: Benefits and chorea, Parkinson’s disease and other movement complications during six years experience. Mov disorders. Life Sci (Oxford) 9:697–705. Disord 15:1242–7. 91 Fahn S. (1985) A therapeutic approach to tardive dys- 104 Yianni J, Nandi D, Bradley K, et al. (2004) Senile kinesia. J Clin Psychiat 46:19–24. chorea treated by deep brain stimulation: a clinical, 92 McGavin CL, John V, Musser WS (2003) Levetiracetam neurophysiological and functional imaging study. as a treatment for tardive dyskinesia: a case report. Mov Disord 19:597–602. Neurol 61:419. 105 Thompson TP, Kondziolka D, Albright AL. (2000) 93 Meco G, Fabrizio E, Epifanio A, et al. (2006) Thalamic stimulation for choreiform movement Levetiracetam in tardive dyskinesia. Clin Neuropharm disorders in children. Report of two cases. 29:265–8. J Neurosurg 92:718–21. 94 Konitsiotis S, Pappa S, Mantas C, et al. (2006) 106 Burbaud P, Rougier A, Ferrer X, et al. (2002) Levetiracetam in tardive dyskinesia: an open label Improvement of severe trunk spasms by bilateral study. Mov Disord 21:1219–21. high-frequency stimulation of the motor thalamus in 95 Genel F, Arslanoglu S, Uran N, et al. (2002) Sydenham’s a patient with chorea-acanthocytosis. Mov Disord chorea: clinical findings and comparison of the 17:204–7.

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Historical background commit him to an asylum in Switzerland where he remained until his death in 1904. In 1885 Georges Albert Édouard Brutus Gilles de Although Tourette considered the disorder he la Tourette, a 28-year-old student of Jean-Martin described to be hereditary, the etiology was ascribed Charcot, published A Study of a Neurological Condition to psychogenic causes for nearly a century following Characterized by Motor Incoordination Accompanied by the original report. The perception of TS began to Echolalia and Coprolalia [1]. Gilles de la Tourette change in the 1960s when the beneficial effects of (abbreviated in the literature and in this manu- neuroleptic drugs on the symptoms of TS began to script as Tourette) described 9 patients (including be recognized. This observation helped to refocus the Marquise de Dampierre, previously reported by attention from psychogenic to central nervous Itard in 1825, as a reclusive aristocratic lady who system etiology [2]. “ticked and blasphemed” from the age of 7 until her death at the age of 80) and noted that all 9 patients shared one feature – they all exhibited Phenomenology of tics and other brief involuntary movements (motor tics); addi- clinical features of Tourette tionally 6 made noises (phonic tics), 5 shouted syndrome obscenities (coprolalia), 5 repeated the words of others (echolalia), and 2 mimicked the gestures of Tics, the clinical hallmark of TS, are relatively brief others (echopraxia). They likened tics to Jumping and intermittent movements (motor tics) or sounds Frenchmen and the echopraxic syndromes of (vocal or phonic tics). Recognition of the full spec- Myriachit and Latah, that had been previously trum of phenomenology of tics is critical to the described. Shortly after the tragic death of his diagnosis of TS [3, 4]. Currently accepted criteria young son and of his mentor, Charcot, Tourette was for the diagnosis of TS require both types of tic to be shot in the head in his consulting rooms by a para- present. This division into motor and vocal/phonic noid young woman who had been a patient at the tics, however, is artificial, because vocal/phonic tics Salpêtrière and claimed that she had been hypno- are actually motor tics that involve respiratory, tized by Tourette against her will. After 1900, laryngeal, pharyngeal, oral, and nasal musculature. Tourette’s behavior became erratic and bizarre, Contractions of these muscles may produce sounds probably due to neurosyphilis, and his wife had to by moving air through the nose, mouth, or throat,

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hence the term “phonic” rather than “vocal” tic is Complex motor tics consist of coordinated, preferred. According to the criteria outlined by the sequenced movements resembling normal motor Diagnostic and Statistical Manual of Mental acts or gestures that are inappropriately intense Disorders, Fourth Edition (DSM-IV) – which is cur- and timed (Video 12.2). They may be seemingly rently under revision and DSM-5 is expected to be non-purposeful, such as head shaking or trunk released by 2013 – in order to make a diagnosis of bending, or they may seem purposeful, such as definite TS the following features must be present: touching, throwing, hitting, jumping, and kicking. (1) both multiple motor and one or more phonic Additional examples of complex motor tics include tics are present at some time during the illness, gesturing “the finger” and grabbing or exposing although not necessarily concurrently; (2) the tics one’s genitalia (copropraxia) or imitating gestures occur many times a day (usually in bouts), nearly (echopraxia). Burping, vomiting, and retching, and every day or intermittently throughout a period of air swallowing are other complex tics seen in more than 1 year without a tic-free period of more patients with TS [6]. than 3 consecutive months; (3) the onset is before In addition to motor tics, patients with TS exhibit age 18 years; and (4) the disturbance is not due simple phonic tics, such as sniffing, throat clearing, to the direct physiological effects of a substance grunting, squeaking, screaming, coughing, blowing, (e.g. stimulants) or a general medical condition and sucking sounds or complex phonic tics (e.g. Huntington disease or postviral encephalitis). manifested by linguistically meaningful utterances Tics may be simple or complex. Simple motor tics and verbalizations, such as shouting of obscenities involve only a small group of muscles, causing a or profanities (coprolalia) [7], repetition of someone brief, jerk-like movement. They are usually abrupt else’s words or phrases (echolalia), and repetition in onset and rapid (clonic tics), but they may be of one’s own utterances, particularly the last slower, causing a briefly sustained abnormal pos- syllable, word or phrase in a sentence (palilalia). ture (dystonic tics) or an isometric contraction Some TS patients also manifest sudden and (tonic tics). Examples of simple clonic motor tics transient cessation of all motor activity (blocking include blinking, nose twitching, and head jerking, tics) without alteration of consciousness. while simple dystonic tics include blepharospasm, Motor (particularly dystonic) and phonic tics are oculogyric movements, bruxism, sustained mouth preceded by premonitory sensations in over 80% opening, torticollis, and shoulder rotation (Video of patients [8, 9]. This premonitory phenomenon 12.1). Tensing of abdominal or limb muscles is an consist of sensations or discomforts, such as a example of a tonic tic. Tics and dystonia rarely burning feeling in the eye before an eye blink, occur in the same family or the same patient [5]. tension or a crick in the neck that is relieved by stretching of the neck or jerking of the head, a feeling of tightness or constriction that is relieved Video 12.1 Phenomenology of tics in Tourette syndrome Young man with TS who exhibits typical facial clonic Video 12.2 Phenomenology of tics in and dystonic tics with transient blepharospasm and Tourette syndrome oculogyric tics. A boy with TS exhibiting complex, stereotypic tics.

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Video 12.3 Phenomenology of tics in Video 12.4 Phenomenology of Tourette Tourette syndrome syndrome A girl with simple and complex phonic tics including 18 year old woman with a long-standing TS manifested coprolalia. by complex motor and phonic tics and self-injurious behavior. She has violent head and neck jerking movements and intermittent kicking and punching. She punches herself, others, and objects. She also exhibits premonitory urge, dystonic tics, blocking tics and coprolalia.

http://bit.ly/sal9LB

Box 12.1 Clinical characteristics of tics http://bit.ly/uRF6B3 • Premonitory feelings or sensations • Temporary suppressibility • Suggestibility Video 12.5 Phenomenology of Tourette • Increase with stress syndrome • Increase during relaxation after stress 17 year old girl with a 2-year history of motor and • Decrease with distraction and with concentration phonic tics, associated with marked coprolalia. • Waxing and waning, transient remissions • Persist during sleep

by arm or leg extension, localized to one body part of more generalized feeling of an urge to perform the tic [10]. The presence of premonitory sensations helps to differentiate tics from other abrupt, jerk- http://bit.ly/uRF6B3 like, hyperkinetic movement disorders such as myoclonus and chorea (Box 12.1). Furthermore, in contrast to other hyperkinetic movement disorders exacerbation of childhood-onset TS. During the that are usually completely suppressed during course of TS, phonic and complex motor tics, self- sleep, motor and phonic tics may persist during all injurious behaviors, and ADHD tend to improve, stages of sleep [11]. but facial, neck, and trunk tics dominate the adult Although TS typically occurs in children, it can TS phenotype. also affect adults. We reviewed 43 adults with TS Tics, although rarely disabling, can be quite referred to our Movement Disorders Clinic over the troublesome for TS patients because they cause past 5 years and compared them with100 TS embarrassment, interfere with social interactions, patients 18 years old or younger [12]. We found and at times can be quite painful or uncomfortable. that adult TS patients had significantly more facial Rarely, cervical tics may be so forceful and violent, and truncal tics, as well as a greater prevalence of the so-called “whiplash tics,” that they may cause substance abuse and mood disorders, but fewer secondary neurologic deficits, such as cervical phonic tics, and lower rates of ADHD and opposi- artery dissection, and compressive or non- tional behavior than children with TS. Furthermore, compressive cervical myelopathy [13]. Patients adult TS largely represented a re-emergence or with life-threatening tics, self-injurious behavior,

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suggest that up to 24% of children may have tics at Video 12.6 Phenomenology of Tourette some time during their childhood [17, 18]. Most syndrome epidemiological studies have shown that 20–30% 22 year old man with severe TS and history of attention of children exhibit tics at some time during child- deficit disorder with hyperactivity and obsessive compulsive disorder. At the age of 17, he started having hood and 2–3% of children develop some features motor tics characterized by arm jerks that rapidly of TS, although the worldwide prevalence of TS in progressed to different complex motor behaviors, children has been reported to range from 0.3 to including what he calls “kangaroo” habits that consist 0.8% [19]. of jumping in place and flapping his arms. The tics are usually preceded by a premonitory sensation, and obsessive thoughts about performing the tics. Other tics involve coprolalia and involuntary name shouting. Etiology He also has complex ritualistic behaviors consisting in generalized muscle tensing, jaw opening, retrocollis, TS has been considered a genetic disorder since its and pointing the ceiling with one or both index fingers. first description, but the causative gene or genes These behaviors are accompanied by grunting noises and severe compulsions. He also exhibits ritualistic and have eluded the scientists, despite intensive efforts self-injurious behaviors. by many geneticists and consortia. Two genes have been recently identified as potentially causative genes: the Slit and Trk-like 1 (SLITRK1) gene on chromosome 13q31.1 [20] and the L-histidine decarboxylase (HDC) gene located on 15q21.1– 15q21.3 [21]. No mutations in these two genes, however, have been found in large populations of TS patients, thus it is unlikely that the reported http://bit.ly/sTl7IO mutations are relevant to the pathogenesis of most cases of TS. One possible explanation for the lack of known gene(s) for TS is the observation that and other severe symptoms of TS have been labeled bilineal transmission, which violates the standard as having “malignant” TS [14, 15]. principle of one-trait, one-locus, may play a role in In addition to ADHD and OCD, patients with TS a large proportion of all TS cases. often manifest a large variety of behavioral Although genetic factors are thought to account comorbidities, particularly impulse control disor- for the majority of tics, particularly in children, tics der, oppositional defiant disorder, anxiety, depres- and other features of TS may also be caused by a sion, conduct disorder, severe temper outbursts, variety of etiologies such as infection, trauma, rage attacks, inappropriate sexual behavior, and stroke [22], multiple sclerosis, cocaine and neurolep- other psychiatric problems. Some of these features tic drugs, static encephalopathy, autistic spectrum are being captured in the Tourette International disorders, neuroacanthocytosis, pantothenate Consortium Database [16]. kinase-associated neurodegeneration, head trauma, and peripheral injury [23]. The study of the mechanisms of the secondary tourettism could provide Epidemiology insights into the pathogenesis of TS as TS symptoms have been reported to be exacerbated by various Epidemiological studies of TS have been hampered structural lesions involving the basal ganglia and by the lack of a disease-specific, diagnostic, marker the limbic system [24]. and other challenges including different study The potential role of immunologic mechanisms populations, methodological problems, which has in the pathogenesis of tics has attracted a great deal resulted in a marked variability in the reported of attention over the past few decades. Several prevalence and incidence. Some prevalence figures studies have suggested that exacerbations of TS

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symptoms correlated with an antecedent group A inhibition of unwanted impulses (prefrontal, β-hemolytic streptococcus (GABHS) infection parietal, temporal, and cingulate cortices). (demonstrated by elevated antistreptococcal titers) Examining the resting–state functional connectivity and the presence of serum antineuronal antibodies. MRI (rs-fcMRI) in 33 adolescents with TS, Church Variably referred to as pediatric autoimmune et al. [31] found anomalous connections primarily neuropsychiatric disorders associated with in the fronto–parietal network, suggesting streptococcal infections (PANDAS) or pediatric widespread immature functional connectivity, infection-triggered autoimmune neuropsychiatric particularly in regions related to adaptive online disorders (PITANDS), this area is one of the most control. Transcranial magnetic stimulation studies controversial topics in pediatric neurologic and have demonstrated that TS children have a shorter psychiatric literature [25, 26]. In a case-control cortical silent period but that their intracortical study of a large primary care database of 678,862 inhibition was not different from that of controls, patients with an average follow-up of 5.08 years, although intracortical inhibition is reduced in no support was found for a strong relationship children with ADHD [32]. between streptococcal infections, neuropsychiatric Although standard anatomic neuroimaging syndromes such as OCD, or TS or PANDAS [27]. studies in TS are unremarkable, by using special This and other recent studies cast doubts on the volumetric, metabolic, blood flow, ligand, and proposed link between GABS and TS. functional imaging techniques, several interesting findings have been reported that have strong implications for the pathophysiology of TS. Careful Pathophysiology volumetric MRI studies have suggested that the normal asymmetry of the basal ganglia is lost in TS. Although the pathogenic mechanisms of TS are still Caudate volumes have been reported to correlate unknown, the weight of evidence supports an significantly and inversely with the severity of tic organic rather than a psychogenic origin, probably and OCD in early adulthood [33]. An MRI-DTI involving the basal ganglia circuitry [2, 24, 28]. study of monozygotic twins showed that the mean Although direct evidence is still lacking, TS is fractional anisotropy values were significantly currently viewed as a disorder of synaptic lower particularly in the posterior portion of the transmission involving disinhibition of the cortico- corpus callosum in the twin affected with TS [34]. striatal-thalamic-cortical circuitry. Several studies Using tractography of the fronto–striato–thalamic have provided evidence in support of the notion circuit, TS patients were found to have significantly that the basal ganglia, particularly the caudate lower probability of connection between caudate nucleus, and the inferior prefrontal cortex, play an nucleus and anterior-dorsolateral-frontal cortex on important role in the pathogenesis not only of TS the left [35]. Additional imaging studies have but also of comorbid disorders, particularly OCD. identified frontal and parietal cortical thinning, Although there are no animal models of TS, studies most prominent in ventral portions of the sensory of stereotypies in animals may provide insight into and motor homunculi in patients with TS [36]. the pathogenesis of habits, rituals, tic-like, and Positron emission tomography (PET) scanning impulsive behaviors in humans [29, 30]. has shown variable rates of glucose utilization in Conventional neurophysiological investigations basal ganglia as compared to controls. In one study, have found that TS patients have defective [18F]fluorodeoxyglucose, PET has shown evidence inhibitory mechanisms. Functional MRI showed of increased metabolic activity in the lateral premo- decreased neuronal activity during periods of tor and supplementary motor association cortices suppression in the ventral globus pallidus, putamen, and in the midbrain (pattern 1), and decreased and thalamus and increased activity in the right metabolic activity in the caudate and thalamic areas caudate nucleus, right frontal cortex, and other (limbic basal ganglia–thalamocortical projection cortical areas that are normally involved in the system) (pattern 2) [37]. Pattern 1 is reportedly

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associated with tics, and pattern 2 correlates with transporter (DAT), in 33 adults with TS no differences the overall severity of TS. In a follow-up study between subjects with TS and controls were found involving 12 TS adult patients (untreated for >2 [43]. In a study of 8 patients with TS and 8 controls years) and 12 controls, the investigators found a [11C]FLB 457 PET in conjunction with an TS-related metabolic pattern which was character- amphetamine challenge used to evaluate extrastriatal ized by increased premotor cortex and cerebellum D2/D3 receptor binding and DA release, TS patients activity and reduced resting activity of the striatum showed decreased [11C]FLB 457 binding potentials and orbitofrontal cortex [38]. bilaterally in cortical and subcortical regions outside In contrast to dystonia – which is characterized the striatum, including the cingulate gyrus, middle by lentiform nucleus-thalamic metabolic disso- and superior temporal gyrus, occipital cortex, insula, ciation, attributed to overactivity of the direct and thalamus [44]. Furthermore, amphetamine striatopallidal inhibitory pathway – the pattern of challenge induced widespread increased DA release TS is characterized by concomitant metabolic in TS patients, which extended more anteriorly to reduction in striatal and thalamic function. The involve anterior cingulate and medial frontal gyri. authors suggested that this pattern can be explained The authors suggested that “reductions in D2/D3 by a reduction in the indirect pathway resulting in receptor binding in both frontal cortex and thalamus reduction in subthalamic nucleus (STN) activity. are consistent with recently published preliminary This is in part consistent with another study that data demonstrating similar abnormalities of D2/D3 found evidence of increased activation in the direct binding in TS patients using a different PET ligand.” pathway, but the activity in the prefrontal cortex Reduced metabolism or blood flow to the basal and STN has been found to be increased presumably ganglia, particularly in the ventral striatum, most as a result of compensatory activation [39]. Using often in the left hemisphere, has been demonstrated PET to study metabolic activity, robust activation of in majority of the studies involving TS subjects. cerebellum, insula, thalamus, and putamen was These limbic areas are thought to be involved in found during tic release [40]. impulse control, reward contingencies, and executive An autopsy study of three TS brains found functions, and these behavioral functions appear to consistent increases in DAT and D2 receptor as well be abnormal in most patients with TS. The radioligand as D1 and α-2A density, suggesting that dopaminergic studies have been less consistent, but they provide hyperfunction in the frontal lobe may play a role in some support for increased D2 receptor density in the the pathophysiology of TS [41]. Another pathological caudate nucleus. Imaging studies of presynaptic study showed a marked increase in total number of markers such as dopa decarboxylase, dopamine, and neurons in the globus pallidus internum (GPi) and dopamine transporter have produced results that are decreased number in the globus pallidus externa even less consistent. Future imaging and ligand (GPe) and in the caudate nucleus of brains of patients studies should include children, since this population with TS [42]. Furthermore, an increased number and has been largely excluded because of ethical proportion of the GPi neurons were positive for the considerations. The studies should also rigorously calcium-binding protein parvalbumin in tissue from characterize comorbid disorders and should take into TS subjects, whereas lower densities of parvalbumin- consideration potential confounding variables, such positive interneurons were observed in both the Cd as the secondary effects of chronic illness and and putamen of TS subjects. These abnormalities medications. have been interpreted as indicating a developmental defect in the migration of some GABAergic neurons. PET with the vesicular monoamine transporter type Treatment 2 ligand [11C]dihydrotetrabenazine that binds to type 2 vesicular monoamine transporter (VMAT2) to The first step in the management of patients with quantify striatal monoaminergic innervation and TS is the proper education of the patient, relatives, [11C]methylphenidate, a ligand for dopamine teachers, and other individuals who frequently

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interact with the patient about the nature of the most troublesome symptoms should be targeted disorder [2, 4, 45]. In addition, the parents and the first. Medications should be instituted at low doses, physician should work as partners in advocating titrated gradually to the lowest effective dosage, the best possible school environment for the child. and tapered during non-stressful periods (e.g. This might include extra break periods and a refuge summer vacations). Another important principle of area to allow release of tics, waiving time limita- therapy in TS is to give each medication and dosage tions on tests or adjusting timing of tests to the regimen an adequate trial. This approach will avoid morning, and other measures designed to relieve needless changes made in response to variations in stress. National and local support groups can pro- symptoms during the natural course of the disease. vide additional information (e.g. www.tsa-usa.org) While an evidence-based approach, based on and can serve as a valuable resource for the patient double-blind, placebo-controlled studies is desirable and his or her family. to objectively evaluate the efficacy of a drug, long- Because of the broad range of neurologic and term observational studies provide useful infor- behavioral manifestation and varying severity, mation not only on the drug’s efficacy but also on therapy of TS must be tailored specifically to the its safety. needs of the individual patient (Box 12.2). The Before discussing the pharmacologic therapy of TS symptoms, it is appropriate to make a few remarks about behavioral therapy. Different forms of behavioral modification have been recommended Box 12.2 Treatments reported effective since the disorder was first described, but until in the treatment of Tourette recently, very few studies of behavioral treatments syndrome have been subjected to rigorous scientific scrutiny. Tics Fluvoxamine The behavioral intervention, called Comprehensive Clonazepam Paroxetine Behavioral Intervention for Tic (CBIT) disorders is Fluphenazine Venlafaxine Pimozide Citalopram primarily based on HRT which employs competing Haloperidol Lithium response training, which is different from deliberate Thiothixene Buspirone tic suppression in that it teaches the patient to Trifluoperazine Clonazepam initiate a voluntary behavior to manage the Molindone Trazodone premonitory urge. CBIT also includes relaxation Sulpiride Clonazepam training and a functional intervention. In a Tiapride Attention-Deficit Disorder/ multicenter study designed to test the efficacy of Flunarizine Attention-Deficit Olanzapine Hyperactivity Disorder CBIT, 126 children aged 9 to 17 with moderate to Risperidone Clonidine severe TS were randomly assigned to receive either Quetiapine Imipramine CBIT or supportive counseling and education Clozapine Nortriptyline about TS [46]. The success of this behavioral Tetrabenazine Desipramine management is critically dependent on active Pergolide Deprenyl Nicotine Bupropion involvement by the parents and the therapist, both Naltrexone Guanfacine of whom must be well trained and skilled in the Flutamide Carbamazepine various CBIT techniques [10]. Given the demands Cannabinoid Dextroamphetamine on time and effort on the part of the patient, the Botulinum toxin Methylphenidate therapist, and parents, it is unlikely that all parties Obsessive-Compulsive Adderal Disorder Pemoline will be able to maintain the needed compliance Imipramine Modafinil with the training program to provide sustained Clomipramine Atomoxetine benefit. There is also some concern as to whether Fluoxetine Mecamylamine the mental effort required to fully comply with the Sertraline Neurosurgery various components of CBIT could actually Nefazodone interfere with the patient’s attention and learning.

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While there has been a great deal of effort exerted Several non-neuroleptic treatments have been over the last several decades making the scientific, reported to be effective in the treatment of tics. These clinical, and lay community understand the include clonazepam and topiramate [12]. Motor tics biological basis of TS, the reported response to may be also successfully treated with botulinum behavioral therapy may be misinterpreted by some toxin injections in the affected muscles [48, 49]. as evidence that tics and TS are of psychological Such focal chemodenervation ameliorates not only etiology. This is one reason why behavioral the involuntary movements but also the premoni- therapies are often not covered by insurance or tory sensory component. The so-called “whiplash” other third party payers. Thus, only a limited tics that involve the neck muscles and potentially number of patients will be able to access this cause compressive myelopathy or radiculopathy, can behavioral therapy as compared to pharmacologic be effectively treated with injections of botulinum treatment, which actually may be more effective. toxin into neck extensor muscles [14, 49]. Nevertheless, behavioral therapies are useful CNS stimulants, such as methylphenidate, ancillary techniques in patients whose response dexmethylphenidate, methamphetamine, dex- to other therapies, including pharmacotherapy, is troamphetamine, levoamphetamine, pemoline, not entirely satisfactory. and lisdexamfetamine dimesylate are clearly Placebo-controlled and open-label, observational the most effective agents in the treatment of trials have found that the dopamine receptor-block- ADHD. Although CNS stimulants may exacerbate ing drugs (neuroleptics) are clearly most effective in or precipitate tics in up to 25% of patients, the controlling motor and phonic tics (Box 12.2). National Institute of Mental Health (NIMH) Although haloperidol and pimozide are the only Collaborative Multimodal Treatment Study of neuroleptics that have actually been approved by Children with Attention Deficit Hyperactivity the Food and Drug Administration (FDA) for the Disorder found that CNS stimulants were safe in treatment of TS, we rarely used them because of the setting of TS and were superior to behavioral sedation, weight gain, school phobia, and other treatment [50]. potentially serious adverse effects, including Other classes of drugs reported to effective in prolonged QT interval torsades de pointes. We the treatment of ADHD and other behavioral prefer fluphenazine or risperidone as these neuro- comorbitities associated with TS include the leptics appear to be relatively well tolerated. All α2-adrenergic agonists and tricyclic antidepressants. neuroleptics, however, block dopamine receptors Clonidine, a presynaptic α2-adrenergic agonist, has and may, therefore, cause tardive dyskinesia. Even been found to improve not only symptoms of though the second- or third-generation (atypical) ADHD, but also impulse control problem. Although neuroleptics have been promoted to have a lower initially reported to be marginally effective in risk of tardive dyskinesia, all have been reported to controlling motor tics, clonidine has not been found cause this side effect. to be an effective antitic agent in other studies. Tetrabenazine – which is a monoamine-depleting Side effects include sedation, light-headedness, drug that acts by inhibiting VMAT2, and was headache, dry mouth, and insomnia. Because of its approved in 2008 for the treatment of chorea sedative effects, some clinicians use clonidine as associated with Huntington disease – has been shown a night-time soporific agent. The Available also as a to be a powerful antitic drug [47]. The drug is well transdermal patch, it can cause local irritation, but tolerated, although some patients experienced it seems to be overall better tolerated than oral drowsiness (32.6%), nausea/vomiting (8.7%), clonidine. Another drug that is increasingly used in depression (7.6%), insomnia (6.5%), akathisia the treatment of ADHD and impulse control (5.4%), and other less frequent, dose-related side problems is guanfacine. Pharmacologically similar effects. It has the advantage over the conventional to clonidine, guanfacine may be effective in patients neuroleptics in that it does not cause tardive in whom clonidine failed to control the behavioral dyskinesia. symptoms and may have some advantages over

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clonidine in that it has a longer half-life, it appears and secondary outcome measures. In the largest to be less sedating, and it produces less hypotension. reported series, 18 TS patients underwent bilat- It also seems to be a more selective α2-noradrenergic eral DBS of the centromedian parafascicular receptor agonist and binds more selectively to the (CM-Pfc) and ventralis oralis (Vo) complex of the postsynaptic α2A-adrenergic receptors located in thalamus [58]. Followed up to 18 months, most the prefrontal cortex. While both clonidine and patients apparently showed improvement in tics guanfacine appear to be effective in the treatment as well as OCD, self-injurious behavior, and other of attention deficit with and without hyperactivity, comorbidities. In a prospective 24-month follow- they appear to be particularly useful in the up of 15 of the original 18 patients, there contin- management of oppositional, argumentative, ued to be a marked improvement in tics, OCD, impulsive, and aggressive behavior. anxiety, and depression with subjective percep- Although imipramine and desipramine have tion of improved social functioning and quality of been reported to be useful in the treatment of life [59]. Finally, the observation that vagal nerve OCD, the most effective drugs are the selective stimulation also favorably modifies the frequency serotonin reuptake inhibitors (SSRIs) [51]. These and intensity of facial tics suggests that the brain- include fluoxetine, fluvoxamine, clomipramine, stem plays a role in generation of modulation of paroxetine, sertraline, venlafaxine, citalopram, tics [60]. Further studies are needed to determine and escitalopram, and citalopram. Sertraline, par- which TS patients are best candidates for stereo- ticularly when combined with cognitive behavioral tactic surgery and which targets may be most therapy, has been found to significantly reduce appropriate for particular symptoms. anxiety in a randomized-controlled trial involving 488 children with anxiety disorder [52]. Surgical treatment of TS should be reserved for Conclusion patients with disabling symptoms unresponsive to medical therapy. While the overall experience TS is a complex neurobehavioral disorder mani- of stereotactic ablative surgery in the treatment of fested by phonic and motor tics as well as a variety tics has been rather disappointing, an increasing of behavioral comorbidities, particularly ADHD, number of reports have provided evidence that OCD, and poor impulse control. Genetic factors deep brain stimulation (DBS) involving the thala- clearly play a role in the pathogenesis of this disor- mus, the globus pallidus and other targets may be der even though no causative gene mutation a very effective strategy to treat uncontrollable applicable to most patients with TS has been found. tics [53–55]. Careful selection of patients, experi- The pathophysiology of TS is not well understood ence with the DBS procedure, and comprehen- but disinhibition of the cortico-striatal-thalamic- sive assessments at baseline and at follow-up cortical circuit has been suggested by physiological visits are essential for the successful outcome of and functional imaging techniques. While the DBS in TS [56]. Based on a double-blind assess- selection of therapy must be individualized for ment of 5 patients with TS undergoing bilateral each patient, antidopaminergic drugs and local thalamic DBS, there was a significant (p < 0.03) injections of botulinum toxin have been found to reduction in the modified Rush Video-Based be most effective in the treatment of tics. Even Rating Scale score (primary outcome measure) though CNS stimulants may possibly transiently and improvement was also noted in motor and exacerbate tics they are not absolutely contraindi- phonic tic counts as well as on the Yale Global Tic cated in the treatment of ADHD associated with Severity Scale (YGTSS) and TS Symptom List TS. SSRIs and other pharmacologic and behavioral scores (secondary outcome measures) [57]. In therapies are also useful in the management of TS. addition, there was evidence of improvement in DBS targeting thalamus of GPi is considered the the quality of life indices and 3 of 5 patients had best surgical approach to patients with extremely marked improvement according to all primary severe TS.

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References 16 Freeman RD, Fast DK, Burd L, et al. Tourette Syndrome International Database Consortium: An 1 Goetz CG, Chmura TA, Lanska DJ. Seminal figures in international perspective on Tourette syndrome the history of movement disorders: Gilles de la selected findings from 3500 individuals in 22 coun- Tourette, Oppenheim, the Vogts, von Economo, tries. Dev Med Child Neurol 2000; 42:436–47. Wilson, and Marsden. Part 12 of the MDS-sponsored 17 Robertson MM. The prevalence and epidemiology of History of Movement Disorders exhibit, Barcelona, Gilles de la Tourette syndrome. Part 1: the epidemio- June 2000. Mov Disord 2001 Sep; 16(5):940–6. logical and prevalence studies. J Psychosom Res. 2008; 2 Jankovic J, Kurlan R. Tourette Syndrome: Evolving 65:461–72a. concepts. Mov Disord 2011 May; 26:1149–56. 18 Robertson MM. The prevalence and epidemiology of 3 Jankovic J. A Video Guide to the Diagnosis of Tourette Gilles de la Tourette syndrome. Part 2: tentative Syndrome. Tourette Syndrome Association, www.tsa- explanations for differing prevalence figures in GTS, usa.org, 2008. including the possible effects of psychopathology, 4 Jankovic J. Treatment of hyperkinetic movement dis- aetiology, cultural differences, and differing orders. Lancet Neurol 2009; 8:844–56. phenotypes. J Psychosom Res 2008; 65:473–86b. 5 Yaltho TC, Lotze T, Jankovic J. The association of 19 Scahill L, Bitsko RH, Blumberg SJ. Prevalence of Tourette syndrome and dopa–responsive dystonia. diagnosed Tourette syndrome in persons aged 6–17 Mov Disord 2011 Feb; 26:359–60. years – United States, 2007. MMWR Morb Mortal 6 Weil RS, Cavanna AE, Willoughby JM, Robertson Wkly Rep 2009; 58:581–5. MM. Air swallowing as a tic. J Psychosom Res 2008; 20 Abelson JF, Kwan KY, O’Roak BJ, et al. Sequence 65:497–500. variants in SLITRK1 are associated with Tourette’s 7 Freeman RD, Zinner SH, Müller-Vahl K, et al. syndrome. Science 2005; 310:317–20. Coprophenomena in Tourette syndrome. Developmental 21 Ercan-Sencicek AG, Stillman AA, Ghosh AK, et al. Medicine & Child Neurol 2009; 51:218–27. L-histidine decarboxylase and Tourette’s syndrome. 8 Kwak C, Vuong KD, Jankovic J. Premonitory sensory N Engl J Med 2010; 362:1901–8. phenomenon in Tourette’s syndrome. Mov Disord 22 Gomis M, Puente V, Pont-Sunyer C, et al. Adult onset 2003; 18:1530–3. simple phonic tic after caudate stroke. Mov Disord 9 Prado HS, Rosario MC, Lee J, et al. Sensory phenom- 2008; 23:765–6. ena in obsessive–compulsive disorder and tic disor- 23 Jankovic J, Mejia NI. Tics associated with other ders: a review of the literature. CNS Spectr 2008; 13: disorders. In: Tourette Syndrome, Walkup J, Mink J, 425–32. Hollenbeck P, eds. Adv Neurol, Lippincott Williams & 10 Woods DW, Piacentini J, Chang S, et al. Managing Wilkins, Philadelphia, 2006, pp 61–8. Tourette’s syndrome: A behavioral intervention for 24 Jankovic J. Tourette’s syndrome. N Engl J Med 2001; children and adults. (Therapist Guide). Oxford 345:1184–92. University Press. 2008. 25 Martino D, Dale RC, Gilbert DL, Giovannoni G, 11 Hanna PA, Jankovic J. Sleep and tic disorders. In Leckman JF. Immunopathogenic mechanisms in Chokroverty S, Hening Walters A (eds): Sleep and Tourette syndrome: A critical review. Mov Disord Movement Disorders. Woburn, Mass, Butterworth– 2009; 24:1267–79. Heinemann, 2003, pp 464–71. 26 Brilot F, Merheb V, Ding A, Murphy T, Dale RC. 12 Jankovic J, Jimenez-Shahed J, Brown LW. A ran- Antibody binding to neuronal surface in Sydenham domised, double-blind, placebo-controlled study of chorea, but not in PANDAS or Tourette syndrome. topiramate in the treatment of Tourette syndrome. Neurology 2011; 76:1508–13. J Neurol Neurosurg Psychiat 2010; 81:70–3. 27 Schrag A, Gilbert R, Giovannoni G, Robertson MM, 13 Isaacs JD, Adams M, Lees AJ. Noncompressive mye- Metcalfe C, Ben-Shlomo Y. Streptococcal infection, lopathy associated with violent axial tics of Tourette Tourette syndrome, and OCD. Is there a connection? syndrome. Neurol 2010; 74:697–8. Neurol 2009; 73:1256–63. 14 Cheung MY, Shahed J, Jankovic J. Malignant Tourette 28 Albin RL, Mink JW. Recent advances in Tourette syndrome. Mov Disord 2007; 22:1743–50. syndrome research. Trends Neurosci 2006; 29: 15 Motlagh MG, Seddigh A, Dashti B, et al. 175–82. Consanguineous Iranian kindreds with severe 29 Graybiel AM. Habits, rituals, and the evaluative brain. Tourette syndrome. Mov Disord 2008; 23:2079–83. Ann Rev Neurosci 2008; 31:359–87.

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30 Cools R. Role of dopamine in the motivational and Randomized controlled trial. JAMA 2010; cognitive control of behavior. Neuroscientist 2008; 303:1929–37. 14:381–95. 46 Steeves TD, Ko JH, Kideckel DM, et al. Extrastriatal 31 Church JA, Fair DA, Dosenbach NU, et al. Control dopaminergic dysfunction in tourette syndrome. Ann networks in paediatric Tourette syndrome show Neurol 2010; 67:170–81. immature and anomalous patterns of functional 47 Kenney C, Hunter C, Mejia N, Jankovic J. connectivity. Brain 2009; 132:225–38. Tetrabenazine in the treatment of Tourette syndrome. 32 Orth M, Amann B, Robertson MM, Rothwell JC. J Ped Neurol 2007; 5:9–13. Excitability of motor cortex inhibitory circuits in 48 Aguirregomozcorta M, Pagonabarraga J, Diaz-Manera Tourette syndrome before and after single dose nico tine. J, et al. Efficacy of botulinum toxin in severe Tourette Brain 2005; 128:1292–1300. syndrome with dystonic tics involving the neck. 33 Bloch MH, Leckman JF, Zhu H, Peterson BS. Caudate Parkinsonism Relat Disord 2008 14:443–5. volumes in childhood predict symptom severity in adults 49 MTA Cooperative Group: A 14-month randomized with Tourette syndrome. Neurol 2005; 65:1253–8. clinical trial of treatment strategies for attention- 34 Cavanna AE, Stecco A, Rickards H, et al. Corpus deficit/hyperactivity disorder: The MTA Cooperative callosum abnormalities in Tourette syndrome: an Group. Multimodal Treatment Study of Children with MRI-DTI study of monozygotic twins. J Neurol ADHD. Arch Gen Psychiat 1999; 56:1073–86. Neurosurg Psychiat 2010; 81:533–5. 50 Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in 35 Makki MI, Govindan RM, Wilson BJ, Behen ME, the treatment of tics. Arch Neurol 2000; 57:1190–3. Chugani HT. Altered fronto-striato-thalamic connec- 51 Silay Y, Jankovic J. Emerging drugs in Tourette syn- tivity in children with Tourette syndrome assessed drome. Expert Opin Emerg Drugs 2005; 10:365–80. with diffusion tensor MRI and probabilistic fiber 52 Walkup JT, Albano AM, Piacentini J, et al. Cognitive tracking. J Child Neurol 2009; 24:669–78. behavioral therapy, sertraline, or a combination in 36 Sowell ER, Kan E, Yoshii J, et al. Thinning of sensori- childhood anxiety. N Engl J Med 2008; 359:2753–66. motor cortices in children with Tourette syndrome. 53 Temel Y, Visser-Vandewalle V. Surgery in Tourette Nat Neurosci 2008; 11:637–9. syndrome. Mov Disord 2004; 19:3–14. 37 Eidelberg D, Moeller JR, Antonini A, et al. The meta- 54 Shahed J, Poysky J, Kenney C, Simpson R, Jankovic J. bolic anatomy of Tourette’s syndrome. Neurol 1997; GPi deep brain stimulation for Tourette syndrome 48:927–34. improves tics and psychiatric comorbidities. Neurol 38 Pourfar M, Feigin A, Tang CC, et al. Abnormal 2007; 68:159–60. metabolic brain networks in Tourette syndrome. 55 Ackermans L, Duits A, van der Linden C, et al. Double- Neurol 2011 Mar; 76:944–52. blind clinical trial of thalamic stimulation in patients 39 Baym CL, Corbett BA, Wright SB, Bunge SA. Neural with Tourette syndrome. Brain 2011; 134(Pt 3):832–44. correlates of tic severity and cognitive control in children 56 Mink JW, Walkup J, Frey KA, et al. for the Tourette with Tourette syndrome.Brain 2008; 131:165–79. Syndrome Association, Inc. Patient selection and 40 Lerner A, Bagic A, Boudreau EA, et al. Neuroimaging of assessment guidelines for deep brain stimulation in neuronal circuits involved in tic generation in patients Tourette syndrome. Mov Disord 2006; 21:1831–8. with Tourette syndrome. Neurol 2007; 68:1979–87. 57 Maciunas RJ, Maddux BN, Riley DE, et al. Prospective 41 Yoon DY, Gause CD, Leckman JF, Singer HS. Frontal randomized double-blind trial of bilateral thalamic dopaminergic abnormality in Tourette syndrome: a deep brain stimulation in adults with Tourette postmortem analysis. J Neurol Sci 2007; 255:50–6. syndrome. J Neurosurg 2007; 107:1004–14. 42 Kalanithi PS, Zheng W, Kataoka Y, et al. Altered 58 Servello D, Porta M, Sassi M, Brambilla A, Robertson parvalbumin-positive neuron distribution in basal MM. Deep brain stimulation in 18 patients with severe ganglia of individuals with Tourette syndrome. Proc Gilles de la Tourette syndrome refractory to treatment: Natl Acad Sci 2005; 102:13307–12. the surgery and stimulation. J Neurol Neurosurg 43 Albin RL, Koeppe RA, Wernette K, et al. Striatal [11C] Psychiat 2008; 79:136–42. dihydrotetrabenazine and [11C]methylphenidate bind- 59 Porta M, Brambilla A, Cavanna AE, et al. Thalamic ing in Tourette syndrome. Neurol 2009; 72:1390–6. deep brain stimulation for treatment-refractory 44 Shprecher D, Kurlan R. The management of tics. Mov Tourette syndrome: two-year outcome. Neurol 2009; Disord 2009; 24:15–24. 73:1375–80. 45 Piacentini J, Woods DW, Scahill L, et al. Behavior 60 Diamond A, Kenney C, Jankovic J. The effect of vagal therapy for children with Tourette disorder: nerve stimulation in a case of Tourette’s syndrome

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and complex partial epilepsy. Mov Disord 2006; http://www.nih.gov 21:1273–5. http://www.wemove.org http://www.cw.bc.ca/childrens/mhrev05/cats/ APPENDIX catsdrug.html http://www.medscape.com/LCM/ Tourette Syndrome Association (TSA) InfMind/2001/02.01/infinitemind.html 42–40 Bell Boulevard Bayside, NY 11361 Obsessive Compulsive Foundation Telephone: 718–224–2999 http://www.ocfoundation.org/ Website: http://neuro–www2.mgh.harvard.edu/ tsa/tsamain.nclk Children and Adults with Other Relevant Websites Attention–Deficit Disorder http://www.tsa.org.uk http://www.chadd.org/ http://www.ed.gov http://www.ets.org/disability/adhdplcy.html

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Introduction cause of tics. The disease started spontaneously in several different central European cities around The aim of this chapter is to provide an overview of 1916. Over the next 11, it spread relentlessly secondary tics or tourettism according to their around the world, leaving an estimated half a million presumed cause. Tics represent one of the most people dead or disabled. From the outset, it became common movement disorders, reported to occur in established that a subset of surviving patients up to one quarter of children [1–4]. Although the developed postencephalitic parkinsonism [9]. As majority of patients have primary tics associated mysteriously as it began, this disease virtually with Tourette syndrome (TS) (see Chapter 12), in a disappeared. Curiously, its causative agent remains few patients this movement disorder is associated unknown to date. It is uncertain whether recent with an underlying structural abnormality of the cases with similar clinical pictures represent the brain or some external cause. The term tourettism same condition described by von Economo [10,11]. has been used to describe secondary tics [5–7]. To Although parkinsonism was the most common the author’s knowledge, there are no epidemiological movement disorder found in those patients, a studies of the prevalence of secondary tics. subset of subjects presented with motor, vocal, or The literature of secondary tics must be interpreted other phonic tics. Interestingly, similarly to what with caution since, in most instances, the causal happens in TS, some patients with postencephalitic relationship between the movement disorder and parkinsonism also had obsessive-compulsive the associated condition is not firmly established disorder (OCD) [9]. since the studies are reports of a few cases. Moreover, There are reports of tics associated with herpes in some of the reports, it is not clear whether the simplex encephalitis [12] as well as HIV encepha- patients display features commonly found in tics, lopathy [13]. However, more recent studies on a such as the ability to suppress them as well as a possible relationship between infections and tics premonitory urge [8] ]. have focused on streptococcus. PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) is a controversial concept, Tics and infections according to which infection with group A beta-hemolytic streptococcus may induce tics, OCD, Encephalitis lethargica pandemic, also known as and other neuropsychiatric disturbances. The Von Economo disease (named after the Austrian following working diagnostic criteria for this physician who described it), is the classical infectious condition have been proposed: (1) presence of OCD

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or a tic disorder, (2) prepubertal symptom onset, (3) Box 13.1 Drugs associated with onset episodic course of symptom severity, (4) association of tics with group A beta-hemolytic streptococci infections, and (5) association with neurologic abnormalities. Amphetamines Cocaine Anticholinergics L-Dopa According to a description of 50 patients who met Antidepressants Lithium these criteria, the onset of tics and OCDhad a mean Antiepileptics Methylphenidate age of 6. 3 and 7. 4 years respectively [14]. There Antihistamines Neuroleptics remain many doubts whether there is indeed a solid Antipsychotics Pemoline causal relationship between streptococcal infection Atomoxetine and some of these clinical phenomena, and more recent studies have even challenged the existence of a relationship between streptococcal infections the data of the studies. In many cases, the articles and PANDAS [15, 16]. contain a description of a limited number of cases A related issue is the presence of tics in patients without proper controls. In other instances, the with Sydenham chorea (SC). There are reports of a reported patients already had pre-existent tic common occurrence of tics in SC. Caution is disorders which renders it difficult to accept the warranted to interpret these claims since it is virtually causal relationship between the use of the impossible to distinguish simple tics from fragments medications and the worsening of the movement of chorea. Even vocal tics, which were found in 70% disorder since TS and other idiopathic tic disorders or more of patients with SC in one study, cannot be are characterized by fluctuation of their severity easily diagnosed in patients with hyperkinesias [17]. [19]. For instance, there are reports describing the Those physicians who are experienced in movement onset of tics in patients treated with carbamazepine disorders are well aware that involuntary vocali- [20, 21]. Some of the subjects had a pre-existent zations may result from dystonia or chorea of the movement disorder and the tics persisted after the pharynx and larynx [8]. In these circumstances the withdrawal of the antiepileptic drug [20], suggesting vocalization lacks the subjective feeling (premonitory that they had an idiopathic tic disorder. Other urge or sensory tic), so characteristic of idiopathic tic antiepileptic agents implied in triggering or disorders such as TS. In a cohort of 108 SC patients worsening tics are phenytoin and phenobarbital carefully followed up at our unit, we identified [6, 7]. Similar problems are found in the literature vocalizations in just 8% of subjects. We have avoided describing the association of tics and antidepressants the term “tic” because there was no premonitory sign such as imipramine, clomipramine, desipramine, or complex sound and, conversely, the vocalizations fluoxetine, sertraline, fluvoxamine, and buproprion were associated with severe cranial chorea. Taken [6]. Not only did all the patients have TS or some together, these findings suggest that the involuntary other idiopathic tic disorder, but whenever controlled sounds that were present in a few patients with SC trials were performed, such as with desipramine and result from choreic contractions of the upper clomipramine, no association was found between respiratory tract muscles rather than being true tics the use of these drugs and the onset or worsening of [18]. The results of this study further weaken the tics [22, 23]. Similarly, despite reports of tardive hypothesis of a causal relationship between strepto- tourettism as a complication of prolonged use of coccus infections and tics and related disorders. typical neuroleptics [24, 25], in a review of 100 patients with tardive dyskinesia we have not been able to identify any patient with tics [26]. Tics and drugs There is a great deal of interest in the relationship between the induction or worsening of tics and Box 13.1 contains a list of some of the drugs implied the use of stimulant agents [27], which are the in the development or worsening of tics. This is main methods of treating attention deficit and an area where it is particularly difficult to interpret hyperactivity disorder (ADHD] – a comorbid

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feature in up to 60% of patients with idiopathic tic Video 13.1 Tics following peripheral injury disorders [28]. In several reports – including some on the more recent agent, atomoxetine – there are 41 year old involved in a motorcycle accident at age 22 during which he dislocated his left shoulder. Within descriptions of worsening or even induction of tics a few weeks noted occasional jerking of the left with stimulant drugs used to treat ADHD [6, 7, shoulder, preceded by premonitory sensation. The tic 29–31]. However, when controlled studies were has remained stable. The case has been previously performed, there was no definite evidence reported [40]. supporting the notion that stimulant drugs have the potential to induce tics. This led to the conclusion that it is safe to treat patients with ADHD and tic disorders with stimulants [27, 32, 33]. Finally, we and others have described that patients with TS who use cocaine may experience worsening of their tics [34]. http://bit.ly/sRnvna

Tics and structural lesions oligodendroglioma extending to the basal ganglia There are reports of a new onset of tics after vascular who developed de novo tics, ADHD, and OCD [45]. lesions of the brain [6, 7, 35]. In the sole instance where there is a clear description of the topography of a stroke, Jankovic reports one child with an onset Tics and other neurodegenerative of contralateral hemidystonia and facial tics after an disorders infarction of the middle cerebral artery involving the basal ganglia [35, 36]. The discrepancy between There are reports of the occurrence of tics in the common occurrence of vascular lesions and the Huntington disease (HD) [6, 7, 46–48]. Although rarity of tics in this context suggests that there might choreic contractions of the upper respiratory be some underlying genetic predisposition. musculature can be associated with vocalizations, Rarely, trauma of the brain [6, 7, 37–39] or a the reported cases appeared to have phonic tics peripheral injury [40] can cause tics. In most as well as motor tics. Both motor and phonic instances, the patients underwent severe central tics have also been described in patients nervous system lesion resulting in a myriad of with neuroacanthocytosis, an autosomal recessive neurological findings, including tics. There are, disorder characterized by chorea and other move- however, reports describing the onset of tics after ment disorders, self-mutilatory oromandibular relatively minor peripheral injuries [6,40]. Since dyskinesia, seizures, peripheral neuropathy, and mild traumas and tics are common, these reports acanthocytes in the peripheral blood [49]. Some are difficult to interpret. It is possible that the patients with a clinical diagnosis of neurodegenera- presumed association merely reflects a recollection tion associated with brain iron accumulation type 1 bias. Furthermore, some of these patients may have (NBIA-1), formerly known as Hallervoden–Spatz a psychogenic movement disorder [4, 42]. disease, may also exhibit tics [ 6, 7, 50]. There is a Carbon monoxide poisoning induces necrotic wide phenotypic variation related to this condition pallidal lesion often associated with movement and not every patient with NBIA-1 has the “eye of disorders [43]. There is one report in which the the tiger” sign in a MRI of the brain, and this authors describe a patient who, after recovery of an radiological finding is not specific to NBIA-1 [51]. acute coma induced by CO poisoning, developed Most cases of dystonia are primary, and unrelated tics [44]. Finally, recently there is one case report to neurodegenerative diseases [52]. Nevertheless, describing a child with a large temporal lobe the possible association between this movement

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disorder and tics will be discussed in this section. Finally, there are reports describing the coexistence There are reports suggesting that patients with of tic disorders with a number of chromosomal dystonia are at risk of developing tics [6, 7, 53]. abnormalities: Down syndrome, Kleinfelter syn- Conversely, in a survey of a large database of TS drome, XYY karyotype, fragile X syndrome, triple X patients, the authors demonstrated that dystonia and 9p mosaicism, 9p monosomy, partial trisomy has a prevalence of 1,352 per million [54]. This of 16, 18q syndrome, 3q24 deletion, and XXYY finding suggests that the frequency of dystonia in syndrome [6, 64–66]. the TS population falls within the range described for the general population [55]. Management Miscellaneous If the cause of the secondary tic cannot be removed or treated, then the symptomatic therapy of secondary Clinicians have described that patients with autism tics is generally similar to that of primary tic disorders, spectrum disorder may present with clinical discussed in Chapter 12. In some instances, how- features, which meet the criteria for TS [6, 7]. In ever, it is possible to address the specific cause. For some series, the authors have described 29 children example, withdrawal of the offending drug may with such an association, leading them to suggest a improve tardive tics, although tetrabenazine may be pathogenic link between TS and autism [56, 57]. needed to further improve the tic [67]. Tics associated Regardless of the underlying mechanism, more with SC may be treated with a combination of valp- recent data confirms that there is an association roic acid and secondary prophylaxis of streptococcus between the two disorders. For instance, in one infection with penicillin. Antidopaminergic drugs and study of 112 consecutive children with autism immunosuppressive measures are left for patients spectrum disorder, the authors diagnosed chronic who fail to improve with the other measures [68]. tic disorder in 6% of subjects, a figure higher than the 1% prevalence expected for the general population [58]. Older literature describes the presence of tics in References non-treated schizophrenic patients [6, 7, 59]. It is 1 Comings DE, Himes JA, Comings BG. An epidemiologic not easy to assess this data since definitions of the study of Tourette’s syndrome in a single school district. phenomenology of movement disorder have evolved J Clin Psychiat 1990; 51:463–9. along the years, less recent studies could have 2 Kurlan R, Whitmore D, Irvine C, et al. Tourette’s included patients with postencephalitic parkinsonism, syndrome in a special education population: a pilot and more recent reports are potentially confounded study involving a single school district. Neurol 1994; by exposure to neuroleptics. Nevertheless, a recent 44:699–702. study describes that 2. 5% of a cohort of 399 TS 3 Scahill L, Tanner C, Dure L. The epidemiology of tics patients meet the criteria for schizophrenia, and Tourette syndrome in children and adolescents. whose rate in the general population is 1%. The dif- Adv Neurol 2001; 85:261–71. ference was statistically significant [60]. It remains 4 Robertson MM. The prevalence and epidemiology of to be determined whether these patients truly have Gilles de la Tourette syndrome. Part 1: the epidemiological and prevalence studies. J Psychosom Res 2008; idiopathic TS or another condition that mimicks it. 65:461–72. Psychogenic tics (pseudo-tics) are a well-recognized 5 Sacks OW. Acquired tourettism in adult life. Adv Neurol entity [6,7]. Two recent studies demonstrate that 4 1982; 35:89–92. to 6% of all patients with psychogenic movement 6 Kumar R, Lang AE. Secondary tic disorders. Neurol Clin disorder present with tics [61, 62]. Similar to 1997; 15:309–31. seizure disorders, patients with TS may also present 7 Jankovic J, Mejia NI. Tics associated with other with psychogenic tics [63]. disorders. Adv Neurol 2006; 99:61–8.

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8 Jankovic J. Differential diagnosis and etiology of tics. 25 Bharucha KJ, Sethi KD. Tardive tourettism after Adv Neurol 2001; 85:15–29. exposure to neuroleptic therapy. Mov Disord 1995; 9 von Economo C. Encephalitis Lethargica: Its Sequelae 10:791–3. and Treatment. 1931, London, Oxford University Press. 26 Stacy M, Cardoso F, Jankovic J. Tardive stereotypy and 10 Howard RS, Lees AJ. Encephalitis lethargica. A report other movement disorders in tardive dyskinesias. of four recent cases. Brain. 1987; 110 (Pt 1):19–33. Neurol 1993; 43:937–41. 11 Dale RC, Church AJ, Surtees RA, et al. Encephalitis 27 Erenberg G. The relationship between Tourette lethargica syndrome: 20 new cases and evidence syndrome, attention deficit hyperactivity disorder, and of basal ganglia autoimmunity. Brain 2004; stimulant medication: a critical review. Semin Pediat 127(Pt 1):21–33. Neurol 2005; 12:217–21. 12 Northam RS, Singer HS. Postencephalitic acquired 28 Cardoso F, Veado CC, de Oliveira JT. A Brazilian cohort Tourette-like syndrome in a child. Neurol 1991; of patients with Tourette’s syndrome. J Neurol 41:592–3. Neurosurg Psychiat 1996; 60:209–12. 13 McDaniel JS, Summerville MB. Tic disorder associated 29 Varley CK, Vincent J, Varley P, Calderon R. Emergence with encephalopathy in advanced HIV disease. Gen of tics in children with attention deficit hyperactivity Hosp Psychiat 1994; 162:98–300. disorder treated with stimulant medications. Compr 14 Swedo SE, Leonard HL, Garvey M, et al. Pediatric Psychiat 2001; 42:228–33. autoimmune neuropsychiatric disorders associated 30 Ledbetter M. Atomoxetine use associated with onset of with streptococcal infections: clinical description of a motor tic. J Child Adolesc Psychopharmacol 2005; the first 50 cases. Am J Psychiat 1988; 155:264–71. 15:331–3. 15 Kurlan R, Johnson D, Kaplan EL; and the Tourette 31 Párraga HC, Párraga MI, Harris DK. Tic exacerbation Syndrome Study Group. Streptococcal infection and and precipitation during atomoxetine treatment in exacerbations of childhood tics and obsessive- two children with attention-deficit hyperactivity compulsive symptoms: a prospective blinded cohort disorder. Int J Psychiat Med 2007; 37:415–24. study. Pediat 2008; 121:1188–97. 32 The Tourette’s Syndrome Study Group. Treatment of 16 Gilbert DL, Kurlan R. PANDAS: horse or zebra? Neurol ADHD in children with tics. A randomized controlled 2009; 73:1252–3. trial. Neurol 2002; 58:527–536. 17 Mercadante MT, Campos MC, Marques-Dias MJ, et al. 33 Roessner V, Robatzek M, Knapp G, et al. First-onset Vocal tics in Sydenham’s chorea. J Am Acad Child tics in patients with attention-deficit-hyperactivity Adolesc Psychiat 1997; 36:305–6. disorder: impact of stimulants. Dev Med Child Neurol 18 Teixeira Jr AL, Cardoso F, Maia DP, et al. Frequency 2006; 48:616–21. and significance of vocalizations in Sydenham’s 34 Cardoso FE, Jankovic J. Cocaine-related movement chorea. Parkinsonism Relat. Disord 2009; 15:62–3. disorders. Mov Disord 1993; 8:175–8. 19 Albin RL, Mink JW. Recent advances in Tourette 35 Jankovic J. Tics in other neurological disorders. In: syndrome research. Trends Neurosci 2006; 29:175–82. Kurlan R (Ed). Handbook of Tourette’s Syndrome and 20 Kurlan R, Kersun J, Behr J, et al. Carbamazepine- related tic and behavioral disorders. Marcel Dekker, induced tics. Clin Neuropharmacol 1989; 12:298–302. New York, 1993:167–83. 21 Robertson PL, Garofalo EA, Silverstein FS, et al. 36 Kwak CH, Jankovic J. Tourettism and dystonia after Carbamazepine-induced tics. Epilepsia 1993; 34: subcortical stroke. Mov Disord 2002; 17:821–5. 965–8. 37 Singer C, Sanchez-Ramos J, Weiner W. A case of post- 22 Caine ED, Polinsky RJ, Ebert MH, et al. Trial of traumatic tic disorder. Mov Disord 1989; 4:342–4. clomipramine and desipramine for Gilles de la Tourette 38 Gaul JJ. Posttraumatic tic disorder. Mov Disord 1994; syndrome. Ann Neurol 1979; 5:305–6. 9:121. 23 Singer HS, Brown J, Quaskey S, et al. The treatment of 39 Krauss J, Jankovic J. Tics secondary to craniocerebral attention-deficit hyperactivity disorder in Tourette’s trauma. Mov Disord 1997; 12:776–82. syndrome: A double-blind placebo-controlled study 40 Erer S, Jankovic J. Adult onset tics after peri- with clonidine and desipramine. Pediat 1995; pheral injury. Parkinsonism Relat. Disord 2008; 14: 95:74–81. 75–76. 24 Klawans HL, Falk DK, Nausieda PA, et al. Gilles de la 41 Schrag A, Trimble M, Quinn N, Bhatia K. The Tourette syndrome after long term chlorpromazine syndrome of fixed dystonia: an evaluation of 103 therapy. Neurol 1978; 28:1064–1068. patients. Brain 2004; 127(Pt 10):2360–72.

Albanese_c13.indd 204 12/24/2011 7:05:17 AM Secondary Tics 205

42 Ibrahim NM, Martino D, van de Warrenburg BP, et al. 56 Ringman JM, Jankovic J. The occurrence of tics in The prognosis of fixed dystonia: a follow-up study. Asperger syndrome and autistic disorder. J Child Parkinsonism Relat Disord 2009; 15:592–7. Neurol 2000; 15:394–400. 43 Lee MS, Marsden CD. Neurological sequelae following 57 Comings DE, Comings BG. Clinical and genetic carbon monoxide poisoning clinical course and out- relationships between autism-pervasive developmental come according to the clinical types and brain computed disorder and Tourette syndrome: A Study of 19 Cases. tomography scan findings. Mov Disord 1994; 9:550–8. Am J Med Genet 1991; 39:180–91. 44 Pulst S, Walshe TM, Romero JA. Carbon monoxide 58 Simonoff E, Pickles A, Charman T, et al. Psychiatric poisoning with features of Gilles de la Tourette’s disorders in children with autism spectrum disorders: syndrome. Arch Neurol 1983; 40:443–4. prevalence, comorbidity, and associated factors in a 45 Luat AF, Behen ME, Juhász C, et al. Secondary tics or population-derived sample. J Am Acad Child Adolesc tourettism associated with a brain tumor. Pediatr Psychiat 2008; 47:921–9. Neurol 2009; 41:457–60. 59 Takeuchi K, Yamashita M, Morikiyo M, et al. Single 46 Penney JB, Young AB, Shoulson I, et al. Huntington’s case study: Gilles de la Tourette’s syndrome and Disease in Venezuela: 7-year follow-up on schizophrenia. J Nerv Ment Dis 1986; 174:247–8. symptomatic and asymptomatic individuals. Mov 60 Kerbeshian J, Peng CZ, Burd L, Tourette syndrome Disord 1990; 5:93–99. and comorbid early-onset chizophrenia. J Psychosom 47 Jankovic J, Ashizawa T. Tourettism associated with Res 2009; 67:515–23. Huntington’s disease. Mov Disord 1995; 10:103–105. 61 Schwingenschuh P, Pont-Sunyer C, Surtees R, et al. 48 Müller J, Wenning GK, Wissel J, Poewe W. Intrafamilial Psychogenic movement disorders in children: a report heterogeneity of facial hyperkinesias: Chance associa- of 15 cases and a review of the literature. Mov Disord tion of tics, cranial dystonia, and Huntington’s disease? 2008; 23:1882–8. Mov Disord 2001; 16:370–2. 62 Ertan S, Uluduz D, Ozekmekçi S, et al. Clinical 49 Walker RH, Jung HH, Dobson-Stone C, et al. characteristics of 49 patients with psychogenic Neurologic phenotypes associated with acanthocyto- movement disorders in a tertiary clinic in Turkey. Mov sis. Neurol 2007; 68:92–98. Disord 2009; 24:759–62. 50 Nardocci N, Rumi V, Combi ML, et al. Complex tics, 63 Dooley JM, Stokes A, Gordon KE, Pseudo-tics in stereotypies, and compulsive behavior as clinical pres- Tourette syndrome. J Child Neurol. 1994; 9:50–1. entation of a juvenile progressive dystonia suggestive 64 Zannolli R, Pierluigi M, Pucci L, et al. 18q-syndrome and of Hallervorden-Spatz disease. Mov Disord 1994; ectodermal dysplasia syndrome: description of a child 9:369–371. and his family. Am J Med Genet A 2003; 116A:192–9. 51 Camargos ST, Gurgel-Giannetti J, Lees A, et al. 65 Zweier C, Guth S, Schulte-Mattler U, et al. 9 Mb Low prevalence of PANK2 mutations in Brazilian deletion including chromosome band 3q24 associated patients with neurodegeneration with brain iron with unsuspicious facial gestalt, persistent ductus accumulation. J Neurol Neurosurg Psychiat (in press). omphaloentericus, mild mental retardation and tic. 52 Schwarz CS, Bressman SB. Genetics and treatment of Eur J Med Genet 2005; 48:360–2. dystonia. Neurol Clin 2009; 27:697–718. 66 Tartaglia N, Davis S, Hench A, et al. A new look at 53 Stone LA, Jankovic J. The coexistence of tics and XXYY syndrome: medical and psychological features. dystonia. Arch Neurol 1991; 48:862–865. Am J Med Genet A 2008; 146A:1509–22. 54 Pringsheim T, Freeman R, Lang A. Tourette syndrome 67 Jankovic J. Treatment of hyperkinetic movement and dystonia. J Neurol Neurosurg Psychiat 2007; disorders. Lancet Neurol 2009; 8:844–56. 78:544. 68 Cardoso F. Huntington disease and other choreas. 55 Defazio G, Abbruzzese G, Livrae P, et al. Epidemiology Neurol Clin 2009; 27:719–36. of primary dystonia. Lancet Neurol 2004; 3:673–8.

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Albanese_p05.indd 207 12/24/2011 7:06:13 AM CHAPTER 14 Inherited Myoclonus Syndromes Emmanuel Roze1,2,3 and Emmanuelle Apartis2,4 1 Fédération des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France 2 INSERM UMR 975-CRICM, Hôpital de la Pitié Salpêtrière, Paris, France 3 Centre d’Investigation Clinique 9503, INSERM, Paris, France 4 Service de Physiologie, Hôpital Saint-Antoine, Paris, France

Historical background genotype/phenotype correlations, and to gain insights into the complex pathogenesis of this This chapter focuses on the myoclonus-dystonia disorder. (M-D) syndrome, which has previously been referred to as familial myoclonia, essential familial myoclonus, benign essential myoclonus, and alco- Phenomenology and other hol-responsive myoclonic dystonia. M-D should be clinical features distinguished from (i) inherited myoclonic dystonia, which comprises primarily dystonic disorders with A positive family history is frequent, and dominant myoclonus occurring in body parts affected by paternal transmission is the rule. The disorder dystonia, usually intermingled with dystonic spasm usually occurs in childhood, with symptom onset at and resulting in myoclonic-like fast dystonic move- a mean age of 6 years [10]. Onset tends to occur ments [1–3]; and (ii) inherited neurometabolic or earlier in girls than in boys, regardless of the heredodegenerative disorders in which secondary underlying genetic abnormality [11]. Onset after myoclonus or myoclonic dystonia is usually part of age 20 is very unusual, although onset as late as in a more complex phenotype [4–6] (Tables 14.1 and the eighth decade has occasionally been reported 14.2). Myoclonus of these patients usually have [12]. In most cases the presenting symptom is neurophysiological characteristics distinct from myoclonus, which may be isolated or associated those of M-D patients (see Figures 14.1, 14.2, and with dystonia (see Video 14.1). Isolated dystonia is 14.3). Following reports of isolated families, the initial manifestation in the remaining 20% of Mahloudji and Pikielny provided the first thorough cases [10, 11, 13–15]. The presenting symptoms are description of the M-D syndrome in 1967 [7], and not related to sex or age [10]. their initial diagnostic criteria have only undergone Myoclonus is usually the main and most disabling minor revisions [8]. The major M-D culprit gene, feature. The typical phenotype consists of very the epsilon-sarcoglycan gene (SGCE), was identified brief, “lightning-like” myoclonic jerks, which may in 1997 and linked to M-D in 2001 [9]. Several be either isolated or associated with mild to moder- attempts have been made over the last decade ate dystonia and generally predominate in the to unravel the genetic basis of M-D, to identify upper body [10, 16] (see Video 14.2).

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(a) (b) r SCM 200 mV 200 mV

r Bi Bra 200 mV 200 mV

r ECR 500 mV 200 mV

r FCR 500 mV 200 mV

(c)

r Vast M 200 mV

I Vast M 200 mV

I Bi Fem 200 mV

I TA 100 mV 200 ms

Figure 14.1 Polymyographic recordings of myoclonus, Also contrasting with the polymyographic patterns in showing typical patterns in the DYT11 myoclonus- M-D, cortical myoclonus is associated with shorter bursts dystonia (M-D) syndrome. (under 70 ms) and is highly synchronous and regularly Typically, surface polymyographic recordings of M-D stimulus-sensitive. Examples of myoclonus recorded myoclonus show both synchronous and asynchronous in DYT11 M-D are shown in a, b, and c. [a] Brief activity (classically erratic) in various segments of the (35–80 ms) isolated erratic arrhythmic myoclonus body, which may include proximal or distal parts of the (arrows) occurring in an upper limb and the neck at rest; limbs, the trunk, neck, or face. Myoclonus can be [b] Rhythmic myoclonus (7 Hz), outstretched hands, isolated, arrhythmic or occasionally rhythmic, the forming a pseudotremorous alternating pattern, frequency not exceeding 10 Hz. These different patterns composed of 80-ms bursts (arrows); [c] Negative are frequently associated. All patients have positive myoclonus (arrows): 48 ms long, recorded when sitting, myoclonus, but negative myoclonus occurs in rare cases. legs extended. Note the positive myoclonus in the biceps The duration of myoclonic bursts, both at rest and during femoris (asterisk), synchronous to the bilateral vastus tonic contraction, can range from 25 to 250 ms (mean medialis negative myoclonus, reinforcing the knee burst duration 90 ms) in a given patient. Other clinical flexion and explaining the falls. The same pattern was neurophysiological tests show no features of motor or obtained in the standing position. somatosensory cortical hyperexcitability. EEG jerk-locked Abbreviations: Bi Bra: biceps brachii, ECR: extensor carpi back averaging fails to show a premyoclonic cortical radialis, FCR: flexor carpi radialis, SCM: transient. Recording of the C-reflex is negative, and sternocleidomastoideus, Vast M: vastus medialis, Bi Fem: there are no giant somatosensory evoked potentials. biceps femoris caput longum.

Myoclonus is often present at rest; it is aggravated [14]. Myoclonus of the lower limbs is also found in by posture and action, and is generally stimulus- about 25% of cases [10, 13, 14, 16, 17]. Myoclonus insensitive. The most frequent pattern is one of usually predominates in the proximal segment of axial myoclonus with predominantly cervical the limbs, although predominantly distal involve- involvement associated with upper-limb myoclonus ment is also observed [12]. Myoclonus involves the

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(a) face and/or voice in about 25% of cases [10, 14, 16, 18]. When present, dystonia is usually mild to r EDB 1 mV moderate – cervical dystonia and writer’s cramp being the most common manifestations. The lower I EDB 1 mV limbs are sometimes involved and can be affected first [17]. Laryngeal dystonia is rarely present [13, (b) 17]. As in most movement disorders, psychological or physical stress can lead to transient aggravation r ECR 200 mV of the motor manifestations. Severity and the rate of progression are both variable and unpredictable, r FCR 200 mV ranging from severe motor disability in adolescence to mild, non-progressive symptoms lasting decades, and onset in old age. Clinical signs may evolve over (c) r ECR 500 mV Video 14.1 Myoclonus-dystonia r FCR 500 mV phenomenology This 7-year-old girl has a myoclonus-dystonia due to 200 ms SGCE mutation. She has postural and action myoclonus of the upper body associated with very mild dystonia of Figure 14.2 Polymyographic features in myoclonic the neck and upper limbs, one year after disease onset. dystonia, differing from those of DYT11 M-D a: Glutaric aciduria. Dystonic spasms (arrows) intermingled with myoclonus (35 ms length) recorded in the feet in the standing position; b: Idiopathic hemi-myoclonic dystonia. Continuous dystonic spasms (arrows) composed of or intermingled with myoclonus (30–70 ms length), wrist outstretched; c: Rett syndrome. Rhythmic (6 Hz) myoclonus (95–195 ms length) and dystonic pattern recorded during hand stereotypia production. Abbreviations: EDB, extensor digitorum brevis muscle, ECR: http://bit.ly/uJLqbM extensor carpi radialis, FCR: flexor carpi radialis.

(a) EE(b)

200 mV r ECR 200 mV

r FCR 200 mV 200 mV

200 ms

Figure 14.3 Agonist/antagonist patterns during flexion/ co-contracting pattern. In DYT11 M-D (b), note the brief extension of the wrist in myoclonic dystonia as myoclonus (asterisks) occurring in the FCR during both compared to DYT11 M-D. extension (E) and flexion of the wrist, interfering with In myoclonic dystonia (a), note that dystonic spasms the continuity of the movement. (arrows) observed in both FCR and ECR impair the Abbreviations: ECR: extensor carpi radialis, FCR: flexor alternating agonist/antagonist physiological activation carpi radialis. expected for a normal movement, thus producing a

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course of the disease (even in old age), or involve Video 14.2 Myoclonus-dystonia body regions that had previously been unaffected phenomenology [10]. This may occasionally lead to considerable The father of the girl shown in video 1 has also a functional disability. myoclonus-dystonia. 30 years after disease onset, he has dystonia of the lower limbs (mostly left) resulting in a Alcohol responsiveness is a striking feature of gait disorder. Note that switching the motor program M-D, most patients having a drastic symptom (backward walking) improves dystonia. He also had mild improvement in response to alcohol ingestion, and cervical dystonia and diffuse myoclonus of the upper rebound worsening on alcohol withdrawal [16]. body with severe functional impairment. For this reason there is a real risk of alcoholism in M-D patients, likely owing more to self-treatment of motor symptoms than to a direct effect of the underlying genetic defect. The place of non-motor manifestations in the M-D phenotype is controversial. There is growing evidence that M-D patients are more prone to http://bit.ly/rMXyMC develop psychiatric disorders, including anxiety disorders, depression, emotional instability and obsessive-compulsive disorder [23–27], but further Video 14.3 Myoclonus-dystonia: work is needed to determine whether these are lightning jerks part of or secondary to the M-D phenotype. This is a 25-year-old patient who carries a mutation Likewise, M-D patients may have subtle cognitive in the DYT11 myoclonus-dystonia gene. At age 2 she dysfunction: mild impairment of verbal learning developed myoclonic jerks and dystonia in the upper and memory have been reported in a limited limbs and the neck. Myoclonus responded well to number of patients [13], but a larger study showed alcohol, but tolerance and dependence gradually occurred. The videotape shows typical lightning jerks, no cognitive defects [25]. which are visible at rest and are activated by speech and spontaneous gesticulations. Walking is normal, with occasional myoclonic jerks; diffuse jerks are observed Epidemiology during handwriting. [Video courtesy of Alberto Albanese, MD, Milan, Italy] The overall incidence of M-D is unknown. The largest series have been reported in Europe and North America, but the disorder seems to occur worldwide.

Etiology

http://bit.ly/sb9346 The M-D syndrome is genetically heterogeneous and has been linked to at least two loci: DYT11 in chromosome region 7p21, corresponding to the time in a given individual, particularly in childhood location of the epsilon-sarcoglycan gene (SGCE; or adolescence. It is noteworthy that limb dystonia OMIM# 604149); and DYT15 in chromosome can improve spontaneously before adulthood region 18p15, in which the culprit gene remains to [10, 19]. The motor disorders usually remain fairly be identified [9, 28–34]. M-D patients can be stable during adulthood and are compatible with divided into three groups with respect to the under- an active life and normal lifespan [20]. In some lying genetic defect: (i) patients with mutations cases, however, M-D may be progressive [21, 22], or deletions within the epsilon-sarcoglycan SGCE and can worsen in severity at any time during the gene, which account for about 40% of cases,

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(ii) patients with SGCE deficiency due to rare genetic abnormalities, including large interstitial Pathophysiology deletions encompassing the entire SGCE gene of paternal origin and maternal disomy of chromo- The pathogenesis of M-D has not yet been eluci- some 7; and (iii) a heterogeneous group of patients dated. However, several abnormalities point to pri- with a similar M-D phenotype in the absence of mary dysfunction of the basal ganglia. Biochemical SGCE deficiency. studies in a mouse model of M-D, and human Mutation or deletion of the SGCE gene is detected neuroimaging studies with 123I-IBZMSPECT, suggest in only about 40% of patients with the typical phe- an altered dopaminergic neurotransmission in the notype, reflecting the genetic heterogeneity of the striatum [49, 50]. Clinical neurophysiological studies disorder [31, 34]. SGCE is an ubiquitous membrane have revealed signs of a subcortical origin of the protein widely expressed in central nervous system myoclonus, including: (i) a polymyographic pattern neurons [35–38]. Its exact function is unknown. (Figure 14.1), (ii) lack of stimulus sensitivity of the In M-D families with mutation or intragenic dele- myoclonus, (iii) negative C-reflex, (iv) absence of tion of SGCE, inheritance is autosomal dominant premyoclonic cortical potential on EEG jerk-locked with reduced penetrance. Transmission is almost back averaging, and (v) absence of giant somatosen- always paternal, due to imprinting (and thus silenc- sory evoked potentials [10, 14, 51–53]. In particular, ing) of the maternal allele by methylation of CpG dysfunction of the internal globus pallidus may play dinucleotides within the promoter region of SGCE a key role in M-D pathogenesis, as: (i) M-D patients [39–41]. De novo mutation of SGCE can occasionally are dramatically improved by deep brain stimulation occur in patients with apparently sporadic M-D [42]. of the internal globus pallidus [54]; (ii) increased In addition, the family history may be hidden coherence between the local field potentials of the by maternal imprinting in the case of maternal GPi and muscle activity has been found in M-D transmission of the mutated allele over successive patients [55, 56]; (iii) a correlation between myo- generations [43]. clonic jerk muscle activity and neuronal activity In rare patients, M-D is part of a contiguous gene within the GPi has been observed in one M-D patient syndrome due to interstitial microdeletions (up to [57]. One hypothesis is that the M-D phenotype is 16 Mb) encompassing the entire SGCE gene of related to increased synchronization of neuronal paternal origin and adjacent genes on chromosome activity in the basal ganglia network [55]. arm 7q. In this case the manifestations accompany- Experimental neurophysiological studies are ing M-D depend on the deletion breakpoints and scarce and include only a small series of patients. frequently include mental retardation, microceph- They have shown subtle cortical dysfunctions, but aly, facial dysmorphism, and intrauterine and it is difficult to determine whether these abnormali- postnatal growth retardation [34, 44–47]. Finally, ties are primary or secondary to basal ganglia or M-D syndrome due to SGCE deficiency can result brainstem dysfunction. Transcranial stimulation from maternal uniparental disomy of chromosome (TMS) studies suggest that the GABAergic cortical 7 owing to methylation, silencing the two maternal inhibitory system is intact in M-D, as short- interval

alleles [41]. Such patients may have additional (mediated by GABAA receptors) and long-interval

manifestations due to abnormal expression of other (mediated by GABAB receptors) intracortical inhibi- imprinted genes located on chromosome 7, or to tion (SICI and LICI, respectively) is normal [52, 58, the unmasking of recessive mutations within 59]. Intracortical facilitation (ICF), reflecting the isodisomic segments. excitability of glutamatergic cortical interneurons, M-D without SGCE deficiency is also likely to be is consistently normal in M-D patients [53, 58, 59]. due to a variety of genetic defects. Basically, the Contrasting with the normal GABAergic and gluta- phenotype of these patients is very similar to that of matergic synaptic transmission, changes in the patients with SGCE deficiency [33, 48], although properties of ion channels in neural membranes are subtle differences have been reported [10, 15]. suspected, based on the increased variability of

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short-interval intracortical facilitation (SICF) [59] Video 14.4 Myoclonus-dystonia: deep and decreased active motor thresholds (aMT), brain stimulation which reflect membrane-related excitability of cor- SGCE tico-cortical axons [58]. SICF is thought to be medi- This patient has a myoclonus-dystonia due to mutation. In segment 1, 20 years after disease onset, she ated by successive activation of different groups of has severe pseudo-tremoric myoclonus of the four limbs cortical interneurons by transcranial stimulation and neck that are aggravated by posture and action, [60]. However, these findings need to be replicated associated with moderate dystonia of the trunk, neck in a large series of patients. One interesting finding and left upper limb. In segment 2, 1 year after bilateral is the enhancement of the recovery curve of the R2 deep brain stimulation of the pallidum, she is almost asymptomatic. component of the blink reflex, suggesting brainstem interneuron hyperexcitability [53]. Finally, an EEG–EMG coherence study of 20 M-D patients failed to detect the normal cortical drive to the muscles in the beta band during sustained contractions of the arm muscles [61]. Conventional MRI is normal in M-D patients. A study of a limited number of patients showed an abnormal activation pat- http://bit.ly/usJUCz tern in the cortex and cerebellum during a standardized motor task, in keeping with disorgan- in Parkinson’s disease or narcolepsy, and for binge ized sensorimotor integration [62]. This is consist- eating, shows promise in this setting [68, 69]. ent with findings in other hereditary dystonias [63, The sodium salt form, sodium oxybate, may be an 64]. Other studies of isolated cases, using single- interesting option for M-D patients, but most photon emission computed tomography or func- countries restrict its use because of safety concerns. tional MRI, have shown inconsistent functional Other possible treatments include botulinum toxin abnormalities in the cortex, striatum, thalamus, or injection for focal dystonic postures (particularly cerebellum [65–67]. cervical dystonia), physical therapy, and relaxation methods. Deep brain stimulation of the internal globus Treatment pallidum is a safe and effective option for patients with severe and disabling M-D. Although they There is no etiological treatment for M-D, and symp- have not been formally evaluated, the benefits tomatic pharmacological treatments are usually dis- seem to be at least equivalent to those seen in appointing. Benzodiazepines and anticholinergics patients with other primary dystonias [70–72], should be tried first. Interestingly, these drugs can be with a motor and functional improvement usually effective not only on dystonia and but also on exceeding 60% [54, 73]. Interestingly, this treat- myoclonus. Many other drugs have been proposed, ment is effective on both myoclonus and dystonia including antiepileptics (piracetam, levetiracetam, (see Video 14.4). Deep brain stimulation of the valproate, barbiturates, primidone, carbamazepine, ventral intermediate thalamic nucleus has also gabapentine, topiramate, zonisamide), L-dopa and been reported to be effective [73]. dopamine agonists, serotonic agents, beta-blockers, tetrabenazine, amantadine, and zolpidem [8, 51]. One striking feature of M-D is the marked symptom Other inherited myoclonus alleviation experienced by most patients after alcohol disorders ingestion, but there is currently no alcohol analogue or equivalent for therapeutic use. Hydroxybutyrate, Besides the myoclonus-dystonia syndrome, inher- a drug used for ethanol withdrawal in chronic ited myoclonic disorders include myoclonic forms alcoholics as well as for excessive daytime sleepiness of dystonic disorders as well as neurometabolic or

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heredogenenerative disorders, in which myoclonus alized myoclonus. Myoclonus is usually associated is part of a complex neurological picture. The main with severe epilepsy and progressive neurological possible etiologies to be considered are listed in deterioration, typically with cerebellar ataxia and Tables 14.1 and 14.2. dementia [74]. Clinical severity and the rate of Among these disorders, progressive myoclonic progression vary widely from one patient to the epilepsies and progressive myoclonic ataxia (PME/ next, mostly depending from the underlying PMA) represent an important syndromic entity. etiology. It ranges from severe disability in Onset usually occurs in childhood or adolescence. adolescence to mild symptoms and normal social The clinical phenotype is characterized by action- interactions with survival into old age. and stimulus-sensitive, severe, multifocal or gener-

Table 14.1 General characteristics of inherited progressive myoclonic epilepsies.

Disease Inheritance Gene2 Protein Associated abnormalities1

Unverricht–Lundborg AR EPM1A Cystatin B disease Lafora disease AR EPM2A Laforin EPM2B Malin Neuronal ceroid AR CLN1/PPT1 PPT1 Retinopathy lipofuscinosis CLN2/TPP1 TPP1 CLN3 CLN3 CLN5 CLN5 CLN6 CLN6 CLN7/MFS MFSD8 D8 CLN8 CLN8 Cathepsin D CLN10/CTS D Myoclonic epilepsy with Maternal MTTK others tRNALys Deafness, Myopathy ragged red fibers Peripheral neuropathy Optic atrophy, Cardiomyopathy Diabetes mellitus, Lipomatosis Sialidosis AR NEU1 Alpha- Macular cherry-red spot neuraminidase Hepatosplenomegaly Type3 Gaucher disease AR GBA Glucocerebrosidase Thrombocytopenia Bone involvement Juvenile dentorubral- AD Atrophin Atrophin Dystonia pallidoluysian atrophy Tremor Akinto-rigid parkinsonism Juvenile Huntington AD IT15 Huntingtin Dystonia disease Tremor Akineto-rigid parkinsonism Encephalopathy with AD SERPINI1 Neuroserpin neuroserpin inclusions PME linked to KCTD7 AR KTCD7 KTCD7 PME linked to PRICKLE 1 AR PRICKLE 1 Prickle 1

1 Can accompany the classical manifestations of progressive myoclonic epilepsy: epilepsy + myoclonus +/− cerebellar signs +/− cognitive impairment. 2 When the culprit gene is known. AR: autosomal recessive; AD: autosomal dominant; PPT1: palmytoyl protein thioesterase; TPP1: tripeptidyl peptidase; KCTD7: potassium channel tetramerization containing domain 7; MFSD8 major facilitator superfamily domain containing protein 8.

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Table 14.2 General characteristics of various inherited dystonic disorders that can manifest as myoclonic dystonia1.

Disease Inheritance Gene2 Protein Associated abnormalities3

DYT1 primary dystonia AD TOR1A Torsin A DYT5 primary dystonia AD GCH1 GTP cyclohydrolase 1 Parkinsonism, Tremor Wilson’s disease AR ATP7B ATP7B Dementia, psychosis Tremor, akinetorigid parkinsonism Liver abnormalities Kayser-Fleischer ring Glutaric aciduria AR GCDH Glutaryl CoA Chorea, Athetosis, Parkinsonism dehydrogenase Mental retardation Macrocephaly GM1 gangliosidosis AR$ GLB1 Beta-galactosidase Akineto-rigid parkinsonism Chorea, Athetosis Skeletal abnormalities Mental retardation Lesch-Nyhan disease X linked HPRT Hypoxanthine-guanine Self injurious behavior recessive phosphoribosyl Gouty arthritis, Nephrolithiasis transferase Mental retardation Creatine deficiency AR GAMT glycine Epilepsy, Mental retardation amidinotransferase4 Behavioral disorders Mitochondrial Various Various Various Various associated movement disorders disorders Multisystem involvement GLUT1 deficiency AD GLUT1 GLUT1 glucose Ataxia, Chorea transporter Mental retardation, Epilepsy Paroxysmal manifestations Niemann Pick C AR NPC1 Niemann Pick C 1 Psychiatric disorders disease NPC2 Niemann Pick C 2 Cerebellar syndrome Vertical supranuclear palsy Tremor, Akineto-rigid parkinsonism Hepatosplenomegaly Type3 Gaucher disease AR GBA Glucocerebrosidase Parkinsonism Hepatosplenomegaly Thrombopenia Pantothenate kinase AR PANK2 Pantothenate kinase 2 Parkinsonism, Pyramidal syndrome associated Mental retardation neurodegeneration5 Retinopathy Rett syndrome6 X-linked MECP2 Methyl-CpG-binding Mental retardation, Epilepsy, Microcephaly dominant protein 2 Stereotypies Psychiatric disorders Spinocerebellar AD PRKCG Protein kinase C Ataxia, nystagmus ataxia 14 gamma Parkinsonism, Tremor Cognitive impairment

1 Note that virtually all dystonic disorders can occasionally manifest as myoclonic dystonia including primary dystonia DYT1, DYT5) and dystonia secondary to neurometabolic disorders. In this setting, myoclonic dystonia is usually not isolated but part of a complex phenotype. 2 When the culprit gene is known. 3 Can accompany myoclonic dystonia. 4 Dystonia related to cerebral creatine deficiency is usually secondary to GAMT deficiency (although other genes can be involved in cerebral creatine deficiency). 5 and other neurodegeneration with brain iron accumulation. 6 Note that most cases are sporadic. AR: autosomal recessive; AD: autosomal dominant.

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Video 14.5 Myoclonus in Unverricht– Video 14.6 Myoclonus in Lafora Lundborg disease body disease This patient has progressive myoclonus epilepsy (Baltic This is a 17-year-old patient with Lafora body disease myoclonus) with EPM1 mutation. [Video courtesy of due to a mutation of the EPM2A gene. Disease onset Joseph Jankovic, MD, Houston, Texas] was at age 13 with episodic generalized myoclonus (causing falls with no loss of consciousness) and generalized seizures preceded by aura. The videotape shows positive and negative myoclonus of the upper limbs (prevalent on the left side). [Video courtesy of the Neurophysiology Unit, Carlo Besta Institute, Milan, Italy]

http://bit.ly/uWh2e7

PME/PMA encompasses a large group of genetic disorders, mostly with autosomal recessive inheritance http://bit.ly/vkV0ws (Table 14.1). The differential diagnosis of PME/ PMA is dominated by five main disorders: Unverricht–Lundborg disease (EPM1) [75], Lafora used including combinations of valproate (except body disease (EPM2) [76], neuronal ceroid lipofus- for mitochondrial disorders), phenobarbital, cinosis [77], sialidosis [78], and mitochondrial benzodiazepine, piracetam, levetiracetam, and encephalomyopathy with ragged-red fibers zonisamide [74]. It is noteworthy that some antie- (MERFF) [79]. The predominant manifestation pileptic drugs can aggravate the clinical condition associated with myoclonus (epilepsy, ataxia, of PME/PMA patients and should thus avoid dementia) and additional features (retinal abnor- phenytoin (particularly in EPM1 patients), carba- malities, deafness, myopathy, polyneuropathy) mazepine, vigabatrin, and gabapentin [74]. vary across the disorders and may guide the clinician to the most likely cause. For example: (i) early or severe cognitive deterioration is rather Conclusion suggestive of Lafora body disease or neuronal ceroid lipofuscinosis, whereas cognition is relatively Inherited myoclonus-dystonia is a clinical and preserved in sialidosis or Unverricht–Lundborg neurophysiological entity resulting in mild to disease; (ii) occipital seizures are typically observed severe disability due to a combination of myoclonus in Lafora body disease; (iii) macula cherry-red spot and dystonia. Precise diagnosis is necessary for are seen in sialidosis; and (iv) myopathy or deafness etiological investigations and treatment. Knowledge are good clues to the diagnosis of mitochondrial of the clinical, neurophysiological and genetic encephalomyelopathy. aspects of myoclonus-dystonia has greatly improved There is currently no way of preventing or even in recent years. However, the function of the slowing the course of the neurological decline protein encoded by the epsilon-sarcoglycan (SGCE) associated with PME/PMA. The treatment thus gene, which is defective in nearly 50% of cases, is consists in symptomatic management of epilepsy largely unknown. Ongoing basic and clinical and myoclonus associated with supportive and research is providing novel insights into the rehabilitative measures. Treatment of myoclonus complex mechanisms responsible for the motor and seizures is difficult in the setting of PME/PMA disorders characteristic of M-D, and point to a as both tend to be refractory. Although their efficacy dysfunction of the basal ganglia network. Drugs are has not been proved, various antiepileptic drugs are poorly effective. Deep brain stimulation of the

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internal globus pallidus is a safe and very effective 13 Doheny DO, Brin MF, Morrison CE, et al. Phenotypic therapeutic option for severely affected patients. features of myoclonus-dystonia in three kindreds. 2002. Neurol 59:1187–96. 14 Nardocci N, Zorzi G, Barzaghi C, et al. Myoclonus- Acknowledgments dystonia syndrome: clinical presentation, disease course, and genetic features in 11 families. 2008. Mov We thank Dr Sabine Meunier, Dr Isabelle An and Disord 23:28–34. Constance Flamand for their help in preparing the 15 Gerrits MC, Foncke EM, de Haan R, et al. Phenotype- manuscript. genotype correlation in Dutch patients with myoclonus-dystonia. 2006. Neurol 66:759–61. 16 Asmus F, Gasser T. Inherited myoclonus-dystonia. References 2004 Adv Neurol 94:113–19. 17 Koukouni V, Valente EM, Cordivari C, et al. Unusual 1 Leuzzi V, Carducci C, Cardona F, et al. Autosomal familial presentation of epsilon-sarcoglycan gene dominant GTP-CH deficiency presenting as a dopa- mutation with falls and writer’s cramp. 2008. Mov responsive myoclonus-dystonia syndrome. 2002. Disord 23:1913–15. Neurol 59:1241–3. 18 Hjermind LE, Werdelin LM, Eiberg H, et al. A novel 2 Kabakci K, Hedrich K, Leung JC, et al. Mutations in mutation in the epsilon-sarcoglycan gene causing DYT1: extension of the phenotypic and mutational myoclonus-dystonia syndrome. 2003. Neurol spectrum. 2004. Neurol 62:395–400. 60:1536–9. 3 Chinnery PF, Reading PJ, McCarthy EL, et al. Late- 19 Thobois S, Gervais-Bernard H, Xie-Brustolin J, et al. onset axial jerky dystonia due to the DYT1 deletion. Evidence for progressive changes in clinical presentation 2002. Mov Disord 17:196–8. of myoclonus-dystonia. 2007. Mov Disord 22:1516–17. 4 Gitiaux C, Roze E, Kinugawa K, et al. Spectrum of move- 20 Nygaard TG, Raymond D, Chen C, et al. Localization ment disorders associated with glutaric aciduria type 1: of a gene for myoclonus-dystonia to chromosome a study of 16 patients. 2008. Mov Disord 23:2392–7. 7q21-q31. 1999. Ann Neurol 46:794–8. 5 Roze E, Paschke E, Lopez N, et al. Dystonia and 21 Quinn NP. Essential myoclonus and myoclonic parkinsonism in GM1 type 3 gangliosidosis. 2005. dystonia. 1996. Mov Disord 11:119–24. Mov Disord 20:1366–9. 22 Trottenberg T, Meissner W, Kabus C, et al. 6 Foncke EM, Beukers RJ, Tijssen CC, et al. Myoclonus- Neurostimulation of the ventral intermediate thalamic dystonia and spinocerebellar ataxia type 14 presenting nucleus in inherited myoclonus-dystonia syndrome. with similar phenotypes: Trunk tremor, myoclonus, and 2001. Mov Disord 16:769–71. dystonia. 2010. Parkinsonism Relat Disord 16:288–9. 23 Hess CW, Raymond D, Aguiar Pde C, et al. Myoclonus- 7 Mahloudji M, Pikielny RT. Hereditary essential dystonia, obsessive-compulsive disorder, and alcohol myoclonus. 1967. Brain 90:669–74. dependence in SGCE mutation carriers. 2007. Neurol 8 Kinugawa K, Vidailhet M, Clot F, et al. Myoclonus- 68:522–4. dystonia: an update. 2009. Mov Disord 24:479–89. 24 Marechal L, Raux G, Dumanchin C, et al. Severe 9 Zimprich A, Grabowski M, Asmus F, et al. Mutations myoclonus-dystonia syndrome associated with a novel in the gene encoding epsilon-sarcoglycan cause epsilon-sarcoglycan gene truncating mutation. 2003. myoclonus-dystonia syndrome. 2001. Nat Genet Am J Med Genet B Neuropsychiatr Genet 119B:114–17. 29:66–9. 25 Foncke EM, Cath D, Zwinderman K, et al. Is psycho- 10 Roze E, Apartis E, Clot F, et al. Myoclonus-dystonia: pathology part of the phenotypic spectrum of clinical and electrophysiologic pattern related to SGCE myoclonus-dystonia?: a study of a large Dutch M-D mutations. 2008. Neurol 70:1010–16. family. 2009. Cogn Behav Neurol 22:127–33. 11 Raymond D, Saunders-Pullman R, de Carvalho Aguiar P, 26 Saunders-Pullman R, Shriberg J, Heiman G, et al. et al. Phenotypic spectrum and sex effects in eleven Myoclonus dystonia: possible association with myoclonus-dystonia families with epsilon-sarcoglycan obsessive-compulsive disorder and alcohol depend- mutations. 2008. Mov Disord 23:588–92. ence. 2002. Neurol 58:242–5. 12 Foncke EM, Gerrits MC, van Ruissen F, et al. Distal 27 Klempir J, Klempirova O, Roth J. Influence of myoclonus and late onset in a large Dutch family with emotional instability on behavioral disorders in myoclonus-dystonia. 2006. Neurol 67:1677–80. DYT11. 2010. Mov Disord 25:791–2.

Albanese_c14.indd 218 12/24/2011 7:07:51 AM Inherited Myoclonus Syndromes 219

28 Vidailhet M, Tassin J, Durif F, et al. A major locus for 43 Gerrits MC, Foncke EM, Koelman JH, Tijssen MA. several phenotypes of myoclonus–dystonia on Pediatric writer’s cramp in myoclonus-dystonia: chromosome 7q. 2001. Neurol 56:1213–16. maternal imprinting hides positive family history. 29 Asmus F, Zimprich A, Naumann M, et al. Inherited 2009. Eur J Paediatr Neurol 13:178–80. Myoclonus-dystonia syndrome: narrowing the 7q21- 44 DeBerardinis RJ, Conforto D, Russell K, et al. q31 locus in German families. 2001. Ann Neurol Myoclonus in a patient with a deletion of the epsilon- 49:121–4. sarcoglycan locus on chromosome 7q21. 2003. Am 30 Schule B, Kock N, Svetel M, et al. Genetic heterogene- J Med Genet A 121A:31–6. ity in ten families with myoclonus-dystonia. 2004. 45 Asmus F, Hjermind LE, Dupont E, et al. Genomic dele- J Neurol Neurosurg Psychiatry 75:1181–5. tion size at the epsilon-sarcoglycan locus determines 31 Tezenas du Montcel S, Clot F, Vidailhet M, et al. the clinical phenotype. 2007. Brain 130:2736–45. Epsilon sarcoglycan mutations and phenotype in 46 Bonnet C, Gregoire MJ, Vibert M, et al. Cryptic 7q21 French patients with myoclonic syndromes. 2006. and 9p23 deletions in a patient with apparently J Med Genet 43:394–400. balanced de novo reciprocal translocation t(7;9) 32 Valente EM, Edwards MJ, Mir P, et al. The epsilon- (q21;p23) associated with a dystonia-plus syndrome: sarcoglycan gene in myoclonic syndromes. 2005. paternal deletion of the epsilon-sarcoglycan (SGCE) Neurol 64:737–9. gene. 2008. J Hum Genet 53:876–85. 33 Han F, Racacho L, Lang AE, Bulman DE, Grimes DA. 47 Saugier-Veber P, Doummar D, Barthez MA, et al. Refinement of the DYT15 locus in myoclonus dystonia. Myoclonus Dystonia Plus Syndrome due to a Novel 7q21 2007. Mov Disord 22:888–92. Microdeletion. 2010. Am J Med Genet A 152A:1244–9. 34 Grunewald A, Djarmati A, Lohmann-Hedrich K, et al. 48 Grimes DA, Han F, Lang AE, et al. A novel locus for Myoclonus-dystonia: significance of large SGCE inherited myoclonus-dystonia on 18p11. 2002. Neurol deletions. 2008. Hum Mutat 29:331–2. 59:1183–6. 35 Ettinger AJ, Feng G, Sanes JR. Epsilon-Sarcoglycan, a 49 Beukers RJ, Booij J, Weisscher N, et al. Reduced broadly expressed homologue of the gene mutated in striatal D2 receptor binding in myoclonus-dystonia. limb-girdle muscular dystrophy 2D. 1997. J Biol Chem 2009. Eur J Nucl Med Mol Imaging 36:269–74. 272:325–48. 50 Yokoi F, Dang MT, Li J, Li Y. Myoclonus, motor defi- 36 Nishiyama A, Endo T, Takeda S, Imamura M. cits, alterations in emotional responses and monoam- Identification and characterization of epsilon- ine metabolism in epsilon-sarcoglycan deficient mice. sarcoglycans in the central nervous system. 2004. 2006. J Biochem 140:141–6. Brain Res Mol Brain Res 125:1–12. 51 Obeso JA, Rothwell JC, Lang AE, Marsden CD. 37 Xiao J, LeDoux MS. Cloning, developmental regula- Myoclonic dystonia. 1983. Neurol 33:825–30. tion and neural localization of rat epsilon-sarcoglycan. 52 Li JY, Cunic DI, Paradiso G, et al. Electrophysiological 2003. Brain Res Mol Brain Res 119:132–43. features of myoclonus-dystonia. 2008. Mov Disord 38 Chan P, Gonzalez-Maeso J, Ruf F, et al. Epsilon- 23:2055–61. sarcoglycan immunoreactivity and mRNA expression 53 Marelli C, Canafoglia L, Zibordi F, et al. A neurophysi- in mouse brain. 2005. J Comp Neurol 482:50–73. ological study of myoclonus in patients with DYT11 39 Muller B, Hedrich K, Kock N, et al. Evidence that myoclonus-dystonia syndrome. 2008. Mov Disord paternal expression of the epsilon-sarcoglycan gene 23:2041–8. accounts for reduced penetrance in myoclonus- 54 Azoulay-Zyss J, Roze E, Welter ML, et al. Bilateral dystonia. 2002. Am J Hum Genet 71:1303–11. pallidal deep brain stimulation for the treatment of 40 Grabowski M, Zimprich A, Lorenz-Depiereux B, et al. myoclonus dystonia due to epsilon sarcoglycan The epsilon-sarcoglycan gene (SGCE), mutated in mutations: a pilot study. 2011. Arch Neurol 68:94–8. myoclonus-dystonia syndrome, is maternally 55 Foncke EM, Bour LJ, Speelman JD, et al. Local field imprinted. 2003. Eur J Hum Genet 11:138–44. potentials and oscillatory activity of the internal 41 Guettard E, Portnoi MF, Lohmann-Hedrich K, et al. globus pallidus in myoclonus-dystonia. 2007. Mov Myoclonus-dystonia due to maternal uniparental Disord 22:369–76. disomy. 2008. Arch Neurol 65:1380–5. 56 Liu X, Griffin IC, Parkin SG, et al. Involvement of the 42 Hedrich K, Meyer EM, Schule B, et al. Myoclonus- medial pallidum in focal myoclonic dystonia: a clinical dystonia: detection of novel, recurrent, and de novo and neurophysiological case study. 2002. Mov Disord SGCE mutations. 2004. Neurol 62:1229–31. 17:346–53.

Albanese_c14.indd 219 12/24/2011 7:07:51 AM 220 Chapter 14

57 Magarinos-Ascone CM, Regidor I, Martinez-Castrillo ethanol-responsive movement disorders. 2005. Mov JC, et al. Pallidal stimulation relieves myoclonus- Disord 20:1330–7. dystonia syndrome. 2005. J Neurol Neurosurg 69 Priori A, Bertolasi L, Pesenti A, et al. Gamma- Psychiat 76:989–91. hydroxybutyric acid for alcohol-sensitive myoclonus 58 Meunier S, Lourenco G, Roze E, et al. Cortical excita- with dystonia. 2000. Neurol 54:1706. bility in DYT–11 positive myoclonus dystonia. 2008. 70 Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral Mov Disord 23:761–4. deep-brain stimulation of the globus pallidus in pri- 59 van der Salm SM, van Rootselaar AF, Foncke EM, mary generalized dystonia. 2005. N Engl J Med et al. Normal cortical excitability in myoclonus- 352:459–67. dystonia – a TMS study. 2009. Exp Neurol 216:300–5. 71 Kupsch A, Benecke R, Muller J, et al. Pallidal deep- 60 Ziemann U, Rothwell JC. I-waves in motor cortex. brain stimulation in primary generalized or segmental 2000. J Clin Neurophysiol 17:397–405. dystonia. 2006. N Engl J Med 355:1978–90. 61 Foncke EM, Bour LJ, van der Meer JN, et al. Abnormal 72 Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral, low frequency drive in myoclonus-dystonia patients pallidal, deep-brain stimulation in primary generalised correlates with presence of dystonia. 2007. Mov dystonia: a prospective 3 year follow-up study. 2007. Disord 22:1299–307. Lancet Neurol 6:223–9. 62 Beukers RJ, Foncke EM, van der Meer JN, et al. 73 Gruber D, Kuhn AA, Schoenecker T, et al. Pallidal and Disorganized sensorimotor integration in mutation- thalamic deep brain stimulation in myoclonus- positive myoclonus-dystonia: a functional magnetic dystonia. 2010. Mov Disord 25:1733–43. resonance imaging study. Arch Neurol 67:469–74. 74 Shahwan A, Farrell M, Delanty N. Progressive 63 Carbon M, Argyelan M, Habeck C, et al. Increased myoclonic epilepsies: a review of genetic and thera- sensorimotor network activity in DYT1 dystonia: a peutic aspects. 2005. Lancet Neurol 4:239–48. functional imaging study. 2010. Brain 133:690–700. 75 Lehesjoki AE. Clinical features and genetics of 64 Carbon M, Su S, Dhawan V, et al. Regional metabo- Unverricht-Lundborg disease. 2002. Adv Neurol lism in primary torsion dystonia: effects of penetrance 89:193–7. and genotype. 2004. Neurol 62:1384–90. 76 Monaghan TS, Delanty N. Lafora disease: epidemiol- 65 Papapetropoulos S, Argyriou AA, Polychronopoulos ogy, pathophysiology and management. 2010. CNS P, et al. Frontotemporal and striatal SPECT abnormali- Drugs 24:549–61. ties in myoclonus-dystonia: phenotypic and pathoge- 77 Mole SE, Williams RE, Goebel HH. Correlations netic considerations. 2008. Neurodegener Dis 5:355–8. between genotype, ultrastructural morphology and 66 Nitschke MF, Erdmann C, Trillenberg P, et al. clinical phenotype in the neuronal ceroid lipofuscino- Functional MRI reveals activation of a subcortical net- ses. 2005. Neurogenet 6:107–26. work in a 5-year-old girl with genetically confirmed 78 Palmeri S, Villanova M, Malandrini A, et al. Type myoclonus-dystonia. 2006. Neuropediat 37:79–82. I sialidosis: a clinical, biochemical and neuroradiologi- 67 Delecluse F, Waldemar G, Vestermark S, Paulson OB. cal study. 2000. Eur Neurol 43:88–94. Cerebral blood flow deficits in hereditary essential 79 DiMauro S, Hirano M, Kaufmann P, et al. Clinical myoclonus. 1992. Arch Neurol 49:179–82. features and genetics of myoclonic epilepsy with 68 Frucht SJ, Bordelon Y, Houghton WH, Reardan D. A ragged red fibers. 2002. Adv Neurol 89:217–29. pilot tolerability and efficacy trial of sodium oxybate in

Albanese_c14.indd 220 12/24/2011 7:07:51 AM CHAPTER 15 Segmental Myoclonus John Nathaniel Caviness Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Scottsdale, AZ, USA

Introduction will discuss the spectrum of myoclonus that is unified by the existence of a circumscribed Segmental myoclonus is an uncommon neurological segmental generator and has circuitry which can disorder, but it is a common form of myoclonus generate movements without stimulation from based on an epidemiological study [1]. Classically, cortical motor systems. segmental myoclonus has a specific clinical appearance that consists of, (1) rhythmic or semirhythmic involuntary activation of muscles Definition corresponding to its brainstem/spinal segment(s) generator, (2) persistence that is relatively unaf- For the purpose of this chapter, we will use the fected by state of consciousness, motor activity, or definition of Jankovic and Pardo, rhythmic or stimulus [2]. In theory, cortical myoclonus may semirhythmic involuntary contractions of muscle also have a limited segmental distribution, but the groups supplied by one or several contiguous classic clinical properties stated above have segments of the brainstem and/or spinal cord [2]. become intertwined with the definition of “seg- More specifically, our definition will imply an mental myoclonus” as a clinical entity. Moreover, abnormal central generator which arises from the implied segmental generator has given the localized segmental interneuron pools along the term “segmental myoclonus” implied physiologi- craniospinal neuraxis that are normally concerned cal properties as well. However, recent observa- with circumscribed segmental muscle control. tions have challenged the classic appearance and Thus, we exclude genesis from control centers that definition. Myoclonic movements that have a use pyramidal long-tract descending pathways and segmental generator do not always have persis- exclude lesions that create “release phenomena” tence nor remain unaffected by external influ- which generate abnormal movements at distant ences (i.e. consciousness, motor activity, or caudal muscle segments by severing control from stimuli). Many of these examples involve the higher integrative centers. This definition includes abdomen and/or respiratory apparatus as well as segmental myoclonus that may spread from a occasional more classic palatal and spinal phe- segmental generator via intersegmental or from a notypes. Moreover, the putative “segmental gen- higher location via non-pyramidal tract pathways. erator” may use non-pyramidal pathways to The involvement of contiguous muscle segments transmit the abnormal excitation to their and generation from a central localized segmental circumscribed motorneuron pools. This chapter origin is key to the definition of segmental

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myoclonus. Non-invasive electrodiagnostic studies still the more commonly used term. Rhythmicity is on segmental myoclonus cases classically show not uncommon in myoclonus, and the definition of rhythmic or semirhythmic surface electromyographic myoclonus does not exclude rhythmic character. (EMG) discharges that are typically synchronous For the purpose of this chapter, the term “palatal with stereotypic duration and frequency. Occa- myoclonus” will be used to refer to this segmental sionally, affected muscles that are far apart may not movement disorder. be synchronized nor have the same frequency. There is no evidence of cortical hyperexcitability Diagnosis and evaluation demonstrated on electroencephalography (EEG) or There are important differences between EPM and its back-averaging, somatosensory evoked poten- SPM, and we are indebted to Deuschl’s work for a tials (SEPs), or transcortical reflexes that elicit comprehensive study of this issue [5–7]. Although EMG responses. These characteristics differentiate many of the clinical characteristics of these entities segmental myoclonus physiology from cortical, overlap, the differences are strong enough to cortical-subcortical, subcortical/non-segmental, and suggest that EPM is indeed distinct from SPM. peripheral types [3]. EPM is usually caused by contractions of the tensor veli palatini, but isolated idiopathic “essential” middle ear myoclonus is caused by contractions of Palatal myoclonus the tensor tympani and/or stapedius muscle [8–11]. EPM is associated with no identifiable MRI Palatal myoclonus is the most common type of lesion, and is unlikely to involve other muscles. segmental myoclonus [1]. The movement is The EPM patients may have tinnitus or ear click- rhythmic and usually bilateral with a rate between ing, and these patients are likely to state that their 1 and –4 Hz, with a reported range of 0.1 to 7 Hz [4]. ear click is the chief complaint [12, 13]. EPM A distinction is made between “essential palatal patients are usually younger than those with SPM. myoclonus” (EPM) and “symptomatic palatal SPM is usually caused by the levator veli palatini, myoclonus” (SPM) [5]. EPM is idiopathic and although other palatal muscles can also be usually isolated. SPM is secondary to a definable involved. Brainstem stroke causes about half of cause and usually has other clinical manifestations the SPM cases. Other etiologies are listed in associated. Some experts prefer the term “palatal Box 15.1 [2, 5, 14–29]. Associated synchronous tremor” over “palatal myoclonus” on the basis of movements may be seen in eye movements, eye- the rhythmic nature of the palatal movements. lid, tongue, larynx, neck, diaphragm, trunk, and Even though this terminology change has been limbs [4]. SPM patients are usually more con- proposed for about 20 years, “palatal myoclonus” is cerned with the other associated neurological problems (e.g. cerebellar ataxia) rather than the palatal movements per se. Video 15.1 Palatal myoclonus This patient presents with a typical palatal myoclonus Clinical neurophysiology (frequency of about 2 Hz). [Video courtesy of Joseph of palatal myoclonus Jankovic, MD, Houston, Texas] Palatal myoclonus demonstrates characteristics of a segmental myoclonus physiology [3]. The EEG and SEP are normal. Brainstem auditory evoked potentials (BAEP) have had abnormal findings in some individuals with palatal myoclonus [4, 30]. These inconsistent BAEP abnormalities probably represent the same lesion type, but not the same exact location, as that responsible for the palatal http://bit.ly/scs8c3 myoclonus pathophysiology. Important differences

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the Guillain–Mollaret triangle, i.e. dentate–rubro– Box 15.1 Causes of palatal myoclonus olivary circuitry [31]. Figure 15.1 summarizes the • Vascular circuitry of these pathways and important patho- Brainstem infarct [14] physiology aspects of SPM. Deuschl concludes Brainstem hemorrhage [15] from his significant work on EPM and SPM that Cerebral vasculitis [16] the pathophysiology of these two entities seems Ectatic vertebral artery compression [17] different [7]. fMRI studies shows abnormal activ- Posterior circulation aneurysm [17] ity in the brainstem/cerebellar structures for SPM, • Essential [5] but prominent activation of the putamen was • Neoplasm [18] shown in EPM [32–34]. It is interesting that EPM • Trauma [19] has been reported in monozygotic twins, but the exact significance of this finding is not known • Demyelination [20] [10]. Commonly, olivary enlargement or atrophy • Infection [21] may be evident on MRI scan in SPM [35, 36]. • Neurodegeneration Pathology may show a neuronal cytoplasmic Spinocerebellar degeneration [22] vacuolation and astrocytic hyperplasia [37, 38]. Progressive supranuclear palsy [23] These changes are believed to result from a trans- • Neurodevelopmental abnormality synaptic degeneration due to deafferentation of (e.g. Arnold–Chiari) [17] the inferior olive. Many of the fibers leaving the • Syringobulbia [21] dentate nucleus that ascend to the red nucleus do • Hydrocephalus [24] not synapse in the parvocellular portion of the red • Alexander’s disease (presumed) [25] nucleus. Rather, the fibers ascend in the superior • Krabbe disease [26] cerebellar peduncle, cross at the midbrain and • Cerebrotendinous xanthomatosis [27] then loop under the red nucleus to descend via • Celiac disease [28] the central tegmental tract to the inferior olive • Anoxia [29] (Figure 15.1). Lesions of either the ascending or descending part of this dentato–olivary pathway are associated with SPM and hypertrophic in neurophysiological testing have also been degeneration of the inferior olive secondary to found between EPM and SPM [6]. EPM shows a presumed deafferentation and transsynaptic complete suppression with sleep, but sleep only degeneration. The inferior olive projects fibers to produces mild variations in rate with SPM. The the contralateral dentate nucleus and cerebellar palatal movement cycle in SPM exerts remote cortex via the inferior cerebellar peduncle. effects on tonic EMG activity of extremity muscles. However, lesions of the inferior cerebellar pedun- As shown by studies of blink reflex activity, jaw cle (base of the “triangle”) have not been associ- jerk, and masseter silent period, EPM had only ated with SPM. In animal models, it has been polysynaptic brainstem reflex abnormalities, demonstrated that the inferior olive possesses gap whereas SPM patients can have abnormalities of junctions which have a tendency to oscillate monosynaptic, oligosynaptic, and polysynaptic [39, 40]. The prevailing theory is that deafferenta- brainstem reflexes. tion increases the amplitude of the oscillations and/or causes them to be abnormally transmitted Pathophysiology of palatal to motorneurons to generate SPM [39, 41]. This myoclonus may be due to removal of the dentato–olivary The exact pathophysiology of palatal myoclonus GABAergic input to the inferior olive [42]. has been elusive. EPM is idiopathic and the lesion However, hypertrophic degeneration of the location is unknown. Classically, SPM is thought inferior olive is not always present in SPM cases, to be due to a lesion within a nucleus or tract in and hypertrophic degeneration may be present

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Figure 15.1 Coronal illustration of the brainstem showing nuclei and pathways that are important in To thalamus the pathogenesis of symptomatic Dentate palatal myoclonus (SPM). nucleus Red nucleus Dentato-olivary pathway disruption Cerebellum Central is believed to be the most cortex tegmental important lesion type for leading tract to SPM. The dorsolateral reticular formation has also been proposed as being involved in SPM pathogenesis. In SPM, the nucleus ambiguous provides nerve supply that provides the abnormal excitation to the levator palatini muscle.

Inferior cerebellar Inferior olivary peduncle nucleus

Dorsolateral reticular Nucleus formation ambiguus

without SPM [43, 44]. Rarely, other lesions are before a treatment trial. The list of drugs with associated with SPM [45]. Some authors have anecdotal success in palatal myoclonus includes suggested that a dentato–olivary lesion in the but is not limited to clonazepam, carbamazepine, brainstem may be associated with other areas baclofen, anticholinergics, tetrabenazine, valproic being affected, and the dysfunction in those areas acid, phenytoin, lamotrigine, sumatriptan, and more directly cause SPM [46]. The dorsolateral piracetam [8, 9, 48, 49]. Most commonly, palatal reticular formation of the brainstem has been pro- myoclonus fails these treatments. Because the ear posed as the top candidate for an alternative to clicking is so disabling when it occurs in palatal the inferior olive as a pathogenic site for the gen- myoclonus, surgical treatments including tensor esis of SPM [47] (Figure 15.1). Whichever site is veli palatini tenotomy and occlusion of the primary, abnormal oscillations reach the motor Eustachian tube have been tried with variable nuclei of the nucleus ambiguous to drive the leva- success [50]. Middle ear myoclonus has been tor palatini in SPM. The movements that are treated with tensor tympani and/or stapedius sometimes associated with SPM must also varia- tenotomy as well as placement of ventilation bly have their motor nuclei so affected. Rarely, tubes [11–13]. palatal myoclonus may occur as a tic in the setting Botulinum toxin injections have been reported of Tourette syndrome [47(a)] or as a psychogenic as effective in palatal myoclonus in a growing movement disorder [47(b)]. number of cases [51–62]. In particular, the obnoxious clicking sound experienced by certain Treatment cases is a common indication to use this therapy. Palatal myoclonus is difficult to treat. All Because the evidence is from case reports, it cannot treatment of palatal is “off-label” with little be considered to be proven effective or safe. Both of controlled evidence. As a result, standard dosages the botulinum toxin A preparations available in and precautions as well as the list of potential North America have been used. Starting doses for side effects for the drug should be considered Botox have been 4 and 5 units per side, while for

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Dysport has been 10–20 units per side. There is a Oculofacialmasticatory wide range of reported response durations from myorhythmia weeks to several months. Repeat injections have been required but may be associated with a higher Sporadic focal myoclonic jerks have been reported risk of side effects. The literature currently contains in Whipple’s disease, but segmental myoclonus is a lack of follow-up in these cases so it is not certain the most characteristic myoclonus form noted for how often injections are needed or in how many this disorder [63–65]. The common location for the instances the palatal myoclonus does not truly segmental myoclonus is an oculofacialmasticatory recur after the initial injection. Side effects may be distribution. This movement has also been termed significant and consist of nasal regurgitation, “myorhythmia” because of its <3 Hz frequency. dysarthria, dysphagia, among others. Other Treatment for the Whipple’s disease may improve considerations are, the myoclonus. A rostral brainstem tegmentum • Botulinum toxin is not yet proven safe nor effec- lesion location has been suggested for the patho- tive in palatal myoclonus physiology of this abnormal movement [66]. The • Injections should be performed by a qualified appearance of oculofacialmasticatory myorhythmia Ears, Nose, Throat surgeon should trigger an evaluation for Whipple’s disease. • Electromyography guidance is considered useful • Patients should be informed about the uncertainty/side effects of this therapy. Spinal segmental myoclonus

Spinal segmental systems may become hyperexcit- Branchial myoclonus able, often by viral infection, structural lesions, (excluding palatal) vascular insults, among other causes (Box 15.3) [2, 67–78]. The muscle jerks may be rhythmic or There are rare cases of branchial myoclonus in semi-rhythmic and occur at a typical frequency which the palate is not involved. The causes are range of 1–3 Hz. Classically, the myoclonus involves listed in Box 15.2 [2, 63]. The term comes from the one or several contiguous spinal myotomes and is branchial arch musculature on a developmental peculiarly resistant to supraspinal influences, such basis. These cases are usually limited to facial nerve as voluntary movement or sleep. However, a few muscles. It is presumed that the lesion is limited recent cases have been reported to be subject to in its distribution since it only causes movements in position, emotional distress, various stimuli, and a restricted muscle segment. Many clinical altered consciousness [79–81]. The vast majority of characteristics are similar to palatal myoclonus. cases have persistent movements, but some are However, the precise pathophysiology of branchial intermittent or even paroxysmal. Certain patients non-palatal myoclonus is unknown. Moreover, we have had their clinical manifestations change over do not know why palatal myoclonus is not time. Upper or lower extremities, or even trunk associated in these instances. muscles may be affected. Sometimes, pain with the muscle contractions is a significant symptom.

Box 15.2 Causes of segmental branchial Diagnosis and evaluation myoclonus (not involving palate) MRI of the whole spinal cord and brain is warranted • Trauma [2] to search for the segmental lesion responsible as well as other possible lesion sites (e.g. neoplasms). • HIV virus [2] Other testing may be needed to determine if a • Brainstem ischemic stroke [2] systemic or diffuse neurologic disorder is present • Whipple’s disease [63] that may help to explain the segmental myoclonus,

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such as vitamin B12 deficiency, HIV infection, Box 15.3 Causes of spinal segmental among others. Studies to exclude other physiological myoclonus types of myoclonus should be considered if doubt • Infection (viral-Herpes Zoster, HIV, Polio, Nipah [67] exists about the spinal generator [3]. This can • Stroke (infarct or hemorrhage) [2] include EEG, EEG back-averaging, SEP, and testing • Neoplasm [68] for elicitation of long-latency reflexes to nerve • Demyelination [2] stimulation. The results of the clinical neurophysi- • Neurodevelopmental abnormality [69] ology studies are discussed below. • Trauma [70] • Spondylosis [2] Clinical neurophysiology of spinal • Peripheral nervous system lesion (root, plexus, segmental myoclonus sympathetic ganglion) [2] Clinical neurophysiology studies have provided • Arteriovenous malformation [71] information that is consistent with a segmental • Neurodegenerative [72] generator. The surface EMG shows synchronous • Electrical injury [2] rhythmic or semirhythmic discharges in muscles supplied by the corresponding spinal segmental • Paraneoplastic syndrome [73] generator (Figure 15.2). The polygraphic surface • Intrathecal catheter [74] EMG study usually shows synchronous activation • Contrast media [75] of the affected muscles. The typical frequency is in • Amputation and soft tissue surgery [76] the range of 1–3 Hz with a broad reported range of • Spinal anesthesia [77] 0.2–8 Hz, and the typical surface EMG discharge • Syringomyelia [78] duration varies widely between 50 and −500 ms [60, 70, 78, 82]. Needle electromyography may Video 15.2 Segmental myoclonus show signs of denervation in lesioned segments, This patient presents with a post-thoracotomy but this is exceptional since the movements are stimulus-sensitive segmental myoclonus. [Video courtesy believed to depend on intact motorneurons. Spinal of Joseph Jankovic, MD, Houston, Texas] segmental myoclonus physiology is without evidence of abnormal cortical excitability [3]. No EEG abnormalities have been detected, back- averaging never elicits a cortical correlate, and no cortical waves are abnormal in the SEP. However, some responses to sensory stimulation are abnormal and may show insight into the segmental phys- http://bit.ly/tDPpCi iological defect. In spinal segmental myoclonus, mixed nerve stimulation can evoke EMG discharges in the affected muscles at latencies longer than Video 15.3 Segmental myoclonus 40 ms, but such findings are variable and the This patient presents with segmental myoclonus latency values vary from case to case. These reflex following a breast implant. [Video courtesy of Joseph Jankovic, MD, Houston, Texas] discharges may reflect hyperexcitability of polysynaptic pathways that contribute to the generation of the myoclonus [83, 84]. Somatosensory evoked spinal potential recovery curves were abnormal in a case of segmental myoclonus involving the L2–L4 myotomes. The authors interpreted this finding as suggesting that dorsal horn interneurons are abnormally hyperactive and are involved in the patho- http://bit.ly/tAiNTc physiology of spinal segmental myoclonus [85].

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Figure 15.2 A surface Left L5–S1 Segmental myoclonus EMG recording that shows left anterior Left tibialis and medial anterior gastrocnemius tibialis discharges from a patient with left L5–S1 spinal segmental Left myoclonus. Note medial the rhythmic and gastrocnemius synchronous character of the discharges.

50 mV 600 ms

Pathophysiology of spinal In later work, Davis et al. and Howell et al. segmental myoclonus separately demonstrated selective destruction of Early studies demonstrated that synchronous jerks small and medium-sized neurons in the spinal gray could develop in the muscles that were innervated matter at the appropriate level in their cases of by the same spinal segments that had also received spinal segmental myoclonus [91, 92]. Using these a lesion. Experimentally, the lesion was produced observations and their own, Parisi et al. argued that initially by 5% phenol in dogs by Turtschaninow altered inhibitory functions of the interneurons at in 1894 [86]. Supraspinal or infraspinal isolation the segmental level allowed anterior horn motor of the affected spinal segment did not alter neurons to be hyperexcitable enough to produce the movements. Proximal or distal sections of the spinal segmental myoclonus. It was also suggested corresponding nerve roots or motor nerves that such disruption of neuronal circuitry could eliminated the movements. L’Hermitte described a occur in different ways [93]. Peripheral lesions patient in case in. 1919 in which complete section have been associated with segmental myoclonus. of the spinal cord had occurred [87]. Campbell and In these instances, it is posited that central Garland reported cases in which there was a reorganization occurs at that spinal segment which presumed viral infection of the spinal cord [88]. produces the abnormal movements [94]. Pathological examination showed changes in the These combined observations allow us to spinal cord gray matter without obvious damage to speculate on how spinal segmental myoclonus is anterior horn cells. Shortly thereafter, in. 1959, generated, but our confidence needs to be tempered Luttrell et al. injected the virus of Newcastle disease by the lack of detail about our assertions and the into the spinal cord of cats which produce rhythmic significant remaining questions. It seems likely that myoclonus [89]. Topical penicillin applied to the segmental myoclonus can be produced by an spinal cord of cats elicits myoclonus with similar abnormal segmental generator that exists within results [90]. Cervical segmental myoclonus was contiguous levels of spinal gray matter which serve reported secondary to a C3–C5 spinal glioma in. contiguous myotomes. This concept also easily 1968. In this patient, the myoclonus was relatively incorporates the possibility of influences from unaffected by external stimuli and persisted during supraspinal or peripheral inputs. We know clinically sleep [68]. All these papers put forth the basic that such influences are real because of the concepts that were used in subsequent reporting of sometimes reported effects of emotional excitement spinal segmental myoclonus. and sensory stimuli. The abnormality in the

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segmental generator could be due to abnormal to more widespread areas similar to propriospinal circuitry in the interneurons of dorsal, intermediate, myoclonus physiology. or ventral gray matter of the spinal cord. There is Spinal segmental myoclonus can be caused by a considerable evidence that interneuron circuits, wide variety of pathological processes. Infectious/ when denied afferent input or have partial loss of inflammatory, neoplastic, and vascular lesions are intrinsic interneurons, begin to have abnormal common etiologies, but multiple other etiologies oscillations. In many cases, these changes may have been reported (Box 15.3) [2, 67–78]. How- occur through plasticity changes, accounting for ever, only a fraction of cases for any lesion type the delay between the segmental circuit lesion and result in segmental myoclonus. Most often, these clinical manifestations. It is presumed that these lesions cause the clinical syndrome of myelopathy abnormal oscillations are transmitted to anterior without involuntary movement. This suggests that horn neurons in the corresponding myotomes. The the lesion type is not nearly as important for gen- clinical result may be rhythmic or semirhythmic erating spinal segmental myoclonus as the particu- relatively low frequency movements of segmental lar profile of the interneuron lesion that is the myoclonus. Drug treatments, when effective, are result of the pathology. Moreover, segmental myo- able to dampen these transmitted oscillations by clonus in patients may change over the clinical augmenting still intact inhibitory mechanisms. course, and in some cases is modified or com- Other successful treatments may restore the pletely disappears with treatment. This may balance between oscillatory and non-oscillatory suggest that the interneuron circuit abnormality interneuron network activity. (ies) that causes spinal segmental myoclonus may Rothwell points out that abnormal activity in be capable of changing over time, perhaps through spinal interneurons may more often result in plasticity. rigidity and sustained contractions of muscle rather than the intermittent contractions of seg- Treatment mental myoclonus, although sometimes it results All treatments of spinal segmental myoclonus are in both [95]. He hypothesized that myoclonus off-label. Clonazepam, in dosages up to 6 mg daily, occurs when strong enough inhibitory mecha- is the favored drug for the initial choice in spinal nisms still exist so that the muscle activity stops segmental myoclonus but usually leads to only periodically and accounts for synchronization partial improvement when there is an effect [96]. among the myotomes. In addition, Rothwell Nevertheless, complete suppression of the believes that in some instances, pathologically myoclonus has been reported [94]. Levetiracetam altered motorneurons may have their intrinsic has recently been reported to provide relief [82, electrical properties affected to contribute to the 97]. Topiramate, also an antiseizure medication, abnormal oscillations [95]. has had some success [76]. Tetrabenazine is useful Spinal segmental myoclonus cases vary with in cases refractory to other treatments [76]. regard to how widespread, or how many segments Diazepam, carbamazepine, other antiseizure medi- or myotomes are involved in the jerking. The cation has been tried historically with no clear pat- Newcastle disease virus cat model of segmental tern of success. Botulinum toxin injections used for myoclonus demonstrated that the movements can the pain associated with spinal segmental be induced for several segments even though the myoclonus may be useful [98]. More recently, virus had not spread to those spinal interneuron botulinum toxin injections also have been reported segments [89]. It may be that the spinal interneuron to dramatically suppress the movements as well abnormality may induce a similar abnormality [79]. Since the disease process causing the above and below the initial segment through myoclonus sometimes evolves and has a natural entrainment of the otherwise normal segments. history to remit, one must be careful in determining For other cases, intersegmental fiber tracts (e.g. that a presumably symptomatic treatment cures the propriospinal) may carry the abnormal physiology underlying pathophysiological process.

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Diaphragmatic myoclonus [103]. EMG discharges have been reported over a wide range of 0.5–15 Hz but a 1–5 Hz range is the This disorder is believed to represent what was most common. The discharges often have some reported by Leeuwenhoek in 1723, who described irregularity, and vary in frequency and amplitude this movement disorder in himself [99]. He from discharge to discharge within a given case described himself as being “seized” by a violent enough to give the movement an irregular movement disorder around the diaphragm. In appearance, thus adding to its categorization as present day, fluoroscopy is necessary to diagnose “myoclonus.” The contractions observed by EMG diaphragmatic myoclonus, so it may be difficult are often bilateral and synchronous as would be to know exactly what afflicted the father of expected from the movement appearance, but in microscopy. Diaphragmatic myoclonus is referred certain instances more distant muscles from the to as involuntary repetitive brief contractions of diaphragm may not be synchronous or have a the diaphragm and other inspiratory muscles. different frequency. Certain authors have argued The movements are rhythmic or semirhythmic. that the higher frequency cases (>9 Hz) have clinical Numerous names for this disorder have been differences, but with a small number of cases used such as diaphragmatic flutter, respiratory this is not certain. The EMG discharge duration is myoclonus, Leeuwenhoek’s disease, as well as almost never below 100 ms and a range of other terms using convulsions, flutter-fibrillation, 100–300 ms is typical. Longer durations up to cramps, rumbles, pulsations, and spasms [100]. several hundred milliseconds are possible. Evidence Diaphragmatic myoclonus may just involve the of cortical hyperexcitability or dysfunction causing diaphragm or be associated with movements of diaphragmatic myoclonus is non-existent. other muscles which are involved with inspiration, scalenes; intercostal and abdominal muscles. The Pathophysiology of diaphragmatic oscillatory movements are usually bilateral and myoclonus synchronous between muscles. In most reported Most cases of diaphragmatic myoclonus are cases, the observation is made that these movements idiopathic. The known causes consist of encephalo- are superimposed on a normal breathing pattern myelitis, trauma, tardive forms, and “irritation” of [101]. In some cases, voluntary breath-holding or the phrenic nerve or diaphragm [104]. Neither the hyperventilation can alter or suppress diaphragmatic idiopathic nor the uncommon causes give much myoclonus [102]. However, there can be prominent insight with regard to pathophysiology of diaphrag- symptoms of epigastric pulsations, dyspnea, matic myoclonus. Various authors have offered hyperventilation, hiccups, and belching. Fluoro- arguments on an empiric basis with citing evidence scopy, in addition to confirming the diagnosis, can for where the generator should not be. The medul- also be used to study the relationship of normal lary respiratory center has been suggested for the breathing and symptoms to the involuntary origin of diaphragmatic myoclonus, since that such movements [100]. This condition can occur in an origin could explain involvement of multiple paroxysmal bursts lasting a few minutes or persist respiratory muscles that are innervated by multi- for several hours or days. Its presence during sleep is ple segments of the spinal cord [105]. An alterna- variable. Some case series show sensitivity to tive view suggests that it arises from more rostral sensory stimulation around the chest and abdomen, centers, while others believe that spinal inter- both in terms of triggering the movements or in neuron abnormalities create the movement and other cases suppressing them. recruitment of other muscles occurs via intersegmental pathways [101, 104]. A combination of Clinical neurophysiology these sources is also plausible. However, until more of diaphragmatic myoclonus direct information about the pathophysiology of Electromyographic studies have complemented the diaphragmatic myoclonus is available, both the information gained by fluoroscopy in these cases source and mechanism are unknown.

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Treatment tardive dyskinesia, axial dystonia, and “belly Treatment of diaphragmatic myoclonus is difficult, dancer’s dyskinesia” [84]. off-label, and the rare occurrence of this condition Symptoms of abdominal myoclonus can be only provides anecdotal reports on treatment similar to diaphragmatic myoclonus. Although efficacy. Therefore, neither effectiveness nor a side usually bilateral, significant asymmetry may occur. effect profile for a given patient can be reliably In contrast to diaphragmatic myoclonus, predicted, and caution is required. Clonazepam is abdominal myoclonus often involves more the most frequently cited symptomatic treatment widespread areas, such as paraspinal and proximal with favorable results, although it is often not a extremity muscles, even without involvement of complete response. Diazepam and phenytoin, the diaphragm by fluoroscopy [111, 112]. When sometimes given intravenously or orally, have had the diaphragm is not involved, voluntary limited success [100, 106]. Carbamazepine, gabap- breath-holding or hyperventilation produces less entin, and haloperidol have also had some efficacy dramatic changes on the physical appearance of [104, 107, 108]. Quinidine and Benzhexol have the movements. The myoclonus may begin each been reported to be effective in one case [109]. abruptly, be paroxysmal, sensitive to somatosensory Narcotics and muscle relaxants have been tried but stimulation of the trunk, and be present or absent are not effective. Lesion or block of the phrenic during sleep [113]. Emotional excitation has also nerve has been reported in a case where only the been reported to evoke an episode of the left side was affected [110]. The possible side effects movements. Patients may notice some effect of of these treatments need to be carefully considered body posture on the intensity, frequency, and even and monitored. Remissions do occur but are not the presence of the movements. predictable. Surface EMG studies may show similar discharges as what has been reported for diaphragmatic myoclonus. An example of surface EMG discharges Abdominal/truncal myoclonus in a case of abdominal myoclonus is shown in Figure 15.3. Discharge duration is most commonly Abdominal myoclonus is believed to be a form of between 50 and 400 ms and can be somewhat segmental myoclonus arising from the spinal cord, shorter when compared to diaphragmatic but it will be discussed separately due to some myoclonus [84, 113, 114]. The activation of distinct characteristics. Other names for this entity abdominal muscle is synchronous, although more are abdominal flutter and belly dance myoclonus distant muscles to the abdominal muscles may not [84]. It is distinguished from diaphragmatic myo- be synchronous. The involvement of paraspinal clonus by variable involvement of the diaphragm. and proximal extremity muscles is often best When the diaphragm is affected in abdominal myo- documented by electrode placement over these clonus, other muscles besides those involved with muscle groups. Stimulus sensitivity of these inspiration are involved. It may be difficult to deter- abnormal electromyographic discharges has been mine solely on clinical grounds whether there is documented [84]. Evidence of cortical hyperexcit- active diaphragmatic movement, since movement ability or dysfunction is non-existent. of the abdominal contents alone may secondarily Abdominal myoclonus is usually idiopathic. move the diaphragm. Fluoroscopy is an effective Cases with known causes are B12 deficiency, way to evaluate whether the diaphragm is involved. association with pregnancy, Graves’s disease and Assessment by diaphragmatic needle EMG may be syringomyelia [111, 114]. Clonazepam is cited as risky even by experienced electromyographers in being effective in suppressing the abdominal wall the presence of quick involuntary unpredictable movements [113, 114]. Other antiseizure agents diaphragm movements. Abdominal myoclonus have also been tried but assessing their effec- should also be distinguished from other quick tiveness is difficult. Spontaneous remission may movements of the abdominal wall such as seizure, occur.

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Abdominal myoclonus

Left internal intercostal muscles

Right internal intercostal muscles Left upper abdominal quadrant muscles Right upper abdominal quadrant muscles Left lower abdominal quadrant muscles Right lower abdominal quadrant muscles 250 mV 200 ms

Figure 15.3 A surface EMG recording that shows internal intercostal and abdominal muscle discharges from a patient with abdominal myoclonus. Note the semirhythmic and abrupt character of the discharges.

Conclusion particularly noted for being persistent. However, voluntary suppression and intermittency of typical The clinical spectrum of segmental myoclonus has palatal myoclonus movements has been observed grown in recent years. Propriospinal myoclonus is [115, 116]. These combined observations suggest usually considered to be a non-segmental type of the possibility that both clinically and physiologi- spinal myoclonus [96]. However, propriospinal cally, segmental myoclonus exhibits a spectrum. On myoclonus arises from similar lesion types as does one end of the spectrum, segmental myoclonus is spinal segmental myoclonus. It occurs in a paroxys- intermittent and stimulus sensitive, and on the mal fashion and is sensitive to sensory stimuli, other end is completely persistent and insensitive to while segmental myoclonus is usually considered modulation by any outside influence or stimuli. to be continuous and relative insensitive to stimuli More physiological information about segmental or mental state. The movement in propriospinal interneuron circuits will help us to understand the myoclonus may be a single jerk or a short train of clinical variability that is seen among segmental jerks with EMG discharge duration between 100 ms myoclonus patients. The ultimate goal will be to and a few seconds. Showing some clinical similarity use this information to design improved and more to propriospinal myoclonus, recent reports of spinal specific treatments for segmental myoclonus. segmental myoclonus have cases with intermittent jerks and sensitivity to both sensory stimuli, mental state, and movement [79, 81]. In some instances, References patients first develop movements on a sporadic or 1 Caviness JN, Alving LI, Maraganore DM, et al. 1999. paroxysmal manner, but then subsequently evolve The incidence and prevalence of myoclonus in Olmsted to more continuous segmental myoclonus [94]. County, Minnesota. Mayo Clin Proc. 74, 565–69. Abdominal and diaphragmatic myoclonus, as 2 Jankovic J, Pardo R. 1986. Segmental myoclonus. discussed above, typically have paroxysmal and Clinical and pharmacologic study. Arch Neurol. stimulus sensitivity present. Palatal myoclonus is 43:1025–31.

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3 Caviness JN. 2003. Clinical neurophysiology of 18 Legros B, Sheikoleslam Z, Hildebrand J, et al. 2001. myoclonus. In, Hallett M (ed) Movement Disorders. Palatal myoclonus appearing 8 years after removal of Handbook of Clinical Neurophysiology. Elsevier, a cerebellar low-grade astrocytoma. J Neurol Amsterdam, pp 521–48. 248:990–2. 4 Westmoreland BF, Sharbrough FW, Stockard JJ, et al. 19 Birbamer G, Buchberger W, Kampfl A, et al. 1993. 1983. Brainstem auditory evoked potentials in 20 Early detection of post-traumatic olivary hypertrophy patients with palatal myoclonus. Arch Neurol 40, by MRI. J Neurol 240:407–9. 155–58. 20 Revol A, Vighetto A, Confavreux C, et al. 1990. 5 Deuschl G, Mischke G, Schenck E, et al. 1990. [Oculo-palatal myoclonus and multiple sclerosis]. Rev Symptomatic and essential rhythmic palatal myo- Neurol (Paris) 146:518–21. clonus. Brain 113 (Pt 6):1645–72. 21 Pogorzelski R, Drozdowski W, Rogowski M. 2006. 6 Deuschl G, Toro C, Valls-Sole J, et al. 1994. Symptomatic Symptomatic palatal myoclonus with ear click after and essential palatal tremor. 1. Clinical, physiological tick-borne meningoencephalitis. Eur Arch Otorhino- and MRI analysis. Brain 117 (Pt 4):775–88. laryngol 263:711–13. 7 Deuschl G, Wilms H. 2002. Palatal tremor, The clinical 22 Phanthumchinda K. 1999. Syndrome of progressive spectrum and physiology of a rhythmic movement dis- ataxia and palatal myoclonus, a case report. J Med order. In Fahn S, et al. (eds) Myoclonus and Paroxysmal Assoc Thai 82:1154–7. Dyskinesias. Advances in Neurology. Lippincott 23 Suyama N, Kobayashi S, Isino H, et al. 1997. Williams & Wilkins, Philadelphia, pp 115–30. Progressive supranuclear palsy with palatal myo- 8 Wakata N, Sugimoto H, Iguchi H, et al. 2002. A case of clonus. Acta Neuropathol 94:290–3. voluntary palatal myoclonus with ear click, relation- 24 Hommet CD, De Toffol B, Cottier JP, et al. 1998. ship between palatal myoclonus and click. Eur Neurol Bilateral olivary hypertrophy and palatal myoclonus. 48:52–3. Surg Neurol 49:215–16. 9 Fabiani G, Teive HA, Sa D, et al. 2000. Palatal myo- 25 Okamoto Y, Mitsuyama H, Jonosono M, et al. 2002. clonus, report of two cases. Arq Neuropsiquiat Autosomal dominant palatal myoclonus and spinal 58:901–4. cord atrophy. J Neurol Sci 195:71–6. 10 Kutukcu Y, Imirzalioglu N, Odabasi Z, et al. 2003. 26 Yamanouchi H, Kasai H, Sakuragawa N, et al. 1991. Essential palatal myoclonus in monozygotic male Palatal myoclonus in Krabbe disease. Brain Dev twins. J Neurol 250:885–6. 13:355–8. 11 Bento RF, Sanchez TG, Miniti A, et al. 1998. Continuous, 27 Donaghy M, King RH, McKeran RO, et al. 1990. high-frequency objective tinnitus caused by middle ear Cerebrotendinous xanthomatosis, clinical, electro- myoclonus. Ear Nose Throat J 77:814–18. physiological and nerve biopsy findings, and response 12 Golz A, Fradis M, Netzer A, et al. 2003. Bilateral tinnitus to treatment with chenodeoxycholic acid. J Neurol due to middle-ear myoclonus. Int Tinnitus J 9:52–5. 237:216–19. 13 Golz A, Fradis M, Martzu D, et al. 2003. Stapedius 28 Tison F, Arne P, Henry P. 1989. Myoclonus and adult muscle myoclonus. Ann Otol Rhinol Laryngol coeliac disease. J Neurol 236:307–8. 112:522–4. 29 Martinez-Vila E, Martinez-Lage Alvarez P, Luquin 14 Yanagisawa T, Sugihara H, Shibahara K, et al. 1999. MR, et al. 1993. Palatal myoclonus and opioid Natural course of combined limb and palatal tremor peptides. Acta Neurol Scand 88:227–8. caused by cerebellar-brain stem infarction. Mov 30 Kurauchi T, Kaga K, Shindo M. 1996. Abnormalities Disord 14:851–4. of ABR and auditory perception test findings in 15 Sakai T, Oishi H. 2004. Olivary hypertrophy and acquired palatal myoclonus. Int J Neurosci palatal myoclonus. Arch Neurol 61:1965. 85:273–83. 16 Iwasaki Y, Kinoshita M, Ikeda K, et al. 1991. Palatal 31 Gautier JC, Blackwood W. 1961. Enlargement of the myoclonus following Behcet’s disease ameliorated by inferior olivary nucleus in association with lesions of ceruletide, a potent analogue of CCK octapeptide. the central tegmental tract or dentate nucleus. Brain J Neurol Sci 105:12–13. 84:341–61. 17 Brown SR, Walsh SA. 2004. Palatal myoclonus associ- 32 Boecker H, Kleinschmidt A, Weindl A, et al. 1994. ated with compression of the brain stem by an ecstatic Dysfunctional activation of subcortical nuclei in vertebral artery. Ann Otol Rhinol Laryngol palatal myoclonus detected by high-resolution MRI. 113:418–19. NMR Biomed. 7:327–9.

Albanese_c15.indd 232 12/24/2011 7:10:10 AM Segmental Myoclonus 233

33 Nitschke MF, Kruger G, Bruhn H, et al. 2001. Voluntary 47 Dietrichs E, Heier MS, Faye-Lund H, et al. 1999. Bulbar palatal tremor is associated with hyperactivation of myoclonus without palatal myoclonus. A hypothesis the inferior olive, a functional magnetic resonance on pathophysiology. Eur J Neurol 6:367–70. imaging study. Mov Disord 16:1193–5. 47(a) Adam OR, Ferrara JM, Jankovic J. 2009. Motor- 34 Haller S, Winkler DT, Gobbi C, et al. 2006. Prominent phonic tic mimicking essential palatal myoclonus. activation of the putamen during essential palatal Mov Disord 24:2030–2; tremor, a functional MR imaging case study. AJNR Am 47(b) Gupta A, Lang AE. 2009. Psychogenic movement J Neuroradiol 27:1272–4. disorders. Curr Opin Neurol 22(4):430–6. 35 Salamon-Murayama N, Russell EJ, Rabin BM. 1999. 48 Scott BL, Evans RW, Jankovic J. 1996. Treatment of Diagnosis please. Case 17, hypertrophic olivary degen- palatal myoclonus with sumatriptan. Mov Disord eration secondary to pontine hemorrhage. Radiology 11:748–51. 213:814–17. 49 Nasr A, Brown N. 2002. Palatal myoclonus respond- 36 Venturi F, Tampieri D, Brassard R, et al. 2001. ing to lamotrigine. Seizure 11:136–7. Hypertrophic olivary degeneration (HOD), An unu- 50 Ensink RJ, Vingerhoets HM, Schmidt CW, et al. sual way to degenerate. Neuroimage 17:7–8. 2003. Treatment for severe palatoclonus by occlusion 37 Goto N, Kakimi S, Kaneko M. 1988. Olivary enlarge- of the eustachian tube. Otol Neurotol 24:714–16. ment, stage of initial astrocytic changes. Clin 51 Deuschl G, Lohle E, Heinen F, et al. 1991. Ear click Neuropathol 7:39–43. in palatal tremor, its origin and treatment with 38 Koeppen AH, Barron KD, Dentinger MP. 1980. Olivary botulinum toxin. Neurology 41:1677–9. hypertrophy, histochemical demonstration of hydro- 52 Bryce GE, Morrison MD. 1998. Botulinum toxin lytic enzymes. Neurology 30:471–80. treatment of essential palatal myoclonus tinnitus. 39 Llinas R, Baker R, Sotelo C. 1974. Electrotonic J Otolaryngol 27:213–16. coupling between neurons in cat inferior olive. J 53 Jamieson DR, Mann C, O’Reilly B, et al. 1996. Ear Neurophysiol 37:560–71. clicks in palatal tremor caused by activity of the 40 Llinas R, Yarom Y. 1986. Oscillatory properties of levator veli palatini. Neurol 46:1168–9. guinea-pig inferior olivary neurones and their phar- 54 Varney SM, Demetroulakos JL, Fletcher MH, et al. macological modulation, an in vitro study. J Physiol 1996. Palatal myoclonus, treatment with Clostri- 376:163–82. dium botulinum toxin injection. Otolaryngol Head 41 Matsuo F, Ajax ET. 1979. Palatal myoclonus and Neck Surg 114:317–20. denervation supersensitivity in the central nervous 55 Saeed SR, Brookes GB. 1993. The use of clostridium system. Ann Neurol 5:72–8. botulinum toxin in palatal myoclonus. A prelimi- 42 Sotelo C, Gotow T, Wassef M. 1986. Localization of nary report. J Laryngol Otol 107:208–10. glutamic-acid-decarboxylase-immunoreactive axon 56 Cho JW, Chu K, Jeon BS. 2001. Case of essential terminals in the inferior olive of the rat, with special palatal tremor, atypical features and remarkable emphasis on anatomical relations between GABAergic benefit from botulinum toxin injection. Mov Disord synapses and dendrodendritic gap junctions. J Comp 16:779–82. Neurol 252:32–50. 57 Krause E, Leunig A, Klopstock T, et al. 2006. 43 Nishie M, Yoshida Y, Hirata Y, et al. 2002. Generation Treatment of essential palatal myoclonus in a of symptomatic palatal tremor is not correlated with 10-year-old girl with botulinum neurotoxin. Otol inferior olivary hypertrophy. Brain 125:1348–57. Neurotol 27:672–5. 44 Yang YW, Chang FC, Tsai CH, et al. 2005. Clinical and 58 Srirompotong S, Tiamkao S, Jitpimolmard S. 2002. magnetic resonance imaging manifestations of Holmes Botulinum toxin injection for objective tinnitus tremor. Acta Neurol Taiwan 14:9–15. from palatal myoclonus, a case report. J Med Assoc 45 Cerrato P, Grasso M, Azzaro C, et al. 2005. Palatal Thai 85:392–5. myoclonus in a patient with a lateral thalamic infarc- 59 Penney SE, Bruce IA, Saeed SR. 2006. Botulinum tion. Neurology 64:924–5. toxin is effective and safe for palatal tremor, a report 46 Kane SA, Thach WT. Palatal myoclonus and function of five cases and a review of the literature. J Neurol of the inferior olive, Are they related? In, Strata P 253:857–60. (ed.) Experimental Brain Research Series 17, The 60 Jero J, Salmi T. 2000. Palatal myoclonus and click- Olivocerebellar System in Motor Control. Springer, ing tinnitus in a 12-year-old girl – case report. Acta Berlin, Heidelberg, pp 427–60. Otolaryngol Suppl 543:61–2.

Albanese_c15.indd 233 12/24/2011 7:10:10 AM 234 Chapter 15

61 Pal PK, Lakshmi PS, Nirmala M. 2007. Efficacy and 77 Fores Novales B, Aguilera Celorrio L. 2009. Spinal complication of botulinum toxin injection in palatal myoclonus following intrathecal anaesthesia with myoclonus, experience from a patient. Mov Disord prilocaine. Anaesth Intensive Care 37:498–9. 22:1484–6. 78 Bagnato S, Rizzo V, Quartarone A, et al. 2001. 62 Laskawi R. 2008. The use of botulinum toxin in head Segmental myoclonus in a patient affected by and face medicine, an interdisciplinary field. Head syringomyelia. Neurol Sci 22:27–9. Face Med 4:5. 79 Lagueny A, Tison F, Burbaud P, et al. 1999. 63 Henning S, Tings T, Schmidt H, et al. 2006. A case Stimulus-sensitive spinal segmental myoclonus of cerebral Whipple’s disease initially presenting improved with injections of botulinum toxin type with isolated focal myoclonus. Eur J Neurol 13: A. Mov Disord 14:182–5. 659–61. 80 Massimi L, Battaglia D, Paternoster G, et al. 2009. 64 De Jonghe P, Martin JJ, Budka H, et al. 1979. Cerebral Segmental spinal myoclonus and metastatic cervical manifestations of Whipple’s disease. Acta Neurol Belg ganglioglioma, an unusual association. J Child Neurol 79:305–13. 24:365–9. 65 Schwartz MA, Selhorst JB, Ochs AL, et al. 1986. 81 Marrufo M, Politsky J, Mehta S, et al. 2007. Paroxysmal Oculomasticatory myorhythmia, a unique movement Kinesigenic Segmental Myoclonus due to a spinal cord disorder occurring in Whipple’s disease. Ann Neurol glioma. Mov Disord 22:1801–3. 20:677–83. 82 Keswani SC, Kossoff EH, Krauss GL, et al. 2002. 66 Stamboulis E, Kararizou E, Manta P, et al. 1995. Amelioration of spinal myoclonus with levetiracetam. Segmental myoclonus in Whipple’s disease. Electro- J Neurol Neurosurg Psychiat 73:457–8. myogr Clin Neurophysiol 35:113–16. 83 Hopkins AP, Michael WF. 1974. Spinal myoclonus. 67 Lam SK, Chua KB. 2002. Nipah virus encephalitis out- J Neurol Neurosurg Psychiatry 37:1112–15. break in Malaysia. Clin Infect Dis 34 Suppl 2, S48–51. 84 Kono I, Ueda Y, Araki K, et al. 1994. Spinal myoclonus 68 Garcin R, Rondot P, Guiot G. 1968. Rhythmic resembling belly dance. Mov Disord 9:325–9. myoclonus of the right arm as the presenting symptom 85 Di Lazzaro V, Restuccia D, Nardone R, et al. 1996. of a cervical cord tumour. Brain 91:75–84. Changes in spinal cord excitability in a patient with 69 Warren JE, Vidailhet M, Kneebone CS, et al. 2003. rhythmic segmental myoclonus. J Neurol Neurosurg Myoclonus in spinal dysraphism. Mov Disord 18: Psychiat 61:641–4. 961–4. 86 Turtschaninow P. 1894. Experimentella Studien uber 70 Calancie B. 2006. Spinal myoclonus after spinal cord den Ursprungsort einiger klinisch wichtiger toxischer injury. J Spinal Cord Med 29:413–24. Krampt-formen. Archiv fur Experimentelle Pathologie 71 Levy R, Plassche W, Riggs J, et al. 1983. Spinal myoclonus und Pharmakologie 34:208–46. related to an arteriovenous malformation. Response to 87 L’Hermitte J. 1919. La section totale de la moelle clonazepam therapy. Arch Neurol 40:254–5. dorsale. Tardy Pigelet, Bourges. 72 Shivapour E, Teasdall RD. 1980. Spinal myoclonus 88 Campbell AM, Garland H. 1956. Subacute myoclonic with vacuolar degeneration of anterior horn cells. spinal neuronitis. J Neurol Neurosurg Psychiat 19: Arch Neurol 37:451–3. 268–74. 73 Roobol TH, Kazzaz BA, Vecht CJ. 1987. Segmental 89 Luttrell CN, Bang FB, Luxenberg K. 1959. Newcastle rigidity and spinal myoclonus as a paraneoplastic disease encephalomyelitis in cats. II. Physiological syndrome. J Neurol Neurosurg Psychiat 50:628–31. studies on rhythmic myoclonus. AMA Arch Neurol 74 Ford B, Pullman SL, Khandji A, et al. 1997. Spinal Psychiat 81:285–91. myoclonus induced by an intrathecal catheter. Mov 90 Kao LI, Crill WE. 1972. Penicillin-induced segmental Disord 12:1042–5. myoclonus. I. Motor responses and intracellular 75 Micheli F, Gatto E, Lehkuniec E. 1991. [Spinal recording from motoneurons. Arch Neurol 26:156–61. myoclonus secondary to the intravenous administra- 91 Davis SM, Murray NM, Diengdoh JV, et al. 1981. tion of iodine contrast media.] Medicina (B Aires) Stimulus-sensitive spinal myoclonus. J Neurol 51:548–50. Neurosurg Psychiat 44:884–8. 76 Siniscalchi A, Mancuso F, Russo E, et al. 2004. Spinal 92 Howell DA, Lees AJ, Toghill PJ. 1979. Spinal myoclonus responsive to topiramate. Mov Disord internuncial neurones in progressive encephalomyelitis 19:1380–1. with rigidity. J Neurol Neurosurg Psychiat 42:773–85.

Albanese_c15.indd 234 12/24/2011 7:10:10 AM Segmental Myoclonus 235

93 Parisi L, Valente G, Calandriello E, et al. 1990. Spinal 105 Chen R, Remtulla H, Bolton CF. 1995. myoclonus, case report and physiopathogenetic Electrophysiological study of diaphragmatic hypothesis. Riv Neurol 60:160–3. myoclonus. J Neurol Neurosurg Psychiat 58:480–3. 94 Devetag Chalaupka F, Bernardi M. 1999. A case of 106 Phillips JR, Eldridge FL. 1973. Respiratory myoclonus segmental myoclonus in amputation stump, evi- (Leeuwenhoek’s disease). N Engl J Med. dence for spinal generator and physiopathogenetic 289:1390–5. hypothesis. Ital J Neurol Sci 20:327–31. 107 Vantrappen G, Decramer M, Harlet R. 1992. High- 95 Rothwell JC. 2002. Pathophysiology of spinal frequency diaphragmatic flutter, symptoms and myoclonus. In, Fahn S, et al. (eds) Myoclonus and treatment by carbamazepine. Lancet. 339:265–67. Paroxysmal Dyskinesias. Advances in Neurology. 108 Abio JG, de Freixo MF, Adan PV, et al. 2003. Aspectos Lippincott Williams & Wilkins, Philadelphia, pp 37–44. clinicos y terapeuticos de las mioclonias 96 Caviness JN, Brown P. 2004. Myoclonus, current con- diagragmaticas. Neurologia 18:473–77. cepts and recent advances. Lancet Neurol 3:598–607. 109 Iliceto G, Thompson PD, Day BL, et al. 1990. 97 Estraneo A, Saltalamacchia AM, Loreto V. 2007. Diaphragmatic flutter, the moving umbilicus Spinal myoclonus following herpes zoster radiculitis. syndrome, and “belly dancer’s” dyskinesia. Mov Neurol 68, E4. Disord. 5:15–22. 98 Polo KB, Jabbari B. 1994. Effectiveness of botulinum 110 Cvietusa PJ, Nimmagadda SR, Wood R, et al. 1995. toxin type A against painful limb myoclonus of spinal Diaphragmatic flutter presenting as inspiratory stri- cord origin. Mov Disord. 9:233–5. dor. Chest 107:872–5. 99 Larner AJ. 2005. Antony van Leeuwenhoek and the 111 Tsao JW, Cooper EC. 2003. Reflex-sensitive spinal description of diaphragmatic flutter (respiratory segmental myoclonus associated with vitamin B12 myoclonus). Mov Disord 20:917–18. deficiency. Neurol 61:867–8. 100 Young CR, Clapp L, Salcedo V, et al. 1995. 112 Young B, Driedger A, Wojcik J. 2007. Autoimmune Diaphragmatic myoclonus, diagnosis by fluoroscopy thyroid disease and segmental myoclonus. Mov and electromyography with response to phenytoin. Disord 22:434–6. South Med J 88:1270–3. 113 Dogan EA, Yuruten B. 2007. Spinal myoclonus asso- 101 Nakajima M, Hirayama K, Suzuki J, et al. 1986. ciated with vitamin B12 deficiency. Clin Neurol [Diaphragmatic myoclonus of spinal origin.] Rinsho Neurosurg 109:827–9. Shinkeigaku 26:13–19. 114 Gregoire SM, Laloux P, Hanson P, et al. 2006. 102 Espay AJ, Fox SH, Marras C, et al. 2007. Isolated Segmental spinal myoclonus and syringomyelia, diaphragmatic tremor, is there a spectrum in A case report. Acta Neurol Belg 106:37–40. “respiratory myoclonus”? Neurol 69:689–92. 115 Soso MJ, Nielsen VK, Jannetta PJ. 1984. Palatal 103 Kobayashi I, Tazaki G, Hayama N, et al. 2004. A case myoclonus. Reflex activation of contractions. Arch of the diaphragmatic flutter with an electromyo- Neurol 41:866–9. graphic study of the respiratory muscles. Tokai J Exp 116 Montagna P, Cirignotta F, Lugaresi E. 1983. Clin Med 29:151–4. Disappearance of palatal myoclonus during sleep. 104 Iriarte J, Narbona J, Garcia del Barrio L, et al. 2005. Sleep. 6:386–7. Diaphragmatic flutter after spinal cord trauma in a child. Neurol 65:1839.

Albanese_c15.indd 235 12/24/2011 7:10:10 AM CHAPTER 16 Other Jerks and Startles Codrin Lungu and Mark Hallett National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA

Introduction Sleep myoclonias and other physiologic myoclonias Hyperkinetic disorders that do not conveniently fit The hypnic jerk is part of the normal sleep–wake into the standard classification of movement transition motor phenomena. It consists of a single disorder are grouped in this chapter. They all short (<1 s), non-periodic, non-rhythmic whole involve excessive movement, a predisposition to body myoclonic jerk produced by contractions of startle, or a combination of the above. Some of the large and/or axial muscles, rarely accompanied by entities described are myoclonic in nature, others an utterance [4, 5]. These “startles” are often are various startle syndromes, and others are accompanied by a subjective sensation of falling. related to peripheral nerve pathology. We also Another normal sleep phenomenon is frag- include here otherwise unclassified jerks or startles. mentary myoclonus (or physiologic hypnic myoclonus), which consists of small multifocal jerks. It was first described by De Lisi in 1932 [6], Myoclonias and occurs not only in humans, but also in other species, notably dogs and cats [7]. These phenomena Myoclonus can be defined as a sudden, brief are very common, occurring in at least 70% of the movement. It can be positive, caused by muscle general population. Hypnic myoclonus has been contraction, or negative, due to brief loss of muscle investi gated electrophysiologically in a few small tonus [1]. Etiologic classifications can be complex studies. In a study of young male volunteers, and daunting, but considering broad categories, the Montagna et al., using electromyography (EMG), myoclonias can be divided into physiologic (jerks found that the jerks are associated with single occurring in certain circumstances in normal motor units or short bursts, lasting less than subjects) and symptomatic (as manifestations of 100 ms, occurring asynchronously in the different underlying disease) [2]. Inherited and segmental muscles investigated. Single motor units can myoclonus have been considered in earlier chapters mimic fasciculation potentials [8]. The jerks occur (Chapters 14 and 15, respectively), and we will not only at the transition from wakefulness to consider other entities. Epileptic myoclonus can sleep, but in all stages of sleep as well as in relaxed be classified separately as a standalone entity. wakefulness. They do, however, occur most Symptomatic myoclonus may be the most common frequently in stage I and in REM sleep [8, 9]. category of myoclonus [3]. Dagnino and collaborators conclude that the

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incidence of hypnic myoclonus appears inversely (commonly multiple sclerosis, vascular, or related to the degree of EEG synchronization, given neoplastic lesion), epilepsy, or a large number of the findings of reduced incidence with deeper iatrogenic causes. A number of folk remedies are stages of sleep. The muscles most reliably anecdotally reported to interrupt bouts of hiccups, displaying EMG activity are the distal limb and but no formal studies have been undertaken for facial muscles. No EEG correlate was found for the these. Our favorite remedy for common hiccups is hypnic jerks, both during direct analysis and with a slow continuous sipping of water, but for back-averaging techniques [8, 9, 10]. The findings intractable hiccups, more intervention is needed. of a normal peripheral nervous system and lack of The only FDA-approved pharmacologic interven- EEG correlates point to a likely brainstem generator tion for hiccups is chlorpromazine, a phenothiazine for hypnic myoclonus. antipsychotic, but other agents have been shown to While fragmentary myoclonus is a physiologic give potential benefit [14]. occurrence and does not require therapy, instances Other physiologic myoclonias include anxiety- of excessive fragmentary myoclonus have been induced myoclonus, exercise-induced myoclonus, described and are considered to be pathologic and benign infantile myoclonus with feeding [15]. [10, 11]. These may cause sleep onset insomnia, and can be representative of underlying pathology. Symptomatic (secondary) myoclonias Treatment consists of correction of the underlying Symptomatic myoclonus is the most common of cause, when present, and, if needed, symptomatic the broad etiologic categories of myoclonus, and it therapy, with clonazepam the agent most likely to manifests in the setting of an identifiable underlying provide relief. disorder. It is typically progressive and associated Singultus, or hiccups (or hiccoughs) consists of a with encephalopathy or ataxia. We are excluding sudden inspiration immediately followed by active from this category the myoclonias associated with glottis closure generating a characteristic sound. It an epileptic syndrome, in which seizures dominate, is essentially universal, but its physiologic purpose as these deserve a separate nosologic entity. is unknown. Physiologically it can be regarded as A wide variety of causes can be responsible for a slow, semirhythmic diaphragmatic myoclonus, symptomatic myoclonus [16, 17, 18]. Table 16.1 occurring at various intervals for each patient, presents the major categories of secondary between 4 and 60 per minute. A possible reflex arc (symptomatic) myoclonus. Some of the entities has been proposed, with the afferent arm including listed are covered in other chapters. the phrenic and vagus nerves, closing centrally in the brainstem, involving the respiratory and glottis closure centers, and an efferent arm consisting mainly of the phrenic nerve. Askenasy proposed as Video 16.1 Focal myoclonus a mechanism for hiccups a failure of reciprocal This is a 27-year-old patient who suffered of severe inhibition between inspiration and glottis closure, perinatal distress with early occurrence of seizures with the two phenomena occurring at the same that are now well controlled. The video shows a focal myoclonus of the left hand, with position-specific time [12]. Phylogenetically, singultus may repre- jerks of variable amplitude. [Video courtesy of the sent a persistent archaic motor pattern, shared with Neurophysiology Unit, Carlo Besta Institute, Milan, Italy] lower vertebrates. Its persistence in mammals, including humans, may be related to the generation of functions such as suckling and eupneic breathing [13]. Pathologic or excessive hiccups may be indicative of phrenic or vagus nerve irritation (caused, for example, by gastric, diaphragmatic, cardiac, or http://bit.ly/tiFiON mediastinal pathology), brainstem disturbance

Albanese_c16.indd 237 12/24/2011 5:44:56 PM Table 16.1 Causes of secondary myoclonus.

Category Entities

Metabolic storage disorders • Lafora body disease • Gangliosidosis (GM1 and GM2) • Tay–Sachs disease • Gaucher disease • Krabbe leukodystrophy • Neuronal ceroid lipofuscinosis • Sialidosis Spinocerebellar degenerations • Progressive myoclonic ataxia (Ramsey Hunt syndrome) • Friedreich ataxia • Ataxia-telangectasia • Adult spinocerebllar ataxias • Dentatorubropallidoluysian atrophy • Other spinocerebellar degenerations Basal ganglia degenerations • Wilson disease • Dystonia • Neurodegeneration with brain iron accumulation type I • Progressive supranuclear palsy • Multiple system atrophy • Parkinson disease • Corticobasal degeneration • Huntington disease Dementias • Alzheimer disease • Creutzfeldt–Jacob disease • Dementia with Lewy bodies • Frontotemporal dementia • Rett syndrome Infectious or post-infectious • Subacute sclerosing panencephalitis • Encephalitis lethargica • Arbovirus infections • Herpes simplex encephalitis • Human T-cell lymphotropic virus type I • HIV • Postinfectious encephalitis • Bacterial infections • Malaria • Syphilis • Cryptococcosis • Lyme disease • Progressive multifocal leukoencephalopathy Metabolic • Hyperthyroidism • Hepatic failure • Renal failure • Dialysis syndrome • Hyponatremia • Hypoglycemia • Non-ketotic hyperglycemia • Multiple carboxylase deficiency • Biotin deficiency • Mitochondrial • Hypoxia

(continued)

Albanese_c16.indd 238 12/24/2011 5:44:56 PM Table 16.1 (cont’d).

Category Entities

• Metabolic alkalosis • Vitamin E deficiency Toxic and drug-induced • Bismuth toxicity • Heavy metal toxicity • Methyl bromide • Serotonin syndrome • Gasoline inhalation • Toluene • Marijuana • Ecstasy • Cocaine Medication induced • Opioids • Selective serotonine reuptake inhibitors • Cyclic antidepressants • Monoamine oxidase inhibitors • Lithium • First- and second-generation antipsychotics • Anesthetic agents • Contrast media • Antiarrhythmics • Calcium channel blockers • Selected antibiotics Physical encephalopaties • Post-hypoxic (Lance–Adams syndrome) • Post-traumatic • Heat stroke • Electric shock • Decompression injury Focal nervous system damage • Stroke (ischemic or hemorrhagic) • Thalamotomy • Tumor • Trauma • Inflammation • Mobius syndrome • Developmental Malabsoptive syndromes • Celiac disease • Whipple disease Opsoclonus-myoclonus syndrome • Paraneoplastic • Idiopathic • Infectious Exaggerated startle syndromes • Hereditary • Sporadic Multiple system degenerations • Allgrove syndrome • DiGeorge syndrome • Membranous lipodystrophy Others • Hashimoto encephalopathy • Rasmussen encephalitis • Unknown cause

Adapted from [16], [2], and [15].

Albanese_c16.indd 239 12/24/2011 5:44:56 PM 240 Chapter 16

(A) (B) L. finger taps L. median nerve stimulation

100 μV 100 μV

C4 C4

L. F. Ext L. F. Flex

125 ms 250 ms

Figure 16.1 Enhanced somatosensory evoked potential was given to the left median nerve while the finger in cortical myoclonus. (A) Taps were delivered to the flexor muscles are tonically active. There may be a small left finger flexors and EMG and EEG are recorded. positive myoclonic response in the muscle, but the main The left finger flexor muscles show a myoclonic response response is negative myoclonus. Again the EEG shows (C reflex) and the EEG at the contralateral sensorimotor a giant somatosensory-evoked potential. (Courtesy of area (C4) shows a giant somatosensory evoked potential. Dr Camilo Toro, MD.) (B). In a similar recording situation, an electric shock

Pathophysiologically, secondary myoclonus is most Video 16.2 Generalized myoclonus often cortical in origin. Electrophysiologically, cortical myoclonus is associated with EMG discharges of This patient presents with post-anoxic generalized myoclonus. [Video courtesy of Joseph Jankovic, MD, short duration (typically <50 ms), EEG spikes closely Houston, Texas] preceding the myoclonus localized to the contralateral motor region for the muscle group involved, and enhanced early components of somatosensory- evoked potentials, often accompanied by enhanced C-reflexes [1, 19]. See Figure 16.1. Progressive myoclonic ataxia includes a heterogeneous group of progressive disorders http://bit.ly/sdU76e dominated by myoclonus and ataxia, and has some overlap with progressive myoclonic epilepsy. Most myoclonic-ataxic syndromes are caused by inborn (Video 16.2). Opsoclonus–myoclonus is a myoclonic errors of metabolism. Most commonly identified is syndrome associated with characteristic eye Unverricht–Lundborg myoclonus, or EPM1, due to a movements [21], and can be paraneoplastic or mutation in the gene for cystatin B. Dementing and associated with other causes. The paraneoplastic parkinsonian syndromes often include myoclonus in variety is most often associated with neuroblastoma their late stages, but early prominent myoclonus in children and with ovarian, lung, or breast cancer with parkinsonism usually suggests corticobasal in adults [22]. Rasmussen encephalitis is typically degeneration [20]. Periodic myoclonus associated associated with epilepsia partialis continua, but focal with rapidly progressive encephalopathy is suggestive myoclonus has also been described among of Creutzfeldt–Jacob disease. Post-anoxic myoclonus the various movement disorders caused by the can have a variety of forms, including action and condition [23]. negative myoclonus, and the same is also true for Treatment of symptomatic myoclonus rests other myoclonias induced by physical agents primarily on correction of the underlying cause,

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where possible [24]. Special mention in this regard Anatomically, the origin of the startle response is in is the opsoclonus–myoclonus syndrome. Of course, the medullopontine reticular formation, the nucleus an underlying tumor should be treated if identified. reticularis pontis oralis, as shown in both animal and Failing that, attention can be directed to the human studies [38, 39]. Functional imaging studies autoimmune nature of the illness. show changes in regional blood flow at this location Beyond correction of the underlying causes, with startle in normal subjects [40, 41]. In addition symptomatic treatment employs agents used to exaggerated magnitude of response to stimula- for treatment of myoclonus of any origin. tion, the abnormal startle also displays abnormal Benzodiazepines are the most widely used medi- habituation characteristics and this is the usual way cation class for myoclonus of most subtypes, of documenting the abnormality [42, 43]. with clonazepam the most frequently used. The Broadly, hyperekplexia can be subdivided antiepileptic valproate is also widely used, parti c- into hereditary hyperekplexia, secondary hyper- ularly for the treatment of cortical myoclonus [17]. ekplexia, and the culturally linked startle syn- Levetiracetam is a newer generation antie pileptic dromes, including Latah. with notable antimyoclonic activity. It modulates GABA-mediated neurotransmission and is effec- Hereditary hyperekplexia tive primarily in cortical myoclonus [25–28]. Hereditary hyperekplexia was first described in a γ-hydroxybutirate (GHB) modulates both GHB Dutch pedigree that demonstrated exaggerated receptors and GABA neurotransmission and has startle responses transmitted in an autosomal been shown to effectively treat certain types of dominant fashion [33]. Two different forms are myoclonus [29, 30]. Its use is strictly regulated due recognized since the first descriptions, a major and to the potential for abuse, and, at present, should a minor form. be considered only experimental. Other agents The major form is diagnosed by the presence of more rarely used for selected types of myoclonus the following cardinal features [44, 45]: include 5-hydroxytryptophan, tetrabenazine, • Generalized stiffness following birth, worsened zonisamide, and botulinum toxin [17, 18, 23, 24, by handling and disappearing in sleep, improving 31, 32]. Myoclonus can be very difficult to treat, in the first years of life [46] and it is often necessary to use more than one oral • Excessive startle with unexpected, particularly agent. Negative myoclonus can continue even with auditory, stimuli, without alteration of conscious- successful treatment of positive myoclonus, and ness, present from birth there are virtually no agents that influence negative • Brief (seconds) generalized stiffness following a myoclonus consistently. startle response, sometimes causing falls with preserved consciousness [47]. Minor hyperekplexia is characterized by exces- Startle syndromes sive startle without stiffness, and it can include excessive hypnic jerks and PLMS [48, 34]. These Exaggerated startle syndromes, or hyperekplexia, additional features can also be part of the major consist of an exaggerated motor response (some- form. Another characteristic feature for both forms times called a jump) to unexpected stimuli, most is the “head retraction response,” consisting of often auditory [33–35]. The startle reflex is a brisk, involuntary backward jerking of the head phylogenetically conserved physiological response with light face tapping [33, 49]. [36], and the exaggerated startle syndromes refer The first abnormal gene identified in relation to conditions with abnormally enhanced response, with hereditary hyperekplexia is a point mutation although quantification is often difficult [37]. in the α–1 subunit of the glycine receptor gene Clinically, a typical startle response consists of facial (GLRA1) [50, 51], and this remains the major grimacing, flexion of the neck and trunk, and raising genetic cause to date. Several missense and non- of the arms or generalized limb flexion [36, 2]. sense mutations have been identified as causing the

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disease, and exon deletions have also been found • Multiple sclerosis [69] to cause the phenotype [52]. Other genes known to • In-born errors of metabolism [70] be associated with hereditary hyperekplexia • Other genetic syndromes [71] include: SLC6A5, encoding the presynaptic glycine • Stiff-person syndrome. transporter 2; GLRB, encoding glycine receptor Increased startle is associated with anxiety and subunit β; GPHN, encoding the glycinergic cluster- other psychiatric pathology, particularly post- ing molecule gephryn; ARHGEF9, X-linked gene traumatic stress disorder (PTSD) [72]. Increased encoding collybistin [ [34, 45, 53–56]. startle is even sometimes used as a diagnostic Glycine is an inhibitory neurotransmitter in a aid for PTSD. Psychogenic hyper-startles have also number of spinal interneurons as well as medullo- been described [73, 74]. This category can overlap pontine reticular neurons. A lack of inhibitory with the culturally-linked startles described next, glycinergic neurotransmission can explain the and the classification has been the subject of exaggerated motor startle response in major extensive controversy in the literature. The hyperekplexia, given the common anatomophysi- differentiation of psychogenic from organic ologic substrate of the normal and pathologic etiologies can be difficult with hyperekplexia, but startle [37, 57]. In addition, abnormal Ia reciprocal organic startle has a specific EMG signature that inhibition in the spinal cord can explain the infan- can be helpful [43, 60]. tile hypertonia and the stiffness of major form hereditary hyperekplexia [58]. It should be noted Latah syndrome and other culturally- that the pathophysiology of the minor form of determined startle syndromes hyperekplexia is significantly different from the A number of culturally-determined startle major form, and many of the details remain syndromes have been described [75]. All involve unknown [59, 48, 60, 34, 2]. There is some con- non-habituating hyper-startle responses to auditory troversy in regard to the minor form, which might or tactile stimuli, and are associated with complex actually be a phenocopy of the major form on a but stereotyped motor or behavioral abnormalities psychogenic basis. following the startle reaction, lasting several seconds. Secondary hyperekplexia Latah is the syndrome described in Indonesia and Secondary, or symptomatic hyperekplexia, is due to Malaysia, known in the local culture since the 15th an identifiable underlying neurologic condition. century and in Western medicine since the late 19th Most cases described have involved various types of century [76]. Those affected exhibit exaggerated insult affecting the brainstem, which is in keeping startle responses accompanied by involuntary utter- with the pathophysiology of the syndrome and the ances, echolalia, echopraxia, and forced obedience, role of the medullopontine reticular structures. provoked by sudden touch or loud noises. The com- These have included: plex behavior following the startle can involve • Stroke [61] involuntary striking out, coprolalia, and an emo- • Encephalopathy [62, 63] tional response. Onset is typically in adulthood and • Malformations [64, 65] the episodes are often preceded by vivid dreams. • Extrinsic mechanical compression [66, 41]. The other culturally-bound startle syndromes In addition to brainstem pathology, other diffuse appear to represent the same entity in different cerebral insults or generalized disease states have cultural contexts. The Jumping Frenchmen of also been associated with symptomatic hyperek- Maine were described in 1878 by George Beard plexia. It is worth noting that in many of these [77] among French Canadian lumberjacks. Those cases the brainstem is also involved, blurring the affected exhibit a startle reaction consisting of distinction. Reported cases include: jumping, vocalizations, throwing objects, forced • Cerebral palsy [39, 67] obedience, echolalia, and echopraxia, provoked by • Stroke [68] loud noises or sudden commands or gestures [78].

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The other similar syndromes include Myriachit in • Onset of the movement disorder within days or Siberia, Imu in Japan, Goosey in Southern USA months (up to 1 year) after the injury. [79], and Ragin’ Cajuns in Louisiana [76]. These criteria are meant to be used as guidelines Given the striking similarity between all these only, and are not a strict requirement for classification syndromes, it is likely that they share a neurophysi- of a movement disorder as peripherally induced. ologic substrate. No physiology studies are available in any of these syndromes, so their classification Hemifacial spasm with the other startle syndromes is based on their Hemifacial spasm (HFS) is the best known clinical manifestation. One accepted view is that example of a peripherally-induced abnormal they represent an exaggerated startle syndrome movement. It consists of unilateral, involuntary, modulated by a cultural context determining socially intermittent, irregular, tonic or clonic synchro- acceptable behavior [80, 75], although overlap with nous contractions of muscles innervated by tic disorders, stereotypies and psychogenic condi- cranial nerve VII [86]. The extent of involvement tions can be argued [34]. is variable, but typically the periocular region is most severely (and earliest) involved. Chronic Treatment isolated eyelid myokymia is an important Treatment of hyperekplexia depends on the etiology differential diagnosis, as it is a benign condition When secondary causes are present, these should requiring no treatment [87]. be addressed. The psychogenic and culturally- Cases of bilateral HFS have been described, determined syndromes should theoretically benefit indicating that the contractions on the two sides are from psychotherapy and counseling. In the autoso- not synchronous. HFS is a sporadic disorder, mal-dominant hereditary forms genetic counseling although rare familial cases have been described, is important. In terms of pharmacotherapy, the and it is generally confined to the adult population. benzodiazepines have the highest chance of suc- While HFS is common, good epidemiologic data is cess, and clonazepam has been shown in a double scarce. In one study in Olmstead County, MN, the blind placebo-controlled study to be effective in prevalence was 14.5/100,000 in women and treating hyperekplexia [81]. Clonazepam facilitates 7.4/100,000 in men [88] and a Norwegian study GABAergic neurotransmission and appears to found the overall prevalence in Oslo to be 9.8/100, 000 compensate for the loss of glycine. [89]. It is more common in women and much more common in Asians [90]. In the vast majority of cases, HFS is associated Syndromes with peripheral injury with a vascular compression of the facial nerve [91]. Even when a direct insult to the nerve is not While most hyperkinetic movement disorders have found on imaging, it is likely that all cases involve a central nervous system causes, occasionally lesions degree of impingement on the facial nerve root, of the peripheral nervous system can cause abnor- and surgical exploration can find compressions that mal movements. A variety of insults can be had not been apparent on imaging. Most often the responsible for inducing abnormal movements, and insult consists of vascular compression by an ectatic, here we will cover the major syndromes. Criteria ectopic, aneurismal, or atherosclerotic anterior or have been proposed for diagnosing a movement posterior cerebellar artery or vertebral artery at the disorder as peripherally induced from a specific root exit zone [91–93]. In addition, the nerve injury, but these are arbitrary [82–85]: compression can be due to various cerebellopontine • Trauma severe enough to cause local symptoms angle tumors [94], arachnoid cyst [95], or parotid for at least 2 weeks or requiring medical evaluation tumors [96]. In some cases, an apparent trigger within 2 weeks after trauma event is identified as a precipitant, such as acute • Initial manifestations of the movement disorder facial palsy, but most cases start without an related to the site of injury identifiable precipitant.

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Pathophysiologically, the theory of ectopic excitation and ephaptic transmission asserts that the area of demyelination at the site of compression is the origin of abnormal discharges and the pathologic manifestations [97–99]. Ectopic discharges occur at sites of demyelination, and lateral transmission occurs between adjacent demyelinated nerves (ephaptic transmission), which explains the synchronous involvement of the entire face. This improves after surgical decompression of the nerve [100]. An alternative hypothesis is based on findings of a hyperexcitable blink reflex in HFS, and proposes that the discharges arise from a hyperexcitable facial nucleus, induced in turn by the peripheral lesion [101, 103]. Oral treatment of HFS can be attempted but it is usually of limited value. Agents attempted in the past included carbamazepine, baclofen, clonaze- Figure 16.2 BoNT injections for HFS. The arrowheads pam, anticholinergics, and first generation antip- mark the sites of injection, and the direction of the sychotics [104, 93]. Recently, two newer generation arrows mark the orientation of the needle. (Adapted antiepileptics have been added to the list of from Hallett, et al. [113] with permission from Neurotoxin Institute, University of California.) potentially useful agents: gabapentin [105, 106] and levetiracetam [107]. For most patients, the treatment of choice is Figure 16.2). Caution is needed with zygomaticus a focal injection of botulinum neurotoxin (BoNT). since excessive weakness will lead to an It has been shown to have efficacy around 95% in asymmetrical smile, a bad cosmetic result. open trials, and the benefit is maintained for Surgical treatment, consisting of vascular decom- years [108–111]. Treatments are repeated at pression, is used either as an additional option for approximately 3 month intervals (the duration of patients who do not have satisfactory results with action of the botulinum toxin) and are well BoNT, or as an initial approach, depending on the tolerated. The actual targeted sites of injection circumstances, patient preferences, availability of depend on the distribution of the spasm, but in an experienced surgical center, and identification of most patients it appears that targeting the a clear anatomic abnormality on imaging. Large periocular region (orbicularis oculi) is most long-term studies show a “cure” rate, generally effective, and sometimes diffuse hemifacial spasm defined by absence of residual spasms, between 90 is symptomatically controlled only with orbicularis and 95% [114, 115]. The most common complica- oculi injections. The pattern of injection in tions are temporary or permanent hearing loss or orbicularis oculi is the one commonly accepted for facial palsy, each of these permanent in approxi- treatment of all spasms, including blepharospasm mately 1% of cases [114, 116]. Intraoperative [112]. Injections are made away from the midline multimodal electrophysiology monitoring has been on the upper eyelid to avoid the levator, and away shown to increase the rate of success and help the from the medial aspect of the lower lid to avoid loss early detection of complications [117, 118]. of control of tears. (See Figure 16.2, white arrows.) In our practice, the next most common injections Focal myoclonus due to peripheral beyond the eye area are in the zygomaticus or nerve injuries rizorius when lateral and upward movement of the Several examples of focal myoclonus caused by corner of the mouth is prominent (black arrows in root, plexus, or peripheral nerve injuries have been

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Table 16.2 Focal myoclonus due to peripheral injuries.

Putative causative insult Myoclonus distribution Reference

Thoracic root tumor Paraspinal muscles [119] Lumbosacral radiculo-pathy Legs and hips [120] Lumbar laminectomy Proximal unilateral leg [120] Brachial plexus electrical injury Proximal arm [120] Femoral nerve sarcoma Quadriceps [121] Distal CN XI lesion Bilateral trapezius [122] Axillary radiotherapy; abduction trauma of the shoulder Upper limb [123] Deep peroneal nerve Trauma First dorsal interosseus muscle of the foot [124] Palmar digital branch of the median entrapment Hand [125] Long thoracic nerve trauma Scapula, serratus anterior muscle [126] Elbow/ulnar nerve trauma 4th dorsal interosseus muscle [127]

described. The Table 16.2 lists peripheral etiologies changed to CRPS type II [131]. CRPS type I was reported in association with focal myoclonus. described later when the same signs and symptoms Clinically, all myoclonias of peripheral origin are were identified in patients without an obvious confined to the muscles innervated by the affected pre-existing nerve injury, and named “reflex sym- nerves, and they are spontaneous and rhythmic, pathetic dystrophy” until changed to CRPS type I often persisting in sleep [128]. [132]. Several distinct pathogenic mechanisms Pathophysiologically, myoclonus induced by have been proposed, and the disorder has been peripheral lesions may well originate from the cor- regarded as a result of the interplay of neurologi- responding spinal segment by enhanced neuronal cal, inflammatory, and psychosomatic etiologies excitability, thus sharing a mechanism with spinal [133, 134]. segmental myoclonus [129, 2], although an origin A number of involuntary movements have been within the nerve itself is possible (analogous associated with CRPS. These include myoclonic to HFS). EMG investigation of a case of focal jerks, dystonia, tremor, and spasms [135–137, 128]. myoclonus caused by brachial plexus injury showed Dystonia is the most common of these movements, the origin of the contractions in a segment of the accounting for over 90% of the abnormal move- posterior cord of the brachial plexus [123]. ments in some series, and the onset interval is very Treatment of peripheral focal myoclonus relies variable, as is the course [138, 139]. It can lead to on correction of the underlying cause when possi- deforming spasms, and cases have been described ble and benzodiazepines for symptomatic therapy, of “mirror” involvement of the contralateral side of with limited success. Clonazepam is the agent most the body. frequently used. The mechanism for the movement disorders is the subject of extensive controversy. Primary Muscle spasms associated with CRPS sympathetic involvement certainly appears doubt- Complex regional pain syndrome (CRPS) is a ful. There are some data pointing to central genera- complex and controversial entity. It is currently tors for the involuntary movements in CRPS. divided into CRPS type I and type II, based on the Disturbances of body representation have been presence (type II) or absence (type I) of a presumed identified in CRPS patients, suggesting the possibil- causative nerve lesion [130]. Type II was described ity of a mechanism akin to other dystonias for the by Weir Mitchell in. 1872, and the name he gave it, abnormal movements [140]. Functional imaging in “causalgia”, has been in use until it was recently CRPS shows evidence of reorganization in central

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somatosensory and motor networks [141]. Other [155, 156], blepharospasm [157, 158], focal limb studies however did not show any abnormalities dystonia following electrical injury [159], and of sensorimotor integration in CRPS-associated dys- writer’s cramp [160]. tonia, while these are characteristic in other forms Of course, an association does not imply causal- of dystonia [142]. Furthermore, many of these ity, and it is fair to point out that the vast majority patients exhibit extensive psychiatric pathology and of patients who suffer trauma do not develop many of the movement disorders may in fact be dystonia, and most dystonias are not preceded by psychogenic [143, 144], leading to a strong current trauma. In many patients with genetically-proven of opinion questioning the organic nature of CRPS- familial dystonia, trauma is identified as a putative associated movements [145, 146]. The issue is far precipitant at the onset. In a study of 104 patients from settled and the subject of ongoing debate in with various forms of dystonia, 85% of the cases the neurologic community [147, 148]. We advise had a variable penetrance autosomal dominant that at the very least the abnormal movements genetic cause for the dystonia, yet over 16% of associated with CRPS be interpreted with caution. these cases identified a traumatic event preceding The treatment of CRPS-associated movement or precipitating the dystonia [154, 161]. Similar disorders remains largely unsatisfactory. Multimodal observations have been made by Jankovic and Van therapies have probably the highest chance of der Linden in a smaller series, where approximately working, and if a psychogenic component is found 25% of the patients identified preceding trauma to play a large role, cognitive behavioral therapy [162]. It is conceivable that trauma may trigger and other forms of psychotherapy should be focal dystonia in patients who go on to develop attempted. Various medications, including benzodi- generalized dystonia on a genetic basis. It is also azepines, antiepileptics, antidepressants, and oral possible that the association is an artifact of recall baclofen showed no sustained benefit [137]. bias, with the patients identifying otherwise Intrathecal baclofen showed benefit in 6 out of 7 unrelated trauma as related to the onset of the patients in a double-blind, placebo-controlled dystonia. crossover trial [149], but reproducibility of this Tarsy separated post-traumatic cervical dystonia finding has not yet been demonstrated. into two variants [163]. The first is an acute onset variant, occurring immediately after the trauma, Dystonia associated with peripheral which is different from idiopathic CD in that it is nerve injury associated with significant pain, does not respond Multiple reports exist of associations of peripheral to sensory tricks, and does not increase with activa- nerve pathology with dystonia. Caution is war- tion. The second is a delayed onset post-traumatic ranted when interpreting causality, as dystonia can CD, occurring 3–12 months after the trauma, and is often be the cause rather than the consequence of phenomenologically identical to idiopathic CD. peripheral nerve pathology. Reports include periph- Shoulder elevation in posttraumatic CD may repre- eral nerve lesions causing arm dystonia [82], sent a particular subset, associated with shoulder lumbar canal stenosis causing lower extremity dys- trauma or accessory nerve injury [164, 165].*** tonia [150], and ulnar nerve entrapment causing The mechanism by which peripheral trauma can hand dystonia [151, 152]. induce dystonia is not entirely elucidated and A more common and better characterized asso- remains the subject of ongoing study and contro- ciation is that of trauma with onset of dystonia. In versy. Peripheral lesions have been found to affect a large series of patients with dystonia, 9% of the signal patterns in higher order neurons in the spi- patients had had some form of preceding injury nal cord, brainstem, basal ganglia, and cortex, and [153]. In other series, a preceding neck trauma can induce chemical changes in thalamic nuclei was found in 10–20% of patients with cervical [166, 167]. This can lead to the abnormalities of dystonia (CD) [154, 85]. Preceding insults have sensorimotor integration known to have a causal also been described in oromandibular dystonia association with idiopathic dystonia [83, 128]. On

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the other hand, using paired pulse transcranial changes may occur at spinal or supraspinal levels magnetic stimulation, we have also found evidence as a result of altered sensory inputs following for the thesis that trauma simply acts as a precipi- deafferentation. Notably, the phenomenon of tant on a terrain of predisposing abnormal cortical phantom dyskinesia has also been described as a hyperexcitability, demonstrating abnormal intra- form of tardive dyskinesia in an amputated limb cortical facilitation not only in patients who had following exposure to metoclopramide [179] and developed focal dystonia after trauma, but also in as a psychogenic movement disorder [180]. their family members who were not affected at the No large treatment trials exist, but anecdotal time of the study [168]. reports of effective treatments can be found. Treatment of dystonia associated with peripheral Baclofen at 20–40 mg daily has successfully treated nerve injury relies on multidisciplinary approaches, the movements in two patients [181], and gabap- including physical and occupational therapy and entin was effective in one case [182]. It is not rehabilitation efforts. BoNT therapy can be sympto- known if BoNT could provide any relief. One matically effective as in other forms of dystonia, intriguing study reports highly effective treatment while oral medication has limited use. Deep brain with thalamic high-frequency stimulation targeting stimulation (DBS) is resorted to in cases unrespon- the nucleus ventralis posterolateralis [183]. This sive to other therapies, and while data exist showing involved older approaches to deep brain stimula- efficacy in traumatic dystonia [169, 170], it needs to tion, prior to the emergence of the modern hard- be remembered that, in general, secondary dystonia ware, but the paradigm may be worth revisiting, and post-traumatic dystonia are less responsive to particularly given the recent renewed interest in pallidal DBS than primary dystonia [171, 172]. thalamic DBS for limb dystonia.

“Jumpy stumps” “Belly dancer’s” dyskinesia Weir Mitchell is credited with the first description The term “belly dancer’s dyskinesia” describes a of “jumpy stumps,” in addition to the description of syndrome of involuntary writhing movements and causalgia, in the same 1872 work, referring to the contractions of the abdominal wall muscles [184]. spasms and jerks observed in the residual stumps The movements have a sinuous, writhing, and following amputation [131]. A number of cases flowing character, and typically entrain oscillatory have been described in the literature [173–176, movements of the umbilicus. Electrophysiology 127]. The movements consist of jerking or spasms data in the original report by Iliceto et al. showed of the amputation stump, sometimes associated alternating contractions in the recti and obliques, with tremor, and the term used to describe the characteristic movements is “jactitation”. Transient jerking of amputation stumps in the post-operative period is common, but the cases of pathologic Video 16.3 Belly dancer’s dyskinesia “jumpy stumps” involve prolonged abnormal Seven-year-old girl with history of quasi-continuous movement, lasting at times for decades [175]. The writhing, flowing movements of her abdominal muscles. A thoracic spinal glioma was identified on imaging. motor phenomena are typically associated with Surgical intervention was not successful. The case has severe pain, consistent with the phantom limb sen- been previously reported [185]. sory experience. The epidemiology is hard to estimate, given the rarity of the phenomenon, but incidence has been estimated at approximately 1% of amputations [177]. Pathophysiologically, most authors consider it a form of spinal segmental myoclonus, and electrophysiology studies appear to validate this http://bit.ly/spIGef proposal [174, 178, 127]. Functional and structural

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explaining the circular umbilical movements. abduction, and adduction patterns, typically at a Diaphragmatic flutter can be associated. rate of 1–2 Hz [193, 192]. Pain is commonly the The etiology of the condition is not clearly predominant symptom and the one prompting known. Many, but not all, patients have a history of medical contact in most patients. pre-existing local trauma [186]. A case has been The condition is rare and appears to be heterogene- reported in association with basal ganglia lesions ous, having been described in association with a from central pontine and extrapontine myelinolysis number of presumed causative insults, and on following hyponatremia [187]. A spinal generator occasion without an identified cause. Etiologies with a mechanism similar to segmental myoclonus described to date include: has been proposed and the scant electrophysiologic • generalized peripheral neuropathy of various data available is consistent with this [188]. etiologies – the most common cause [193–195], No systematic therapeutic studies exist. One with a particular subgroup of well-described group reported significant benefit with transcuta- association with HIV neuropathy [196, 197] neous electrical stimulation (TENS) [186], but it • lumbosacral root pathology, cauda equina mechan- should be noted that this case may have represented ical, or inflammatory pathology [192, 198, 193] a tardive syndrome, and spontaneous resolution • focal peripheral nerve pathology, including could have coincided with the therapeutic inter- trauma [199–203] vention [189]. BoNT has been successful in allevi- • unknown [192, 200, 193]. ating the movements in one case [190] and one The syndrome has also been described as a manifes- group reported long-term success in one patient tation of tardive movement disorders following with pallidal DBS [191]. exposure to neuroleptics [204]. The etiology of the condition is not clear. Painful legs and moving toes Peripheral nerve pathology is found in most cases, The syndrome of painful legs and moving toes was and some physiology studies pointed to peripheral described by Spillane and colleagues in 1971 [192]. generators, either in the nerves themselves or in Subsequently a number of case reports have the dorsal root ganglia [198]. Others proposed emerged, as well as several larger case series [193, distinct spinal oscillator circuits as the origin for the 194]. It is a condition of adulthood or late life, and movements [205, 206] and even supraspinal mech- consists of pain (usually the presenting symptom) anisms cannot be excluded. Involvement of the with a deep aching or burning quality, associated sympathetic nervous systems has been proposed as with involuntary, athetoid, “wriggling” movements a mechanism, primarily for the pain component of the toes, in a combination of flexion, extension, [207], and is supported by reports of sympathetic blockade effect in treating pain. It has been Video 16.4 Painful legs and moving toes proposed that the syndrome is in fact a heterogeneous entity, with several possible causes [205, 128]. Sixty-two year old woman, with 2 year history of involuntary toe movements. This is associated with A clinically and electrophysiologically similar sensations of discomfort and pain in the lower leg, condition has been described in which pain is and the movements disappear during voluntary absent, and this is referred to as “painless legs and activity. Additional history and examination revealed moving toes” [208]. It is less disabling than the an associated peripheral neuropathy. painful variant, and it also appears to be heterogeneous, but most cases described appear to have a central cause [209, 199]. No large treatment trials exist, as the condition is rare. Several oral medications have been tried with limited impact [93], and most positive results have been reported with Baclofen [199, 193, 210]. There http://bit.ly/srzjVT is one report of good results with adenosine

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infusion [211], but this has not been duplicated. described in a patient with anoxic encephalopathy Sympathetic blockade had been used with limited demonstrating thalamic anoxic lesions [223], and success [192, 199, 198, 193], but now is largely the movements resolved spontaneously, along with abandoned. Lumbar epidural block and epidural the lesions on imaging. The authors propose a basal cord stimulation have both been reported to ganglia-thalamic circuitry dysfunction analogous to provide short-term relief [212, 213]. After initial dystonia mechanisms as a possible etiology, but the disappointing results, botulinum toxin treatment is issue is far from settled. being revisited with promising results [214, 215]. It is notable that BoNT provides pain relief primar- References ily (through unknown mechanisms) and provides limited alleviation of the movements. 1 Shibasaki H, Hallett M. 2005. Electrophysiological studies of myoclonus. Muscle Nerve 31(2):157–74. Painful hands and moving fingers 2 Fahn S, Jankovic J, Hallett M, Jenner P (eds). 2007. A syndrome similar clinically to painful legs and Principles and Practice of Movement Disorders. moving toes, but affecting the upper extremity, has Churchill Livingstone Elsevier, pp 519–40. been described, with few cases reported to date 3 Caviness JN, Alving LI, Maraganore DM, et al. 1999. [216, 217]. The finger movements have similar The incidence and prevalence of myoclonus in Olmsted characteristics to the toe movements described County, Minnesota. Mayo Clin Proc 74(6):565–969. above, with flexion–extension combined with 4 Oswald I. Sudden bodily jerks on falling asleep. 1959. abduction–adduction, and pain in the limb is Brain 82(1):92–103. commonly associated. Most cases described had an 5 Montagna P. 2004. Sleep-related non epileptic motor disorders. J Neurol 251(7):781–94. associated peripheral nerve insult. The mechanism 6 De Lisi L. 1932. Su di un fenomeno motorio constante may involve central (spinal or supraspinal) plastic del sonno normale: le mioclonie ipniche fisiologiche. changes induced by peripheral nerve pathology, Riv Pat Ment 39:481–96. further resulting in abnormal sensorimotor 7 Gassel MM, Marchiafava PL, Pompeiano O. 1964. integration, which is ultimately responsible for the Phasic changes in muscular activity during desynchro- abnormal movements [206, 218]. Treatment is as nized sleep in unrestrained cats. An analysis of the difficult as in the case of painful legs and moving pattern and organization of myoclonic twitches. Arch toes, and recently BoNT has been reported effective Ital Biol 102:449–70. in one case [219]. 8 Montagna P, Liguori R, Zucconi M, et al. 1988. Physiological hypnic myoclonus. Electroencephalogr Clin Neurophysiol 70(2):172–6 Miscellaneous other jerks 9 Dagnino N, Loeb C, Massazza G, Sacco G. 1969. and startles Hypnic physiological myoclonias in man: an EEG–EMG study in normals and neurological patients. Episodic focal lingual spasms Eur Neurol 2(1):47–58. Several cases of episodic involuntary spasms of the 10 Vetrugno R, Plazzi G, Provini F, et al. 2002. Excessive tongue have been reported. One of the most fragmentary hypnic myoclonus: clinical and neuro- comprehensive descriptions is by Edwards et al. in a physiological findings. Sleep Med 3(1):73–6. woman exhibiting spontaneous episodic tightening 11 Broughton R. 1988. Pathological fragmentary myo- of one side of her tongue, lasting up to 2 minutes, clonus, intensified hypnic jerks and hypnagogic foot tremor: three unusual sleep-related movement disor- multiple times a day [220]. No etiology was apparent ders. In: Koella WP, Obal F, Shulz H, Visser P (eds) in this case. Other cases were presumed dystonic, Sleep. 1986. Fischer Verlag, Stuttgart, pp 240–3. although still without a clear etiology [221]. These 12 Askenasy JJ. About the mechanism of hiccup. Eur appear very similar to the cases dubbed “galloping Neurol 1992. 32(3):159–63. tongue”, consisting of rhythmic 3Hz partial tongue 13 Straus C, Vasilakos K, Wilson RJ, et al. 2003. A phylo- movements following head trauma [222]. A recent genetic hypothesis for the origin of hiccough. case of similar tongue movements has been Bioessays 25(2):182–8.

Albanese_c16.indd 249 12/24/2011 5:44:57 PM 250 Chapter 16

14 Marinella MA. 2009. Diagnosis and management of 30 Frucht SJ, Houghton WC, Bordelon Y, et al. 2005. hiccups in the patient with advanced cancer. J Support A single-blind, open-label trial of sodium oxybate for Oncol 7(4):122–7, 130. myoclonus and essential tremor. Neurol 65(12):1967–9. 15 Caviness JN. 2009. Pathophysiology and treatment 31 Penney SE, Bruce IA, Saeed SR. 2006. Botulinum of myoclonus. Neurol Clin 27(3):757–77. toxin is effective and safe for palatal tremor: a report 16 Marsden CD, Hallett M, Fahn S. 1982. The nosology of five cases and a review of the literature. J Neurol and pathophysiology of myoclonus. In Marsden CD, 253(7):857–60. Fahn S (eds) Movement Disorders. London: Butter- 32 Papapetropoulos S, Singer C. 2007. Botulinum toxin worths, pp 196–248. in movement disorders. Semin Neurol 27(2):183–94. 17 Caviness JN, Brown P. 2004. Myoclonus: current 33 Suhren O, Bruyn GW, Tuynman A. 1966. concepts and recent advances. Lancet Neurol Hyperekplexia: A hereditary startle syndrome. 3(10):598–607. J Neurol Sci 3, 577–604 18 Hallett M, Shibasaki H. Myoclonus and Myoclonic 34 Bakker MJ, van Dijk JG, van den Maagdenberg AM, Syndromes. 2008. In: Engel J Jr, Pedley TA (eds) Tijssen MA. 2006. Startle syndromes. Lancet Neurol Epilepsy: A Comprehensive Textbook. Lippincott 5(6):513–24. Williams & Wilkins, Philadelphia, vol. 3, pp 2765–70. 35 Meinck HM. 2006. Startle and its disorders. 19 Shibasaki H, Yamashita Y, Kuroiwa Y. 1978. Neurophysiol Clin 36(5–6):357–64. Electroencephalographic studies myoclonus. Brain 36 Wilkins DE, Hallett M, Wess MM. 1986. Audiogenic 101(3):447–60. startle reflex of man and its relationship to startle 20 Caviness JN. 2003. Myoclonus and neurodegenerative syndromes. A review. Brain 109 (Pt 3):561–73. disease – what’s in a name? Parkinsonism Relat Disord 37 Brown P, Rothwell JC, Thompson PD, et al. 1991. The 9(4):185–92. hyperekplexias and their relationship to the normal 21 McLean DR. 1970. Polymyoclonia with opsoclonus. startle reflex. Brain 114 (Pt 4):1903–28. Neurol 20(5):508–12. 38 Leitner DS, Powers AS, Hoffman HS. 1980. The neural 22 Dalmau J, Rosenfeld MR. 2008. Paraneoplastic syn- substrate of the startle response. Physiol Behav dromes of the CNS. Lancet Neurol 7(4):327–40. 25(2):291–7. 23 Browner N, Azher SN, Jankovic J. 2006. Botulinum 39 Brown P, Rothwell JC, Thompson PD, et al. 1991. New toxin treatment of facial myoclonus in suspected observations on the normal auditory startle reflex in Rasmussen encephalitis. Mov Disord 21(9):1500–2. man. Brain 114 (Pt 4):1891–1902. 24 Hu S-C, Frucht SJ, Shibasaki H. 2008. Myoclonus. In 40 Pissiota A, Frans O, Fredrikson M, et al. 2002. The Hallett M, Poewe W (eds) Therapeutics of Parkinson’s human startle reflex and pons activation: a regional Disease and Other Movement Disorders. Wiley- cerebral blood flow study. Eur J Neurosci 15(2): Blackwell, pp 363–70. 395–8. 25 Genton P, Gélisse P. 2000. Antimyoclonic effect of 41 Vetrugno R, Mascalchi M, Vella A, et al. 2007. Pontine levetiracetam. Epileptic Disord 2(4):209–12. hyperperfusion in sporadic hyperekplexia. J Neurol 26 Frucht SJ, Louis ED, Chuang C, Fahn S. 2001. A pilot Neurosurg Psychiat 78(9):1001–4. tolerability and efficacy study of levetiracetam in 42 Chokroverty S, Walczak T, Hening W. 1992. Human patients with chronic myoclonus. Neurol 57(6): startle reflex: technique and criteria for abnormal 1112–14. response. Electroencephalogr Clin Neurophysiol 27 Striano P, Manganelli F, Boccella P, et al. 2005. 85(4):236–42. Levetiracetam in patients with cortical myoclonus: a 43 Matsumoto J, Fuhr P, Nigro M, Hallett M. 1992. clinical and electrophysiological study. Mov Disord Physiological abnormalities in hereditary hyperek- 20(12):1610–14. plexia. Ann Neurol 32(1):41–50. 28 Kovács T, Farsang M, Vitaszil E, et al. 2009. 44 Tijssen MA, Shiang R, van Deutekom J, et al. 1995. Levetiracetam reduces myoclonus in corticobasal Molecular genetic reevaluation of the Dutch hyperek- degeneration: report of two cases. J Neural Transm plexia family. Arch Neurol 52(6):578–82. 116(12):1631–4. 45 de Koning-Tijssen MAJ, Rees MI. 2009. Hyperekplexia. 29 Priori A, Bertolasi L, Pesenti A, et al. 2000. gamma- In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. hydroxybutyric acid for alcohol-sensitive myoclonus GeneReviews [Internet]. Seattle (WA), University of with dystonia. Neurol 54(8):1706. Washington, Seattle. 1993–2007.

Albanese_c16.indd 250 12/24/2011 5:44:57 PM Other Jerks and Startles 251

46 Koning-Tijssen MA, Brouwer OF. 2000. Hyperekplexia 60 Brown P. 2002. Neurophysiology of the startle in the first year of life. Mov Disord 15(6):1293–6. syndrome and hyperekplexia. Adv Neurol 89, 153–9. 47 Andermann F, Keene DL, Andermann E, Quesney 61 Watson SR, Colebatch JG. 2002. Focal pathological LF. 1980. Startle disease or hyperekplexia: further startle following pontine infarction. Mov Disord delineation of the syndrome. Brain 103(4):985–997. 17(1):212–18. 48 Tijssen MA, Vergouwe MN, van Dijk JG, et al. 2002. 62 Kellett MW, Humphrey PR, Tedman BM, Steiger MJ. Major and minor form of hereditary hyperekplexia. 1998. Hyperekplexia and trismus due to brainstem Mov Disord 17(4):826–30. encephalopathy. J Neurol Neurosurg Psychiat 49 Shahar E, Brand N, Uziel Y, Barak Y. 1991. Nose 65(1):122–5. tapping test inducing a generalized flexor spasm: a 63 van de Warrenburg BP, Cordivari C, Brown P, Bhatia hallmark of hyperexplexia. Acta Paediatr Scand KP. 2007. Persisting hyperekplexia after idiopathic, 80(11):1073–7. self-limiting brainstem encephalopathy. Mov Disord 50 Shiang R, Ryan SG, Zhu YZ, et al. 1993. Mutations in 22(7):1017–20. the alpha 1 subunit of the inhibitory glycine receptor 64 Chaves-Vischer V, Pizzolato GP, Hanquinet S, et al. cause the dominant neurologic disorder, hyperek- 2000. Early fatal pontocerebellar hypoplasia in prema- plexia. Nat Genet 5(4):351–8. ture twin sisters. Eur J Paediatr Neurol 4(4):171–6. 51 Shiang R, Ryan SG, Zhu YZ, et al. 1995. Mutational 65 Goraya JS, Shah D, Poddar B. 2002. Hyperekplexia in analysis of familial and sporadic hyperekplexia. Ann a girl with posterior fossa malformations. J Child Neurol 38(1):85–91. Neurol 17(2):147–49. 52 Brune W, Weber RG, Saul B, et al. 1996. A GLRA1 66 Salvi F, Mascalchi M, Bortolotti C, et al. 2000. null mutation in recessive hyperekplexia challenges Hypertension, hyperekplexia, and pyramidal paresis the functional role of glycine receptors. Am J Hum due to vascular compression of the medulla. Neurol Genet 58(5):989–97. 55(9):1381–4. 53 Rees MI, Lewis TM, Kwok JB, et al. 2002. 67 Oguro K, Aiba H, Hojo H. 2001. Different responses to Hyperekplexia associated with compound heterozy- auditory and somaesthetic stimulation in patients gote mutations in the beta-subunit of the human with an excessive startle: a report of pediatric experi- inhibitory glycine receptor (GLRB). Hum Mol Genet ence. Clin Neurophysiol 112(7):1266–72. 11(7):853–60. 68 Fariello RG, Schwartzman RJ, Beall SS. 1983. 54 Rees MI, Harvey K, Ward H, et al. 2003. Isoform het- Hyperekplexia exacerbated by occlusion of posterior erogeneity of the human gephyrin gene (GPHN), thalamic arteries. Arch Neurol 40(4):244–6. binding domains to the glycine receptor, and mutation 69 Ruprecht K, Warmuth-Metz M, Waespe W, Gold R. analysis in hyperekplexia. J Biol Chem. 2002. Symptomatic hyperekplexia in a patient with 278:24688–96. multiple sclerosis. Neurol 58(3):503–4. 55 Rees MI, Harvey K, Pearce BR, et al. 2006. Mutations 70 Macaya A, Brunso L, Fernández-Castillo N, et al. in the gene encoding GlyT2 (SLC6A5) define a pre- 2005. Molybdenum cofactor deficiency presenting as synaptic component of human startle disease. Nat neonatal hyperekplexia: a clinical, biochemical and Genet 38(7):801–6. genetic study. Neuropediatrics 36(6):389–94. 56 Davies JS, Chung SK, Thomas RH, et al. 2010. The 71 Stephenson JB, Hoffman MC, Russell AJ, et al. 2005. glycinergic system in human startle disease: a genetic The movement disorders of Coffin-Lowry syndrome. screening approach. Front Mol Neurosci 23:3, 8. Brain Dev 27(2):108–13. 57 Tijssen MA, Schoemaker HC, Edelbroek PJ, et al. 72 Yetkin S, Aydin H, Ozgen F. 2010. Polysomnography 1997. The effects of clonazepam and vigabatrin in in patients with post-traumatic stress disorder. hyperekplexia. J Neurol Sci 149(1):63–7. Psychiat Clin Neurosci 64(3):309–17. 58 Floeter MK, Andermann F, Andermann E, et al. 1996. 73 Thompson PD, Colebatch JG, Brown P, et al. 1992. Physiological studies of spinal inhibitory pathways in Voluntary stimulus-sensitive jerks and jumps mimick- patients with hereditary hyperekplexia. Neurol ing myoclonus or pathological startle syndromes. Mov 46(3):766–72. Disord 7(3):257–62. 59 Tijssen MA, Padberg GW, van Dijk JG. 1996. The star- 74 Grillon C, Baas J. 2003. A review of the modulation of tle pattern in the minor form of hyperekplexia. Arch the startle reflex by affective states and its application Neurol 53(7):608–13. in psychiatry Clin Neurophysiol 114(9):1557–79.

Albanese_c16.indd 251 12/24/2011 5:44:57 PM 252 Chapter 16

75 Simons RC. 1996. Boo! Culture, experience and the 94 Gálvez-Jiménez N, Hanson MR, Desai M. 2001. startle reflex. Oxford University Press. Unusual causes of hemifacial spasm. Semin Neurol 76 Tanner CM, Chamberland J. 2001. Latah in Jakarta, 21(1):75–83. Indonesia. Mov Disord 16(3):526–9. 95 Mastronardi L, Taniguchi R, Caroli M, et al. 2009. 77 Beard G. 1978. Remarks upon jumpers or jumping Cerebellopontine angle arachnoid cyst: a case of Frenchmen. J Nerv Ment Dis 5, 526. hemifacial spasm caused by an organic lesion other 78 Saint-Hilaire MH, Saint-Hilaire JM. 2001. Jumping than neurovascular compression: case report. Frenchmen of Maine. Mov Disord 16(3):530. Neurosurgery. 65(6): E. 1205. 79 Massey EW. 1984. Goosey patients: relationship to 96 Behbehani R, Hussain AE, Hussain AN. 2009. Parotid jumping Frenchmen, Myriachit, Latah and tic convul- tumor presenting with hemifacial spasm. Ophthal sif. N C Med J. 45(9):556–8. Plast Reconstr Surg 25(2):141–2. 80 Simons RC. 1980. The resolution of the Latah para- 97 Nielsen VK. 1984. Pathophysiology of hemifacial dox. J Nerv Ment Dis 168(4):195–206. spasm: I. Ephaptic transmission and ectopic excita- 81 Tijssen MA, Voorkamp LM, Padberg GW, van Dijk JG. tion. Neurol 34(4):418–26. 1997. Startle responses in hereditary hyperekplexia. 98 Nielsen VK. 1984. Pathophysiology of hemifacial Arch Neurol 54(4):388–93. spasm: II. Lateral spread of the supraorbital nerve 82 Schott GD. 1985. The relationship of peripheral reflex. Neurol 34(4):427–31. trauma and pain to dystonia. J Neurol Neurosurg 99 Nielsen VK. 1985. Electrophysiology of the facial Psychiat 48(7):698–701. nerve in hemifacial spasm: ectopic/ephaptic excita- 83 Jankovic J. 1994. Post-traumatic movement disorders: tion. Muscle Nerve 8(7):545–55. central and peripheral mechanisms. Neurol 100 Nielsen VK, Jannetta PJ. 1984. Pathophysiology of 44(11):2006–14. hemifacial spasm: III. Effects of facial nerve decom- 84 Cardoso F, Jankovic J. 1995. Peripherally induced pression. Neurol 34(7):891–7. tremor and parkinsonism. Arch Neurol 52(3):263–70. 101 Møller AR, Jannetta PJ. 1984. On the origin of 85 Jankovic J. 2009. Peripherally induced movement synkinesis in hemifacial spasm: results of intracranial disorders. Neurol Clin 27(3):821–32. recordings. J Neurosurg 61(3):569–76. 86 Wang A, Jankovic J. 1998. Hemifacial spasm: clinical 102 Møller AR. 1987. Hemifacial spasm: ephaptic trans- findings and treatment. Muscle Nerve. 21(12): mission or hyperexcitability of the facial motor 1740–7. nucleus? Exp Neurol 98(1):110–19. 87 Banik R, Miller NR. 2004. Chronic myokymia limited 103 Roth G, Magistris MR, Pinelli P, Rilliet B. 1990. to the eyelid is a benign condition. J Neuroophthalmol Cryptogenic hemifacial spasm. A neurophysio- 24(4):290–2. logical study. Electromyogr Clin Neurophysiol 88 Auger RG, Whisnant JP. 1990. Hemifacial spasm in 30(6):361–70. Rochester and Olmsted County, Minnesota:1960 to. 104 Hughes EC, Brackmann DE, Weinstein RC. 1980. 1984. Arch Neurol 47(11):1233–4. Seventh nerve spasm: effect of modification of 89 Nilsen B, Le KD, Dietrichs E. 2004. Prevalence of hemi- cholinergic balance. Otolaryngol Head Neck Surg facial spasm in Oslo, Norway. Neurol 63(8):1532–3. 88(4):491–9. 90 Wu Y, Davidson AL, Pan T, Jankovic J. 2010. Asian 105 Bandini F, Mazzella L. 1999. Gabapentin as treat- over-representation among patients with hemifacial ment for hemifacial spasm. Eur Neurol 42(1): spasm compared to patients with cranial-cervical 49–51. dystonia. J Neurol Sci 298:61–3. 106 Daniele O, Caravaglios G, Marchini C, et al. 2001. 91 Tan EK, Chan LL. 2004. Clinico-radiologic correlation Gabapentin in the treatment of hemifacial spasm. in unilateral and bilateral hemifacial spasm. J Neurol Acta Neurol Scand 104(2):110–12. Sci 222(1–2):59–64. 107 Deleu D. 2004. Levetiracetam in the treatment of 92 Digre K, Corbett JJ. 1988. Hemifacial spasm: differen- idiopathic hemifacial spasm. Neurol;62(11):2134–5. tial diagnosis, mechanism, and treatment. Adv Neurol 108 Simpson DM, Blitzer A, Brashear A, et al. 2008. 49:151–76. Assessment: Botulinum neurotoxin for the treat- 93 Esper CD, Aia PG, Cloud LJ, Factor SA. 2008. Cramps ment of movement disorders (an evidence-based and spasms. In Hallett M, Poewe W, eds. Therapeutics review), report of the Therapeutics and Technology of Parkinson’s Disease and Other Movement Disorders. Assessment Subcommittee of the American Academy Chichester, Wiley Blackwell; 363–70. of Neurol 70(19):1699–1706.

Albanese_c16.indd 252 12/24/2011 5:44:57 PM Other Jerks and Startles 253

109 Defazio G, Abbruzzese G, Girlanda P, et al. 2002. 123 Banks G, Nielsen VK, Short MP, Kowal CD. 1985. Botulinum toxin A treatment for primary hemifacial Brachial plexus myoclonus. J Neurol Neurosurg spasm: a 10-year multicenter study. Arch Neurol Psychiat 48(6):582–4. 59(3):418–20. 124 Assal F, Magistris MR, Vingerhoets FJ. 1998. Post- 110 Bentivoglio AR, Fasano A, Ialongo T, et al. 2009. traumatic stimulus suppressible myoclonus of Outcome predictors, efficacy and safety of Botox and peripheral origin. J Neurol Neurosurg Psychiat Dysport in the long-term treatment of hemifacial 64(5):673–5. spasm. Eur J Neurol 16(3):392–8. 125 Martinez MS, Fontoira M, Celester G, et al. 2001. 111 Cillino S, Raimondi G, Guépratte N, et al. 2010. Long- Myoclonus of peripheral origin: case secondary to a term efficacy of botulinum toxin A for treatment of digital nerve lesion. Mov Disord 16(5):970–4. blepharospasm, hemifacial spasm, and spastic 126 Camerota F, Celletti C, Paoloni M, et al. 2006. entropion: a multicentre study using two drug-dose Myoclonus of the scapula after acute long thoracic escalation indexes. Eye (Lond). 24(4):600–7. nerve lesion: a case report. Mov Disord 21(1):71–3. 112 Hallett M. 2009. http://www.neurotoxininstitute. 127 Tyvaert L, Krystkowiak P, Cassim F, et al. 2009. com/chapter_blepharospasm.asp Myoclonus of peripheral origin: two case reports. 113 Hallett M, Jankovic J, Silberstein SD (eds). 2009. Mov Disord 24(2):274–7. A Multi specialty Guide to the Use of Botulinum 128 Fahn S, Jankovic J, Hallett M, Jenner P (eds.). 2007. Neurotoxins Revised Edition. Neurotoxin Institute, Principles and Practice of Movement Disorders. School of Medicine, University of California at Irvine. Churchill Livingstone Elsevier, pp 577–88. 114 Yuan Y, Wang Y, Zhang SX, et al. 2005. Microvascular 129 Di Lazzaro V, Restuccia D, Nardone R, et al. 1996. decompression in patients with hemifacial spasm: Changes in spinal cord excitability in a patient with report of 1200 cases. Chin Med J (Engl) rhythmic segmental myoclonus. J Neurol Neurosurg 118(10):833–6. Psychiat 61(6):641–4. 115 Hyun SJ, Kong DS, Park K. 2010. Microvascular 130 Stanton-Hicks M, Jänig W, Hassenbusch S, et al. decompression for treating hemifacial spasm: lessons 1995. Reflex sympathetic dystrophy: changing learned from a prospective study of 1,174 operations. concepts and taxonomy. Pain 63(1):127–33. Neurosurg Rev.33:325–34. 131 Mitchel SW. 1872. Injuries of nerves and their 116 Samii M, Günther T, Iaconetta G, et al. 2002. consequences. Philadelphia, JB Lippincott. Microvascular decompression to treat hemifacial 132 Evans JA. 1946. Reflex sympathetic dystrophy. Surg spasm: long-term results for a consecutive series of Clin North America 26(3):780–90. 143 patients. Neurosurg 50(4):712–18 133 Schwartzman RJ, Alexander GM, Grothusen J. 2006. 117 Huang BR, Chang CN, Hsu JC. 2009. Intraoperative Pathophysiology of complex regional pain syndrome. electrophysiological monitoring in microvascular Expert Rev Neurother 6(5):669–81. decompression for hemifacial spasm. J Clin Neurosci 134 de Mos M, Sturkenboom MC, Huygen FJ. 2009. 16(2):209–13. Current understandings on complex regional pain 118 Sekula RF Jr, Bhatia S, Frederickson AM, et al. 2009. syndrome. Pain Pract 9(2):86–99. Utility of intraoperative electromyography in micro- 135 Marsden CD, Obeso JA, Traub MM, et al. 1984. vascular decompression for hemifacial spasm: a Muscle spasms associated with Sudeck’s atrophy after meta-analysis. Neurosurg Focus 27(4): E10. injury. Br Med J (Clin Res Ed). 2886412:173–6. 119 Sotaniemi KA. 1985. Paraspinal myoclonus due to 136 Schwartzman RJ, Kerrigan J. 1990. The movement spinal root lesion. J Neurol Neurosurg Psychiat disorder of reflex sympathetic dystrophy. Neurol 48(7):722–3. 40(1):57–61. 120 Jankovic J, Pardo R. 1986. Segmental myoclonus. 137 Bhatia KP, Bhatt MH, Marsden CD. 1993. The Clinical and pharmacologic study. Arch Neurol causalgia-dystonia syndrome. Brain 116 (Pt 4): 43(10):1025–31. 843–51. 121 Said G, Bathien N. 1977. [Rhythmic quadriceps 138 van Rijn MA, Marinus J, Putter H, van Hilten JJ. myoclonia related to sarcomatous involvement of 2007. Onset and progression of dystonia in complex the crural nerve] Rev Neurol (Paris) 133(3):191–8. regional pain syndrome. Pain 130(3):287–93. 122 Glocker FX, Deuschl G, Volk B, et al. 1986. Bilateral 139 Oaklander AL. 2004. Progression of dystonia in myoclonus of the trapezius muscles after distal lesion complex regional pain syndrome. Neurol of an accessory nerve. Mov Disord 11(5):571–5. 63(4):751.

Albanese_c16.indd 253 12/24/2011 5:44:57 PM 254 Chapter 16

140 Bultitude JH, Rafal RD. 2010. Derangement of body 155 Koller WC, Wong GF, Lang A. 1989. Posttraumatic representation in complex regional pain syndrome: movement disorders: a review. Mov Disord report of a case treated with mirror and prisms. Exp 4(1):20–36. Brain Res 204:409–18. 156 Schrag A, Bhatia KP, Quinn NP, Marsden CD. 1999. 141 Schwenkreis P, Maier C, Tegenthoff M. 2009. Atypical and typical cranial dystonia following dental Functional imaging of central nervous system procedures. Mov Disord 14(3):492–6. involvement in complex regional pain syndrome. 157 Grandas F, Elston J, Quinn N, Marsden CD. 1988. AJNR Am J Neuroradiol 30(7):1279–84. Blepharospasm: a review of 264 patients. J Neurol 142 van Rijn MA, van Hilten JJ, van Dijk JG. 2009. Neurosurg Psychiat 51(6):767–72. Spatiotemporal integration of sensory stimuli in 158 Defazio G, Livrea P. 2002. Epidemiology of primary complex regional pain syndrome and dystonia. blepharospasm. Mov Disord 17(1):7–12. J Neural Transm 116(5):559–65. 159 Tarsy D, Sudarsky L, Charness ME. 1994. Limb dys- 143 Verdugo RJ, Ochoa JL. 2000. Abnormal movements tonia following electrical injury. Mov Disord in complex regional pain syndrome: assessment of 9(2):230–2. their nature. Muscle Nerve 23(2):198–205. 160 Marsden CD, Sheehy MP. 1990. Writer’s cramp. 144 Reedijk WB, van Rijn MA, Roelofs K, et al. 2008. Trends Neurosci 13(4):148–53. Psychological features of patients with complex 161 Fletcher NA, Harding AE, Marsden CD. 1990. regional pain syndrome type I related dystonia. Mov A genetic study of idiopathic torsion dystonia in the Disord 23(11):1551–9. United Kingdom. Brain 113 (Pt 2):379–95. 145 Ochoa JL, Verdugo RJ. 1995. Reflex sympathetic 162 Jankovic J, Van der Linden C. 1988. Dystonia and dystrophy. A common clinical avenue for somato- tremor induced by peripheral trauma: predisposing form expression. Neurol Clin 13(2):351–63. factors. J Neurol Neurosurg Psychiat 51(12):1512–19. 146 Ochoa JL. 1999. Truths, errors, and lies around 163 Tarsy D. 1998. Comparison of acute- and delayed- “reflex sympathetic dystrophy” and “complex onset posttraumatic cervical dystonia. Mov Disord regional pain syndrome”. J Neurol 246(10):875–9. 13(3):481–5. 147 Munts AG, Van Rootselaar AF, Van Der Meer JN, 164 Thyagarajan D, Kompoliti K, Ford B. 1998. Post- et al. 2008. Clinical and neurophysiological charac- traumatic shoulder ‘dystonia’: persistent abnormal terization of myoclonus in complex regional pain postures of the shoulder after minor trauma. Neurol syndrome. Mov Disord 23(4):581–7. 51(4):1205–7. 148 Lang AE, Angel M, Bhatia K, et al. 2009. Myoclonus 165 Cossu G, Melis M, Melis G, et al. 2004. Persistent in complex regional pain syndrome. Mov Disord abnormal shoulder elevation after accessory nerve 24(2):314–16 injury and differential diagnosis with post- 149 van Hilten BJ, van de Beek WJ, Hoff JI, et al. 2000. traumatic focal shoulder-elevation dystonia: Intrathecal baclofen for the treatment of dystonia in report of a case and literature review. Mov Disord patients with reflex sympathetic dystrophy. N Engl 19(9):1109–11. J Med 343(9):625–30. 166 Goetz CG, Pappert EJ. 1992. Trauma and movement 150 Al-Kawi MZ. 1987. Focal dystonia in spinal stenosis. disorders. Neurol Clin 10(4):907–19. Arch Neurol 44(7):692–3. 167 de Ceballos ML, Baker M, Rose S, et al. 1986. Do 151 Ross MH, Charness ME, Lee D, Logigian EL. 1995. enkephalins in basal ganglia mediate a physiological Does ulnar neuropathy predispose to focal dystonia? motor rest mechanism? Mov Disord 1(4):223–33. Muscle Nerve 18(6):606–11. 168 Bohlhalter S, Leon-Sarmiento FE, Hallett M. 2007. 152 Charness ME, Ross MH, Shefner JM. 1996. Ulnar Abnormality of motor cortex excitability in neuropathy and dystonic flexion of the fourth and peripherally induced dystonia. Mov Disord 22(8): fifth digits: clinical correlation in musicians. Muscle 1186–9. Nerve 19(4):431–7. 169 Zhang JG, Zhang K, Wang ZC, et al. 2006. Deep brain 153 Sheehy MP, Marsden CD. 1980. Trauma and pain in stimulation in the treatment of secondary dystonia. spasmodic torticollis. Lancet. 18171:777–8. Chin Med J (Engl). 119(24):2069–74. 154 Fletcher NA, Harding AE, Marsden CD. 1991. The 170 Pretto TE, Dalvi A, Kang UJ, Penn RD. 2008. A pro- relationship between trauma and idiopathic torsion spective blinded evaluation of deep brain stimulation dystonia. J Neurol Neurosurg Psychiat 54(8): for the treatment of secondary dystonia and primary 713–17. torticollis syndromes. J Neurosurg 109(3):405–9.

Albanese_c16.indd 254 12/24/2011 5:44:57 PM Other Jerks and Startles 255

171 Woehrle JC, Blahak C, Kekelia K, et al. 2009. Chronic 187 Roggendorf J, Burghaus L, Liu WC, et al. 2007. Belly deep brain stimulation for segmental dystonia. dancer’s syndrome following central pontine and Stereotact Funct Neurosurg. 87(6):379–84. extrapontine myelinolysis. Mov Disord 22(6):892–4. 172 Ostrem JL, Starr PA. 2008. Treatment of dystonia 188 Tamburin S, Idone D, Zanette G. 2007. Belly dancer’s with deep brain stimulation. Neurotherapeutics myoclonus and chronic abdominal pain: pain-related 5(2):320–30. dysinhibition of a spinal cord central pattern genera- 173 Canestrini L, Ederli A. 1958. [Late clonus of the tor? Parkinsonism Relat Disord 13(5):317–20. amputation stump.] Riv Neurol 28(5):496–508. 189 Jabre M, Bejjani BP. 2006. Etiological and 174 Steiner JC, DeJesus PV, Mancall EL. 1974. Painful therapeutical observations in a case of belly dancer’s jumping amputation stumps: pathophysiology of a dyskinesia. Mov Disord 21(9):1536. “sore circuit”. Trans Am Neurol Assoc 99, 253–5. 190 Lim EC, Seet RC. 2009. Botulinum toxin injections to 175 Marion MH, Gledhill RF, Thompson PD. 1989. treat belly dancer’s dyskinesia. Mov Disord 24(9):1401. Spasms of amputation stumps: a report of 2 cases. 191 Schrader C, Capelle H, Kinfe T, Krauss JK. 2009. Mov Disord 4(4):354–8. Pallidal deep brain stimulation in “belly dancer’s 176 Kulisevsky J, Martí-Fàbregas J, Grau JM. 1992. dyskinesia”. Mov Disord 24(11):1698–700. Spasms of amputation stumps. J Neurol Neurosurg 192 Spillane JD, Nathan PW, Kelly RE, Marsden CD. 1971. Psychiat 55(7):626–7. Painful legs and moving toes. Brain 94(3):541–56. 177 Carlen PL, Wall PD, Nadvorna H, Steinbach T. 1978. 193 Dressler D, Thompson PD, Gledhill RF, Marsden CD. Phantom limbs and related phenomena in recent 1994. The syndrome of painful legs and moving toes. traumatic amputations. Neurol 28(3):211–17. Mov Disord 9(1):13–21. 178 Devetag Chalaupka F, Bernardi M. 1999. A case of 194 Alvarez MV, Driver-Dunckley EE, Caviness JN, et al. segmental myoclonus in amputation stump: evi- 2008. Case series of painful legs and moving toes: dence for spinal generator and physiopathogenetic clinical and electrophysiologic observations. Mov hypothesis. Ital J Neurol Sci 20(5):327–31. Disord 23(14):2062–6. 179 Jankovic J, Glass JP. 1985. Metoclopramide-induced 195 Montagna P, Cirignotta F, Sacquegna T, et al. 1983. phantom dyskinesia. Neurol 35(3):432–5. “Painful legs and moving toes” associated with 180 Zadikoff C, Mailis-Gagnon A, Lang AE. 2006. A case polyneuropathy. J Neurol Neurosurg Psychiat of a psychogenic “jumpy stump”. J Neurol Neurosurg 46(5):399–403. Psychiat 77(9):1101. 196 Pitágoras de Mattos J, Oliveira M, André C. 1999. 181 Iacono RP, Linford J, Tourian A, Sandyk R. 1987. Painful legs and moving toes associated with Baclofen in the treatment of post-amputation neuropathy in HIV-infected patients. Mov Disord autonomous stump movements. Eur Neurol 26(3): 14(6):1053–4. 141–4. 197 Mattos JP, Rosso AL, Correa RB, Novis SA. 2002. 182 Mera J, Martinez-Castrillo JC, Mariscal A, et al. 2004. Movement disorders in 28 HIV-infected patients. Arq Autonomous stump movements responsive to Neuropsiquiatr 60(3-A):525–30. gabapentin. J Neurol 251(3):346–347. 198 Nathan PW. 1978. Painful legs and moving toes: 183 Mazars G, Merienne L, Cioloca C. 1980. Control of evidence on the site of the lesion. J Neurol Neurosurg dyskinesias due to sensory deafferentation by means Psychiat 41(10):934–9. of thalamic stimulation. Acta Neurochir Suppl 199 Bermejo PE, Zabala JA. 2008. “Painless legs and (Wien). 30, 239–43. moving toes” syndrome due to spinal cord compres- 184 Iliceto G, Thompson PD, Day BL, et al. 1990. sion. Eur Spine J. 17 Suppl 2, S294–5. Diaphragmatic flutter, the moving umbilicus syn- 200 Defazio G, Livrea P. 2002. Epidemiology of primary drome, and “belly dancer’s” dyskinesia. Mov Disord blepharospasm. Mov Disord 17(1):7–12. 5(1):15–22. 201 Mitsumoto H, Levin KH, Wilbourn AJ, Chou SM. 185 Shamim EA, Hallett M 2007. Intramedullary spinal 1990. Hypertrophic mononeuritis clinically present- tumor causing “belly dancer syndrome”. Mov Disord ing with painful legs and moving toes. Muscle Nerve 22(11):1673–4. 13(3):215–21. 186 Linazasoro G, Van Blercom N, Lasa A, et al. 2005. 202 Pla ME, Dillingham TR, Spellman NT, et al. 1996. Etiological and therapeutical observations in a case of Painful legs and moving toes associates with tarsal belly dancer’s dyskinesia. Mov Disord 20(2): tunnel syndrome and accessory soleus muscle. Mov 251–3. Disord 11(1):82–6.

Albanese_c16.indd 255 12/24/2011 5:44:57 PM 256 Chapter 16

203 Zinnuroglu M, Ozkayran T. 2010. Painful legs and 213 Takahashi H, Saitoh C, Iwata O, et al. 2002. Epidural moving toes following a traumatic medial plantar spinal cord stimulation for the treatment of painful nerve injury. Mov Disord 25(1):133–5. legs and moving toes syndrome. Pain 96(3):343–5. 204 Sandyk R. 1990. Neuroleptic-induced “painful legs 214 Eisa M, Singer C, Sengun C, et al. 2008. Treatment and moving toes” syndrome: successful treatment of painful limbs/moving extremities with botulinum with clonazepam and baclofen. Ital J Neurol Sci toxin type A injections. Eur Neurol 60(2):104–6. 11(6):573–6. 215 Schoffer K. 2010. Painful leg moving toes treated 205 Schoenen J, Gonce M, Delwaide PJ. 1984. Painful legs with botulinum toxin type A: a video report. Mov and moving toes: a syndrome with different physio- Disord 25(6):776–7. pathologic mechanisms. Neurol 34(8):1108–12. 216 Verhagen WI, Horstink MW, Notermans SL. 1985. 206 Ebersbach G, Schelosky L, Schenkel A, et al. 1998. Painful arm and moving fingers. J Neurol Neurosurg Unilateral painful legs and moving toes syndrome Psychiat 48(4):384–5. with moving fingers – evidence for distinct oscilla- 217 Funakawa I, Mano Y, Takayanagi T. 1987. Painful tors. Mov Disord 13(6):965–8. hand and moving fingers. A case report. J Neurol 207 Drummond PD, Finch PM. 2004. Sympathetic nerv- 234(5):342–3. ous system involvement in the syndrome of painful 218 Supiot F, Gazagnes MD, Blecic SA, Zegers de Beyl D. legs and moving toes. Clin J Pain 20(5):370–4. 2002. Painful arm and moving fingers: clinical fea- 208 Walters AS, Hening WA, Shah SK, Chokroverty S. tures of four new cases. Mov Disord 17(3):616–18. 1993. Painless legs and moving toes: a syndrome 219 Singer C, Papapetropoulos S. 2007. A case of pain- related to painful legs and moving toes? Mov Disord less arms/moving fingers responsive to botulinum 8(3):377–9. toxin a injections. Parkinsonism Relat Disord 209 Papapetropoulos S, Singer C. 2006. Painless legs 13(1):55–6. moving toes in a patient with Wilson’s disease. Mov 220 Edwards M, Schott G, Bhatia K. 2003. Episodic focal Disord 21(4):579–80. lingual dystonic spasms. Mov Disord 18(7):836–7. 210 Tan AK, Tan CB. 1996. The syndrome of painful legs 221 Lees AJ, Blau JN, Schon F. 1986. Paroxysmal and moving toes – a case report. Singapore Med J hemiglossal twisting. Lancet 28510:812–13. 37(4):446–7. 222 Keane JR. 1984. Galloping tongue: post-traumatic, 211 Guieu R, Sampiéri F, Pouget J, et al. 1994. Adenosine episodic, rhythmic movements. Neurol 34(2): in painful legs and moving toes syndrome. Clin 251–2. Neuropharmacol. 17(5):460–9. 223 Kim DG, Oh SH, Kim HS, et al. 2009. Episodic 212 Okuda Y, Suzuki K, Kitajima T, et al. 1998. Lumbar dystonic spasm of the bilateral edge of the tongue epidural block for ‘painful legs and moving toes’ syn- during a coma following anoxic encephalopathy. drome: a report of three cases. Pain 78(2):145–7. J Clin Neurosci 16(9):1252–3.

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Albanese_p06.indd 257 12/24/2011 7:13:24 AM CHAPTER 17 Clinical and Pathophysiological Features of Cerebellar Dysfunction Giuliana Grimaldi and Mario Manto Fonds National de la Recherche Scientifique (FNRS): Neurologie ULB-Erasme, Brussels, Belgium

Anatomical background somesthetic, vestibular, acoustic, visual, and cortical through the mossy fibers arising from a large The cerebellum overlies the posterior parts of the spectrum of ipsilateral and contralateral sources. pons and medulla, occupying a large part of the Granule cells present about four to five dendrites posterior fossa. Structurally, the cerebellum consists and a thin unmyelinated T-shaped axon whose of four pairs of nuclei – from medial to lateral: branches constitute the parallel fibers running fastigial, globosus, emboliformis, and dentate – between the Purkinje neurons [5]. Inhibitory embedded in white matter, and surrounded by a interneurons are located both in the molecular cortical mantle of gray matter [1]. (basket cells and stellate cells) and in the granular The cerebellar cortex is composed of Purkinje layer (Lugaro cells and Golgi cells). Their function cells, granule cells, and inhibitory interneurons is to balance the excitatory activity targeting the (Figure 17.1). The cortex is organized in a trilayer Purkinje cells (Figure 17.1). structure with the Purkinje cell layer (ganglionic Nucleofugal fibers are excitatory except for the layer) separating the outer molecular from the inferior olive. Nuclei project back to the cerebellar inner granular layer. Purkinje cells are GABAergic cortex. These nucleocortical projections reach mostly and thus inhibitory [2]. Their axons project to the the areas from which they receive Purkinje cells cerebellar nuclei and vestibular nuclei. The cortico- axons [6–8]. The cerebellar output arises exclusively nuclear innervations of the cerebellum is dense [3]. from the cerebellar nuclei (except for the vermal Purkinje cells receive a glutamatergic projection Purkinje cell axon to the lateral vestibular nucleus). through the climbing fibers originating from the Afferent fibers enter the cerebellum through inferior olive [4]. This is one of the most powerful three pairs of peduncles: the inferior peduncle (res- synapses in the brain. The inferior olive receives tiform body): the large middle peduncle (brachium projections from the spinal cord, motor cortex, pontis):and the superior peduncle (brachium sensory root of the trigeminal nerve, and red conjunctivum). Efferent fibers from the cerebellar nucleus [1]. In addition, the inferior olive receives nuclei leave the cerebellum through the superior an inhibitory signal from cerebellar nuclei and inferior peduncles. (nucleo–olivary pathway). Purkinje cells also Jansen has divided the human cerebellum into receive numerous items of information, mainly three main parts: the anterior lobe, the posterior lobe,

259

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CEREBELLAR CORTEX sc + PF bc – c – + + PN GC

Nucleo- cortical loop – + CEREBELLAR NUCLEI +

Nucleo-olivary CF MF tract + + HYPOTHAL – OTHER BRAINSTEM THALAMIC RED INFERIOR OLIVARY NUCLEI – NUCLEI NUCLEI COMPLEX VN RN

VST Ret.ST

CEREBRAL SPINAL CORTEX CORD Rub.ST Guillain-Mollaret triangle

Figure 17.1 Scheme of the anatomical connections of origin of mossy fibers (MF) is more diffuse. These latter the cerebellar circuitry. Purkinje neurons (PN) inhibit target granule cells (GC), whose ascending axon gives cerebellar nuclei and vestibular nuclei (VN). Stellate cells rise to parallel fibers (PF) making numerous synapses (sc), basket cells (bc) and Lugaro cells (lc) are inhibitory with PN. Ret.ST: reticulospinal tract, Rub.ST: rubrospinal interneurons of the cerebellar cortex. Golgi cells are not tract (this tract does not extend beyond the cervical represented. Climbing fibers (CF) originate exclusively segments in human), Hypothal.: hypothalamus. +: from the contralateral inferior olivary complex. The excitatory, −: inhibitory.

and the paraflocculus/flocculus [9]. On the basis of into three zones: a vermal zone projecting to the fas- mossy fiber projections to the cerebellar cortex, three tigial nucleus, an intermediate zone projecting to the areas can be considered [10]: the flocculonodulus interpositus nucleus (globosus and emboliformis), (vestibulocerebellum): the vermal portion of anterior and a lateral zone projecting to the dentate nucleus and posterior lobes with mainly spinal connections (Figure 17.3). (paleocerebellum): and a mediolateral part having principally cortico–ponto–cerebellar connections (neocerebellum). Pontocerebellar and spinocerebel- Physiology of the cerebellum lar afferents are mixed in the intermediate zone. Connections between the cerebellum and the The cerebellum contains more neurons than any cerebral cortex are segregated in re-entrant loops other region of the brain and the number of afferent running in parallel (Figure 17.2). From a functional fibers exceeds the number of efferences by a ratio of point of view, the cerebellar cortex can be divided about 40:1, hence the enormous computational

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Segregated cerebello-cerebral loops capabilities of the cerebellar circuitry [11]. Thanks to its high connectivity to the other brain areas, the PONTINE NUCLEI cerebellum is a key-piece for information processing and planning of sensorimotor activities [4]. There is ample evidence that cerebellar circuitry holds an internal representation of time to govern CEREBELLUM timing processes. It has been concluded from clinical and experimental studies for more than a century that the cerebellum controls the accuracy of movements and the coordination of multijoint move- THALAMIC NUCLEI ments. It is also involved in learning, in particular by tuning the dynamic control of movement [12]. Current views propose that the cerebellum is a mas- PREFRONTAL terpiece for the predictions of fast movements (see CORTEX PARIETAL also “Theories and computational models of cere- CORTEX PARALIMBIC bellar function” below) and the online regulation of CORTEX SUPERIOR TEMPORAL slow movements [13]. The study of the modulation SULCUS of firing rates of neuronal discharges during senso- Figure 17.2 Illustration of the segregated loops rimotor tasks has shown that: (1) the fastigial between the cerebellum and prefrontal cortex, parietal nucleus – together with the vestibular nuclei – con- cortex, paralimbic cortex, and superior temporal trols eye movements, stance/posture, and gait; (2) sulcus. the interpositus nucleus contributes to the modulation of reflexes, including stretch and placing; (3) the dentate nuclei are involved in the control of

(A) (B) (C) MOTOR CORTEX MOTOR MOTOR PREFRONTAL CORTEX CORTEX CORTEX PARIETAL CORTEX TEMPORAL CORTEX LIMBIC CORTEX

THALAMIC THALAMIC THALAMIC NUCLEI NUCLEI NUCLEI

PONTINE PONTINE VERMIS INTERM. PONTINE LATERAL NUCLEI NUCLEI ZONE NUCLEI ZONE

FN NI DN

IOC LVN IOC IOC

Reticular formation Red nucleus Reticular formation

Spinal cord Spinal cord Spinal cord

Figure 17.3 Comparison of anatomical connections of the spinal cord, unlike the lateral cerebellum. the vermal zone (A); the intermediate zone (B); and the Abbreviations: IOC, inferior olivary complex; LVN, lateral lateral zone of the cerebellum (C). The midline zone and vestibular nucleus; FN, fastigial nucleus; NI, nucleus the intermediate zone receive direct information from interpositus; DN, dentate nucleus. (From Manto [11].)

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voluntary movements of the extremities, including Table 17.1 Oculomotor deficits and localization of reaching and grasping [14]. The dentate nucleus cerebellar lesion(s). regulates reaction time through initiation of movements triggered by vision or mental percepts, and Oculomotor disorders Localization of the lesion accuracy of single-joint and multi-joint goal- Dysmetria of saccades Dorsal vermis/Fastigial directed movements. Neurons in the interpositus nucleus nucleus typically fire when a position is perturbed Saccadic pursuit in reaction tasks aiming at keeping the segments of Gaze-evoked nystagmus Flocculus/paraflocculus the limbs in a fixed position [15]. Limb movement Rebound nystagmus representations in the interpositus nucleus may be Downbeat nystagmus Saccadic pursuit instrumental for the control of goal-directed move- Abnormal gain of VOR ments such as grasping or precise foot placement Periodic alternating nystagmus Nodulus, ventral uvula. during gait. The interpositus neuronal activity can parse out the directional from the scalar component Adapted from Manto [19]. (i.e. the movement speed) of a velocity vector associated with movements. A differential role for the The stability of gaze is estimated clinically by hold- anterior and posterior portion of interpositus in ing the index finger in front of the patient at a dis- encoding movement kinematic parameters is tance of about 30 cm and in a lateral position (no emerging. The activity of the posterior interpositus more than 30 degrees), in upward and downward is associated with changes of movement speed [16]. position. Nystagmus consists of rhythmic oscillatory movements of one or both eyes, with a fast and a slow component in opposite directions. Latency, pre- Clinical features of the cerebellar cision, and velocity of saccades are estimated by ask- dysfunction and underlying ing the patient to look laterally at one and the other mechanisms fingers located in each temporal visual fields [4]. Ocular hypermetria, defined as an inaccurate saccade Neurological signs and symptoms occurring in with overshooting of the target, is very suggestive of cerebellar diseases can be grouped into five catego- cerebellar disease [18]. The use of a rotating chair is ries [17, 4]: oculomotor disturbances, speech defi- required to test the VOR. When the chair is rotated at cits, deficits of limb movements, abnormalities of constant velocity and the subject fixates on an object gait and posture, and cognitive disturbances. that moves synchronously with head movement, Deficits of limb movements include dysmetria, dys- intermittent deviations of the eyes with corrective diadochokinesia, tremor, decomposition of move- saccades are observed. In a healthy subject a comments, loss of check and rebound, and disorders of pensative rotation of the head suppresses the VOR. muscle tone. Cerebellar ataxia is defined as the In cerebellar diseases abnormal ocular movements jerky or poorly coordinated character of motion. It are usually due to a lesion at the level of the dorsal appears in the absence of muscle weakness or sen- vermis or fastigial nucleus (i.e. dysmetria of saccades, sory deficit, although fatigability is a common com- saccadic pursuit), the flocculus and paraflocculus (i.e. plaint in cerebellar patients. saccadic pursuit, nystagmus, abnormal VOR, and optokinetic response), and or the uvula and nodulus Oculomotor disturbances (i.e. periodic alternating nystagmus) [20–23]. The The oculomotor alterations observed in cerebellar fastigial nucleus plays a key role not only for eye diseases are, mainly: instability of gaze and nystag- movements, but also for control of the head position. mus, hypermetria/hypometria of saccades, saccadic The rostral fastigial nucleus controls head orientation pursuit, skew deviation (ocular misalignment), and and eye–head gaze shifts [24] whereas the caudal disorders of vestibulo-ocular reflex (VOR) and fastigial nucleus regulates oculomotor aspects, such optokinetic responses (Table 17.1). as saccades or smooth pursuit [25].

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By comparison with cerebellar disorders, the Lesions of the superior paravermal region are main extrapyramidal disorders are characterized by commonly associated with speech deficits [33]. the following oculomotor abnormalities: It has been suggested that, as a result of an asymmetric • In Parkinson disease, multiple step hypometric development of language, damage to the left saccades are abnormally frequent [26]. Peak intermediate cerebellar cortex might be one of the saccadic velocities are significantly reduced. Brief main causes of the cerebellar dysarthria [34, 35]. corrective intervals occur after hypometric saccades. Two separate networks might supervise speech They are attributed to internal (non-visual) motor control [36]: the supplementary motor area, efference copy feedback of eye position errors. the dorsolateral frontal cortex, including the Broca Saccadic reaction times and post-saccadic refractory area, anterior insula, and superior cerebellum would periods are prolonged. Smooth pursuit gain is constitute a preparative loop; the executive loop abnormally low in patients during tracking would include the sensorimotor cortex, basal gan- sinusoidal targets. Frequent square wave jerks are glia, thalamus, and inferior cerebellum. also one of the features of Parkinson disease, but they lack specificity and are nearly always present Mutism in case of extrapyramidal disorder. Mutism occurs mainly as a consequence of posterior • Huntington disease (HD) is characterized by fossa surgery (see also “Posterior fossa syndrome” impaired initiation of saccades and slow saccades below). It is more common in pediatric patients [27]. Early HD shows three types of significant [37]. Mutism is characterized by an absence of abnormalities while performing memory guided speech without other aphasic signs or alteration of and antisaccade tasks: increased error rate, consciousness [38–41]. In most cases, it appears increased saccade latency, and increased variability 12–48 hours after surgery and lasts about 12 weeks. of saccade latency [28]. After resolution of muteness, cerebellar dysarthria • Vertical saccade paralysis and supranuclear is observed. Hydrocephalus and postsurgical edema defects of VOR are suggestive of progressive supra- might contribute to the pathogenesis [42], but a nuclear palsy (PSP) [29]. Analysis of refixation genuine cerebellar contribution is slowly emerging sacades shows hypometria, slow velocity/amplitude in the literature. relationships, and profound prolongation of duration. The pursuit abnormality, characterized Disturbances of limb movements clinically by cogwheel eye movements, repre- The so-called cerebellar syndrome relates to impair- sents the inability to match eye velocity to target ment in performance of limb movements, including velocity. various combinations of dysmetria, dysdiachokine- sia, postural and kinetic tremor, decomposition of Dysarthria and mutism movement, and disorders of muscle tone. Motor defi- Dysarthria cits are lateralized to the side of the cerebellar lesion. Clarity, rhythm and fluency of speech are impaired in cerebellar patients. Speech tends to become slow Dysmetria with slurring. Comprehension is spared and para- Limb dysmetria is a cardinal sign in cerebellar disease. phrasias are absent. Words may be unintelligible Holmes defined dysmetria as an error in trajectory because of the temporal dysregulation of muscles due to a disturbed range, rate and force of the move- activities [30]. Speech is often explosive, with a ment [43–45]. Hypermetria designates the overshoot staccato rhythm and a nasal character. The scanning of the target and is associated with a delayed onset aspect is the most easily recognized deficit [31, 32], latency of the antagonist EMG activity (Figure 17.4). with hesitations, accentuation of some syllables, There is a good correlation between the AS20 score omission of appropriate pauses, and addition of (a clinical rating score of ataxia) on the one hand, inappropriate pauses. A disturbance in the melodic and the severity of hypermetria and the delayed aspect of speech (dysprosody) may also occur. onset latency of the antagonist EMG activity on the

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other [46]. Hypermetria is largest when the movements. In most cases, dysmetria occurs both for ment is made as fast as possible and when the inertia proximal and distal joints [51]. Lesions of the dentate of the moving limb is increased [47–49]. Cerebellar nuclei are typically associated with an overshoot of patients show also deficiencies to adapt to artificial the target and a decomposition of multi-joint move- damping [50]. Hypometria is less common. ments [52, 53]. Cerebellar patients are still able to Hypometric movements are characterized by a pre- describe the direction of the movement without mature arrest before reaching the aimed target. looking at the moving limb, unlike patients with Dysmetria is often followed by corrective move- impaired position sense [35].

(A) Single-joint movements

1. Fast monodirectional movements

Control Patient AGO1 AGO2 AGO

FCR FCR ANTA ANTA

ECR ECR

Latency Latency 100 msec 100 msec

2. Fast reversal movements

–0.3 Control –0.3 Patient –0.2 No Damping –0.2 No Damping +0.1 Nms/rad +0.1 Nms/rad +0.2 Nms/rad +0.2 Nms/rad –0.1 –0.1

0.0 0.0

0.1 0.1 Go Back 0.2 0.2 Amplitude (rad) Amplitude (rad) 0.3 0.3 0.4 0.4

100 msec 100 msec AGO1 AGO1 ANTA2 ANTA2 FCR FCR

ECR ECR ANTA1 AGON2 ANTA1 AGON2

Figure 17.4 (cont’d)

Albanese_c17.indd 264 12/24/2011 5:40:55 PM (B) Multi-joint movements

TORQUES: NET=MUS+EXT+DYN sh. elb.

Control subject 150 Slow 150 Moderate 150 Fast (deg) (deg) (deg)

Joint position 90 Joint position 90 Joint position 90 012 012 012 Time (sec) Time (sec) Time (sec)

Cerebellar ataxia 150 Slow 150 Moderate 150 Fast (deg) (deg) (deg) Joint position Joint position 90 Joint position 90 90 012 012 012 Time (sec) Time (sec) Time (sec)

M1 M2 5 a.u.

0 50 100 Time (msec)

Figure 17.4 (cont’d) A. (1) Electromyographic (EMG) asked to perform a vertical pointing movement towards deficits associated with fast monodirectional single-joint a fixed target at various speeds. The target is located in movements in a control subject (left panel) and in a front of the subjects at a distance of 85% of total arm cerebellar patient (right panel). The onset latency of the length. In the patient, deficits in angular motion are antagonist EMG activity is delayed and the rate of rise of enhanced with increasing velocities, especially the EMG activities is depressed. (2) Fast reversal movements increased angular motion of elbow resulting in during artificial modification of the damping overshoot (hyperextension of the elbow). Black lines: characteristics of movement in a control subject (left angular position of the elbow; grey lines: angular panel) and in a cerebellar patient (right panel). The first position of the shoulder. Abbreviations: sh, shoulder phase of movement is normal in this patient. However, angle; elb, elbow angle. movement is dysmetric during the return to the initial C. Long latency electromyographic (EMG) responses position and the patient is unable to adapt the EMG to stretches of the first dorsal interosseous muscle in a activities to artificial damping. cerebellar patient (black line) and in a control subject B. Effects of increasing velocities on kinematics of the (gray line). Latencies of averaged rectified EMG upper limb pointing movements in a control subject responses are normal, but the M3 response is increased (upper panels) and a cerebellar patient (lower panels). in the cerebellar patient. Surface EMG rectified and Subjects are seated and comfortably restrained in order averaged 200 times. Responses are calibrated in arbitrary to allow only shoulder and elbow movements. They are units (a.u.). (From Manto [11].)

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Action/postural tremor appears during postural Dysdiadochokinesia tasks requiring accuracy. It is tested clinically during Adiadochokinesia (or dysdiadochokinesia) desig- the index-to–index test, the heel-to-knee test, or nate the inability to perform rapid successive the arm-outstretched task (Figure 17.5). The movements [54]. Dysdiadochokinesia is mainly frequency of postural tremor is usually between characterized by irregularly irregular and slow 4 and 12 Hz. Tremor appears immediately but alternating sequential movements [4]. An abnor- increases in amplitude after a few seconds, in the mal sway of the elbow is often present in advanced line of gravity. The oscillations appearing during the cases during successive pronation/supination tasks. heel-to-knee test rapidly evolve into lateral sways in Errors in timing and magnitudes of muscles severe cases. Eye closure and body displacements activities contribute to the errors in the metrics of tend to enhance the oscillations. Postural tremor in motion (see also “Dysmetria” below). cerebellar disease can be further described as: (a) precision tremor – usually due to lesions of cerebel- Tremor lar nuclei – with a frequency of 2–5 Hz, occurring Tremor associated with cerebellar diseases is mainly during the execution of precision tasks and involv- composed of low-frequency oscillations, usually ing the distal musculature; (b) asthenic tremor – in with a kinetic component. Many cerebellar patients case of hemispherical lesion – precipitated by exhibit a concomitant postural tremor. Isometric fatigue; (c) axial postural tremor; and (d) midbrain tremor as well as titubation of the trunk may also tremor associated with mid brain lesions [60]. A occur [55]. The tremor may be bilateral, but in most postural tremor of the shoulder may be precipitated cases, tremor is ipsilateral to the cerebellar lesion. by fatiguing tasks in patients presenting a large In parkinsonian patients, tremor occurs while the cerebellar malformation. body segment is maintained at rest and may disap- Action tremor is often suggestive of anterior pear with action, although this is not a consistent lobe cerebellar pathology. However, it may be finding. Rest tremor is typically in the 3–6 Hz fre- observed also in diffuse cerebellar diseases such as quency range, is usually asymmetrical and often idiopathic late-onset cerebellar atrophy (ILOCA) starts distally in the arms. Typically, parkinsonian or hereditary spinocerebellar ataxias (SCAs) tremor in the upper limbs recalls the “pill rolling” [61–64]. movement. In some cases patients can reduce the Both discontinuities in movements and tremor tremor by holding one hand with the other or could result from impaired stretch reflexes and crossing their legs [56]. Lips and jaw can be affected. disorganized servo-assistance mechanisms, with a Kinetic tremor in ataxic patients appears during contribution of transcortical pathways [65, 4]. the execution of a movement. It is assessed during A detailed analysis of firings of neurons has the finger-to-nose and the knee-to-tibia tests. revealed that the neuronal populations discharging Although it may occur at the initiation of move- strongly in relation to cerebellar tremor respond ment or during the whole range of movement, it is markedly and reciprocally to limb perturbation. usually maximal as the limb approaches the target However, the 3–4 Hz cerebellar tremor is not driven [57]. The frequency is between 2 and 7 Hz in the by a purely central oscillator [66]. Atrophy of the large majority of cases. Oscillations are perpen- anterior lobe of the cerebellum may be associated dicular to the main direction of the intended with a very suggestive 3 Hz leg tremor in alcoholic movement. Tremor tends to be predominant over patients. proximal musculature [45, 35] and decreases with The recent developments of wearable sensors as inertia, unlike cerebellar dysmetria [58, 59]. In well as the advent of sensor fusion approaches some patients, tremor may worsen in the days (integration of various sensors) will very likely and weeks after an acute lesion, probably as a change our appraisal of the mechanisms underly- result of aberrant reorganization within the brain ing the various forms of tremor encountered in circuitry. ataxic patients [67].

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Postural tremor–cerebellar stroke 3.40 Hz

0.30 V2/sec

Accelerometer – upper limb outstreched

10 sec

Flexor carpi radialis – rectified EMG

3.37 Hz 10 sec 0.02 V2/sec

Figure 17.5 Postural tremor in a patient presenting a tract of the cerebellar nuclei.] Bottom: Data from a cerebellar stroke in the territory of the superior monoaxial accelerometer and from a surface cerebellar artery. Top: Axial MRI of the posterior fossa; electromyographic (EMG) sensor are shown, as well as stroke (arrow) in the territory of the superior cerebellar the corresponding power spectra. Note the waveform artery. [Abbreviations: B, brainstem; C.H., cerebellar characteristic, which is characterized by asymmetry. hemisphere; V, vermis. The lesion involves the outflow (From Grimaldi and Manto [56], with permission.)

Decomposition of movement motion [68]. Decomposition of movement is often Ataxic movements tend to be decomposed into accompanied by an inability to generate independ- elementary components, with a lack of synergy ent finger movements. For slow multi-joint move- between joints resulting in a lack of fluidity in ments, decomposition is manifested by errors in the

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direction and rate of the movement. The lack of extensor tone disinhibition [71]. Cerebellar fits are coordination cannot be explained by a simple sum- included in the category of “cerebellar seizures,” mation of the elemental deficits observed during which include also hemifacial seizures associated single-joint movements. Deficits in adaptation of with a dysplastic cerebellar tumor in infants [72]. the interaction torques generated in a multi-degree Ganglioglioma of the cerebellum may be associated of freedom human arm have been demonstrated in with paroxysmal facial contractions [73]. Similar cerebellar patients [69] (see Figure 17.4B). symptoms may be observed in children with hamartoma of the floor of the fourth ventricle [4]. Check and rebound Impaired check is assessed by asking the patient to Posture and gait maintain the upper limbs extended with the hands Cerebellar patients present a broad-based stance pronated [19]. The examiner exerts a tap on the with an increased body sway. They may also exhibit wrist. A large displacement of the limb is observed, distorted anticipatory adjustments and defective immediately followed by an overshoot of the initial postural response to external forces [74]. Gait may position and oscillations around the initial position. be seen as resulting from a combination of balance Impaired check causes a large movement called and locomotor activities. Balance tasks include excessive rebound [19]. The lack of check can be standing in an upright position (antigravity task), evaluated during the Stewart–Holmes maneuver. anticipatory adjustments preceding movements, as The patient is asked to perform a forceful flexion of well as postural responses triggered by external the elbow while the examiner attempts to extend forces. Locomotor tasks include the integration of the joint. When the forearm is suddenly released, the body to the changing environment, taking into the patient hits himself with his hand. This is due to account the rhythmic character of locomotion. a combination of prolonged activity if the biceps Balance and locomotor tasks may be defective in muscle (agonist) and delayed onset latency of the ataxic patients. braking activity of the triceps muscle (antagonist). Ataxia of stance Disorders of muscle tone Ataxia of stance is characterized by an inability to Hypotonia is usually associated with severe cere- maintain the body in a stationary position. Body bellar damage. The decline in resistance to the sway is increased and the trunk tends to lurch from passive manipulation of limbs tends to be more side to side or to drift on one side [45]. This latero- pronounced in proximal joints. Pendular tendon pulsion is usually towards the site of the lesion [75]. reflexes, characterized by limbs oscillating around The wide-base character of stance is typical in cer- the position at rest, may be found. Nevertheless, ebellar disorders. The increased spread of the feet in amplitude and velocity of tendon reflexes are natural position might result from the increased normal as well as cutaneous reflexes. Hypotonia is body sway and/or might be used as a compensatory associated with decreased excitability the stretch strategy aiming at lowering the center of gravity of reflex excitability, because cerebellum tunes the the body [19]. The assumption that ataxia of stance activity of gamma motor neurons [32]. Differential in isolated cerebellar diseases is not influenced by diagnosis of cerebellar hypotonia includes extensive eye closure is false, although the exacerbating effect brainstem lesion, spinal shock, anterior horn cell of closing the eyes might be less evident than in disease, poyradiculitis/polyneuropathy, floppy syn- proprioceptive deficits or in the so-called vestibular drome in children [4]. ataxia [62, 76, 17]. Cerebellar patient may also pre- Cerebellar fits are spasms associated with inter- sent with titubation (rhythmic oscillations of the mittent opisthotonos [70]. They are associated with head, trunk or entire body) [43]. Oscillations occur posterior fossa tumors, Chiari malformations, and in the anterior–posterior plane, in the lateral plane stroke involving the cerebellar cortex but sparing or are rotatory-like. Lesions of the anterior lobe the nuclei [4]. The mechanism is presumably an are associated with a 3 Hz sway predominating in

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the anterior–posterior direction, whereas vestibu- to influence walking via projections to motor corti- locerebellar lesions tend to produce a low- frequency cal areas; the lateral cerebellum influences walking sway (<1 Hz) in all directions [76, 4]. via cortical interactions and contributes to the Sitting, stance, and gait are usually impaired in voluntary modifications of the locomotor cycle [78]. midline cerebellar lesions. Lesions in the medial Lesions at the level of the flocculonodular lobe and intermediate zones of the cerebellum, espe- cause an unsteady gait. An important role of the cially in the anterior lobe, disturb movements nec- posterior inferior cerebellar vermis in tandem gait essarily linked to the equilibrium function [74]. has been shown by Bastian and colleagues who Lower vermal lesions often cause pluridirectional reported an isolated abnormal tandem gait with increased body sway at low frequencies and high preserved regular gait and stance in children amplitudes, whereas lesions in the upper vermal with surgical transection of the posterior inferior zone tend to induce anterior–posterior oscillations cerebellar vermis [82]. at higher velocities and lower amplitudes [77, 78]. Abnormal patterns of gait include irregular The cerebellum controls the adequate scaling of timing of peak flexion at one joint with respect to anticipatory postural responses during standing the other joints and/or joint–joint decomposition, postural perturbations [74]. Cerebellar circuitry which can be seen as a reduction in the movement tunes the magnitudes of long-latency reflexes at one joint during movement of another joint [78]. (LLRs) in four limbs (see Figure 17.4C). LLRs are The analysis of goal-directed leg placement demon- involved in the stabilization of postural activities in strates that the interposed and the adjacent dentate limbs and contribute to stability of trunk [79]. nuclei are more frequently affected [83]. The Cerebellar–cortical loops related to LLRs are intermediate zone seems to play an important role especially involved in adapting postural responses for multi-joint limb control both in goal-directed based on prior experience [80]. We have found leg movements and in locomotion. recently that the ratios of intensities of LLRs divided by intensities of short-latency reflexes (SLRs) are Cerebellum and learning correlated with the onset latencies of antagonist The cerebellum plays several key roles in learning EMG activities, suggesting that similar mechanisms [4]. The cerebellar circuits are involved in many might be involved [81]. aspects of memory, in particular in non-declarative memory [84]. This latter includes procedural Ataxia of gait learning (skills and habits): priming and perceptual Gait is tested clinically during a 10 m test including learning, basic associative learning including simple a half-turn. The maneuvers that can unravel a sub- classical conditioning of emotional and skeletal tle gait deficit are: walking in a line, walking in tan- muscle responses, and non-associative learning dem, walking backwards. Ataxic gait is irregular [85, 4]. While the corticostriatal systems deals with and broad based. Successive steps are spaced in a learning of new sequences, the cerebrocerebellar staggering way, followed by corrections or falls. The systems are primarily engaged in the motor rhythm is distorted and speed is often reduced. The adaptations phases of learning [86]. Cerebellar cerebellum regulates step and stride length and circuits coordinate event sequences. cadence and attenuates the variability of gait during The cerebellum is critical to the adjustments successive cycles. Walking trajectory veers required facing environmental changes or pertur- erratically in cerebellar patients, with difficulties in bations [87]. The prototype of adaptation learning initiation, stops, or turns. is the gain of the vestibulo-ocular reflex (VOR), Due to its anatomical connections, each cerebellar which refers to the amplitude of the eye movements zone influences gait: the medial cerebellar zone due to head motion. Cerebellum and brainstem are integrates spinal and vestibular inputs to influence two of the key players in the adaptation of the VOR vestibulospinal and reticulospinal tracts; the inter- [88]. Selection of the gain is a learning phenome- mediate zone integrates spinal and cortical inputs non, but no apparent new skill is required when

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the gain changes [89]. The VOR operates in dysfunction is commonly encountered in cerebellar conjunction with other systems such as smooth patients [4]. Tasks requiring planning/initiation, pursuit. Another typical example of adaptation to sustaining and inhibiting activity, inferring, judging environmental change is the prism adaptation. In and shifting set are often abnormal in inherited this task, the subject has to adjust movements while ataxias, but premorbid state might influence wearing prism glasses which displace vision. strongly their severity and mode of presentation. Subsequently, the prisms are removed and the Some patients with autosomal dominant spinocer- subject has to readjust movement once again. ebellar ataxia (SCA) may exhibit a clear intellectual Cerebellar patients have difficulties in both tasks. decline, especially in SCA17 or dentato-rubral- The recalibration of misaligned reference frames pallidoluysian atrophy (DRPLA). Mood disorders due to perturbed visual input is dependent upon a and personality changes are not rare. Lexicose- network of cortical (anterior cingulate, anterior mantic knowledge may be impaired in subjects intraparietal region) and cerebellar regions [90]. with advanced SCA, suggesting that language is Cerebellar lesions are associated with impaired affected as the disorder progresses. Attentional eyeblink conditioning [91, 92]. Acquisition of deficits are congruent with the hypothesis of a role eyeblink conditioning is abnormal in various of the cerebellum in providing attentional resources disorders in which the cerebellum plays a key role, allotted in a rapid way [4]. Speech may be charac- for instance in essential tremor. Impairment of terized by a vocal instability, reduced rate, and more complex forms of eyeblink conditioning (for monotony, complicating dysarthria [95]. example, trace eyeblink conditioning) and delay The constellation of these cognitive/behavioral conditioning of other aversive responses (for exam- deficits is suggestive of a disruption of the cerebellar ple limb flexion response) in cerebellar subjects modulation of neural circuits that link prefrontal, suggest a general role of the cerebellum in posterior parietal, superior temporal, and limbic associative learning [85]. Globally, the cerebellum structures including the amygdala, hippocampus, is involved in acquisition, timing and extinction of and septum [96]. Nearly all regions of the associa- conditioned eyeblink responses. tive and paralimbic cortices project to pontine nuclei in a segregated manner, and pontine nuclei Cerebellum and cognitive deficits send mossy fibers to the cerebellum. The prefron- Cerebellum contributes to neural processes beyond tal cortex projects to medial and dorsomedial the motor domain. Cerebellar patients may present regions of the pons, the association areas of the cognitive and behavioral changes. Because these temporal lobes project to the lateral pons, the deficits may be subtle and are not detected by a superior regions of the parietal association cortices conventional neurological examination, they are project to the central pons, the inferior parietal overlooked. A comprehensive neuropsychological regions send projections to the rostral pons, and evaluation is recommended when deficits are paralimbic regions project to medial and lateral suspected. Two entities have been well delineated. pontine nuclei. A “limbic cerebellum” has even They are described below. been suggested [97]. Impaired performance in Wisconsin Card Sorting Task (WCST) points Cerebellar cognitive affective syndrome toward a damage to the dorsolateral prefrontal The concept of cognitive dysmetria has been cortex and/or its subcortical connections including proposed, by extension to the observations of the cerebellar circuits [98]. Behavioral changes motor deficits [93]. The terminology of “cerebel- might be more common in patients presenting lar cognitive affective syndrome” (CCAS) includes lesions of the posterior cerebellar lobe and the impairment of executive functions including vermis. Attention errors and abnormal visuospa- planning and working memory, deficits in visuos- tial skills are reported repeatedly in these patients. patial skills, linguistic deficiencies such as agram- Visuospatial deficits might be more common in matism, and inappropriate behavior [94]. Executive case of left side lesions.

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(A)Pre-operative (B)Post-operative (C) Follow-up

Figure 17.6 Preoperative axial FLAIR slice (A) in a 6-year-old right-handed boy showing a large tumor mass lesion (medulloblastoma) in the posterior fossa. Post-operative follow-up MRI demonstrates a fourth ventricle cystic mass lesion with residual tumor tissue adhering to the wall of the ventricle (B) and multiple metastases in the lateral ventricles (C). (Courtesy of Professor Peter Marien.)

Positive effects of electric cerebellar stimulation develops into dysarthria, which will improve on mood in psychiatric disorders has been reported, markedly. When both the vermis and the right suggesting a role of cerebellum in human emotion cerebellar hemisphere are involved, the recovery of [99]. Indeed, damage to the vermis has been speech is slow and speech often becomes monoto- associated with emotional dysregulation [100]. nous and telegraphic, reminiscent of speech deficits Which form of emotional process is handled by cer- found in frontal lobe lesions [4]. Concomitant ebellar circuitry is still an open question [96, 101]. cognitive deficits are common: impairment in the shifting of attention, perseveration, difficulties in Posterior fossa syndrome problem-solving. The so-called posterior fossa syndrome can be considered as a very acute form of CCAS [4]. The syndrome affects mainly children between the Theories and computational age of 2 and 10 years. Following resection of a models of cerebellar function midline tumor of the cerebellum (see Figure 17.6 for an example), children show mutism, buccal and Several major theories are influencing our concepts lingual apraxia, apathy and poverty of movements of cerebellar function (Table 17.2). According to the [102]. Mutism usually develops 1–5 days after the “sensory” theory, the cerebellum provides an resection. Post-surgical mutism evolves into speech online monitoring of sensory information [103] disorders or language disturbances similar to and tunes the sensory motor coupling in a given agrammatism, and behavioral disturbances ranging condition combining reflexes and voluntary from irritability to behaviors reminiscent of autism, movement [104]. The relation between sensory often with emotional lability (irritability, emotional signals guiding motion and the movement itself reactions, agitation) and regressive personality depends on the relative position of limb segments, changes [4]. When the lesion involves the vermis the position of the body in the gravitational field, and spares the hemispheres, mutism quickly and the external forces interacting with the

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Table 17.2 Main theories of cerebellar functions.

Theory Principles References

Sensory processing The cerebellum monitors and adjusts the acquisition of sensory Bower [109] inputs

Adaptative filter Based upon Marr-Albus theory. Transformation of sets of signals into Fujita [110] hypothesis others. Components are weighted individually and then recombined to minimize the errors in performance caused by unavoidable noise. Cerebellar timer Cerebellum is the main site of temporal representation of action. Braitenberg [111] Timing of sensorimotor activities are under the control of the Ivry and Spencer [112] cerebellar circuitry. Cerebellar circuitry behaves as a regulating clock. Tonic reinforcer The cerebellum tunes the intensities of agonist/antagonist/synergist Eccles et al. [5] Bastian and muscles. Thach [14] Cerebellum exerts an excitatory influence upon extracerebellar Oulad Ben Taib and Manto targets such as thalamic nuclei or reticular nuclei. [113] Internal models The cerebellum contains neural representations to emulate Wolpert et al. [114] movement. Internal models reproduce the dynamic properties of body parts.

Adapted from Manto [50].

movement. The theory of the sensorimotor coordi- the cerebellum contributes to time processing in nate transformer assumes that the cerebellum both perceptual and motor aspects come in partic- implements the correct input–output in sensory ular from functional MRI (fMRI) studies. The motor transformations (mathematical computation right lateral cerebellum (lobule VI) is active dur- of motor commands on the basis of sensory signals), ing a time discrimination task, whereas the left thus transforming an intended movement vector cerebellum (lobule VI) is activated during a timed into a given motor command [105]. The possibility movement generation task [117]. that sensorimotor cortex and its cerebellar connec- The accurate control of joint torques is a pre- tions behave as pairs of reciprocally coupled requisite for normometric movements (see also oscillators is strongly suggested by (a) the coupling “Disturbances of limb movements” above). between the cerebellum and contralateral thalamic Intensities of forces are scaled to the square of nuclei and primary cortex [106], and (b) the movement speed, providing a possible explanation coherent oscillations between sensory cortex and for the increase in clumsiness when patients cerebellar cortex [107]. Cerebellofugal fibers might perform quicker movements. Cerebellar circuitry even trigger oscillations in thalamic nuclei and might keep an internal representation of the motor cortex [108]. biomechanical properties of each body segment, The “timing theory” considers that the cerebellar regularly updated by peripheral sensory informa- circuitry provides an internal timing system tion [118]. This representation might be defective required to perform sensorimotor tasks accurately in cerebellar disorders. [115]. A main goal of the olivocerebellar system and the cerebellar microcircuits would be to Internal models provide a precise temporal representation [116]. One leading theory proposes that the cerebellum Interactions between cerebellum and inferior olive houses neural representations, called “internal are likely involved in the generation of complex models,” to mimic fundamental natural processes temporal patterns producing intervals between such as a joint movement and body motion movements. Data consistent with the idea that [119–121]. Some of the most convincing evidence

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Figure 17.7 Forward models. Communication Primary motor cortex flows for information processing in forward models of motor coding. Cerebellar modules receive an efference copy of motor commands via the corticoponto-cerebellar tract, in order to make Thal. Motor predictions. Reafference signals and corollary command discharges reach the comparator (inferior olive), Copy which generates an error signal updating the plastic cerebellar microcircuits. Expected sensory Error signal Inferior outcomes are conveyed to the primary motor olive cortex via excitatory connections and to Predicted the inferior olive via inhibitory pathways. (corollary discharge) (From Manto [50].) Cerebellar nuclei Cerebellar cortex

Reafference Spinal cord

Muscles/joints

Movement Sensory signals

that the nervous system uses internal forward Accurate predictions would decrease the models in human motor behavior comes from dependence on sensory signals. Purkinje cell firings studies dedicated to the control of grasping forces have several features suggestive of a forward internal during manipulation of objects [120]. This theory model of the arm. Experimental data suggest that is based in particular on the inherent time delay of Purkinje neurons from lobules IV to VI encode sensory feedback to update motor commands position, directional parameters, and velocities of [122]. Sensorimotor delays vary according to the arm movements [124]. A subset of the parallel fiber modality and context and may be in the range of synapses contacting Purkinje cell would control its 50 to 400 ms. The cerebellum may function simi- output by causing a weakening of the strength of the larly to a “forward model” by using efference synapses activated during an erroneous motor copies of motor orders to predict sensory effects of command [125]. A simulated regulation of smooth movements. Cerebellar circuitry would be necessary pursuit eye movements has been obtained in a model to learn how to make appropriate predictions of the cerebellum by minimizing its inputs from using error information about the discrepancies parallel fibers, which carry various signals including between the actual and predicted sensory conse- error and efference copy. In minimizing both error quences, not only for limb movements, but also and efference copy, this model demonstrates how for postural adjustments [123, 50, 4]. The cere- cerebellar learning through parallel fibers renders bellum could compute an expected sensory movements more accurate and more efficient [126]. outcome, which would be sent to cerebral cortical areas via excitatory connections to the thalamus Inverse models and to the inferior olive via inhibitory connections According to this theory, the cerebellum would (Figure 17.7). The inferior olive would operate as a lodge an “inverse model.” In this scheme the comparator, sending signaling errors back to the input to the cerebellum would be the aimed tra- cerebellar cortex. jectory, and the output would be a motor com-

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VISION EXTERNAL STIMULI SENSORY FEEDBACK

POSTERIOR PARIETAL CORTEX Integration of multimodal information PRIMARY SENSORY CORTEX

CEREBELLUM Predictions of sensory outcomes correction of errors PREMOTOR CORTEX Selection of the pattern of MOTOR CORTEX motoneuronal discharges Optimal control of motion BASAL GANGLIA Facilitation of motor commands

Encoding of force/direction of motion

Smooth and accurate motion Low variability Start Target

Figure 17.8 Overview of the motor control strategy for outcomes, as well as sensory feedback, playing a role limb movements. The cerebellum builds internal models of state estimator. The premotor cortex and the motor and corrects motor commands, comparable to a system cortex transform predictions into sets of motoneuronal identification function. The basal ganglia ensures an discharges, encoding for force and direction of movement. optimal control of motion, facilitating motor commands. (Reproduced from Manto [50] with permission from The parietal cortex integrates proprioceptive and visual Springer.)

mand. In order to train this type of model, error learning of a given behavior, an inverse model is information would be best characterized in motor created, allowing skilled motion at an unconscious coordinates in three directions. Both clinical and level [130]. The cerebellum interacts permanently neurophysiological data support the existence of with supratentorial areas, especially the premotor inverse models. Cerebellar patients exhibit diffi- cortex, the motor cortex, the posterior parietal cor- culties in adapting to external force field, in tex, and the primary sensory cortex, in order to agreement with the inverse dynamics hypothesis generate the appropriate encoding of force and [127]. Shidara and colleagues have shown that direction of motion (Figure 17.8). Purkinje cell activity during ocular movements is consistent with signals of an inverse model [128]. References Nevertheless, some doubts exist about the capa- bility of Purkinje cells to really code for dynamic 1 Colin F, Ris L, Godaux E. 2002. Neuroanatomy of the information (i.e. muscle commands) [129]. A cerebellum. In: Manto MU and Pandolfo M (eds). The majority of Purkinje cells do not exhibit any mod- cerebellum and its disorders. Cambridge University ulation in the patterns of discharges as a function Press, Cambridge, pp 6–29. 2 Ito M, Yoschida M. 1964. The cerebellar-evoked mono- of force type or load. In addition, the spatial tun- synaptic inhibition in Deiters’ neurones. Experientia ing pattern seems unaffected, strengthening the 20:515–16. idea of uncoupling between Purkinje cell firing 3 Ito M. 1984. The cerebellum and neural control. Raver and electromyographic activity in limbs. Press, New York. Forward models and inverse models can be seen 4 Manto M. 2010. Cerebellar disorders. A practical as two interrelated models. Forward models are approach to diagnosis and management. Cambridge required for the acquisition of a behavior. During University Press, Cambridge.

Albanese_c17.indd 274 12/24/2011 5:40:59 PM Clinical and Pathophysiological Features of Cerebellar Dysfunction 275

5 Eccles JC, Ito M, Szentagothai J. 1967. The cerebellum overshoot dysmetria. An oculographic, control system as a neuronal machine. Springer-Verlag:, Heidelberg, and clinico-anatomical analysis. Brain 99(3):497–508. New York. 19 Manto M. Clinical signs of cerebellar disorders 2002. In: 6 Buisseret-Delmas C. 1988. Sagittal organization of the Manto MU and Pandolfo M (eds) The Cerebellum and olivocerebellonuclear pathway in the rat. I. Connections Its Disorders. Cambridge University Press, Cambridge. with the nucleus fastigii and the nucleus vestibularis 20 Furman JM, Wall C 3rd, Pang DL. 1990. Vestibular lateralis. Neurosci Res 5(6):475–93. function in periodic alternating nystagmus. Brain. 7 Buisseret-Delmas C, Angaut P. 1988. The cerebellar 113(5):1425–39. nucleocortical projections in the rat. A retrograde 21 Waterson JA, Barnes GR, Grely MA. 1992. A quantita- labelling study using horseradish peroxidase combined tive study of eye and head movements during smooth to a lectin. Neurosci Lett 84(3):255–60. pursuit in patients with cerebellar disease. Brain 8 Trott JR, Apps R, Armstrong DM. 1998. Zonal organi- 115(5):1343–58. zation of cortico-nuclear and nucleo-cortical projec- 22 Lewis RF, Zee DS. 1993. Ocular motor disorders associ- tions of the paramedian lobule of the cat cerebellum 1. ated with cerebellar lesions: pathophysiology and topi- the C1 zone. Exp Brain Res 118(3):298–315. cal localization. Rev Neurol (Paris). 149(11):665–77. 9 Jansen J. 1969. On cerebellar evolution and organiza- 23 Vahedi K, Rivaud S, Amarenco P, Pierrot-Deseilligny tion, from the point of view of a morphologist. In: C. 1995. Horizontal eye movement disorders after Llinas E (ed) Neurobiology of Cerebellar Evolution posterior vermis infarctions. J Neurol Neurosurg and Development. AMA-ERF Inst Biomed RES, Psychiatry 58(1):91–4. Chicago, pp 881–93. 24 Pelisson D, Goffart L, Guillaume A. 1998. Contribution 10 Dow RS. 1942. The evolution and anatomy of the of the rostral fastigial nucleus to the control of cerebellum. Biol Rev 17:179–220. orienting gaze shifts in the head-unrestrained cat. 11 Manto M, Van Den Braber N, Meuleman J, et al. 2009. J Neurophysiol 80:1180–96. Investigation of the Adaptation to Artificial Damping 25 Fuchs AF, Robinson F, Straube A. 1994. Participation in Cerebellar Ataxia Using the Myohaptic Technology. of the caudal fastigial nucleus in smooth-pursuit eye In: IFMBE Proceedings. Springer, pp 448–51. movements: I. Neuronal activity. J Neurophysiol 12 Sánchez-Campusano R, Gruart A, Delgado-García JM. 72:2714–28. 2007. The cerebellar interpositus nucleus and the 26 White OB, Saint-Cyr JA, Tomlinson RD, Sharpe JA. dynamic control of learned motor responses. J Neurosci 1983. Ocular motor deficits in Parkinson’s disease. II. 27(25):6620–32. Control of the saccadic and smooth pursuit systems. 13 Diedrichsen J, Criscimagna-Hemminger SE, Shadmehr Brain 106:571–8. R. Dissociating timing and coordination as functions of 27 Lasker AG, Zee DS. 1997. Ocular motor abnormalities the cerebellum. 2007 Neurosci 27(23):6291–301. in Huntington’s disease. Vision Res 37:3639–45. 14 Bastian AJ, Thach WT. 2002. Structure and function 28 Blekher T, Johnson SA, Marshall J, et al. 2006. of the cerebellum. In: Manto MU and Pandolfo M Saccades in presymptomatic and early stages of (eds) The Cerebellum and Its Disorders. Cambridge Huntington disease. Neurology 67:394–9. University Press, Cambridge, pp 49–66. 29 Troost BT, Daroff RB. 1977. The ocular motor defects in 15 Vilis T, Hore J. 1997. Effects of changes in mechanical progressive supranuclear palsy. Ann Neurol 2:397–403. state of limb on cerebellar intention tremor. 30 Kent RD, Kent JF, Rosenbek JC, et al. 1997. A speak- J Neurophysiol 40(5):1214–24. ing task analysis of the dysarthria in cerebellar disease. 16 Casabona A, Bosco G, Perciavalle V, Valle MS. 2009. Folia Phoniat Logop 49(2):63–82. Processing of Limb Kinematics in the Interpositus 31 Zentay PJ. 1937. Motor disorders of the central nerv- Nucleus. Cerebellum 9(1):103–10. ous system and their significance for speech: cerebral 17 Trouillas P, Takayanagi T, Hallett M, et al. 1997. and cerebellar dysarthrias. Laryngoscope 47:147–56. International Cooperative Ataxia Rating Scale for 32 Gilman S. 1969. The mechanism of cerebellar hypoto- pharmacological assessment of the cerebellar syn- nia. Brain 92:621–38. drome. The Ataxia Neuropharmacology Committee of 33 Lechtenberg R, Gilman S. 1978. Speech disorders in the World Federation of Neurology. J Neurol Sci cerebellar disease. Ann Neurol 3:285–90. 145(2):205–11. 34 Amarenco P, Chevrie-Muller C, Roullet E, Bousser 18 Selhorst JB, Stark L, Ochs AL, Hoyt WF. 1976. MG. 1991. Paravermal infarct and isolated cerebellar Disorders in cerebellar ocular motor control. I. Saccadic dysarthria. Ann Neurol 30(2):211–13.

Albanese_c17.indd 275 12/24/2011 5:40:59 PM 276 Chapter 17

35 Lechtenberg R. 1993. Signs and symptom of cerebellar 52 Thach WT, Goodkin HG, Keating JG. 1992. Cerebellum diseases. In: Lechtenberg R. (ed) Handbook of Cerebellar and the adaptive coordination of movement. Ann Rev Diseases. Marcel Dekker, New York, pp 31–43. Neurosci 15:403–42. 36 Riecker A, Mathiak K, Wildgruber D, et al. 2005. fMRI 53 Bastian AJ, Martin TA, Keating JK, Thach WT. 1996. reveals two distinct cerebral networks subserving Cerebellar ataxia: abnormal control of interaction tor- speech motor control. Neurol 64:700–6. ques across multiple joints. J Neurophysiol 76:492–509. 37 Van Calenbergh F, Van de Laar A, Plets C, et al. 1995. 54 Babinski J. 1902. Sur le rôle du cervelet dans les actes Transient cerebellar mutism after posterior fossa volitionnels nécessitant une succession rapide de mou- urgery in children. Neurosurgery 37(5):894–8. vements (diadococinésie). Rev Neurol 10:1013–15. 38 Rekate HL, Grubb RL, Aram DM, et al.. 1985. Muteness 55 Rondot P, Bathien N. 1995. Cerebellar tremors: physi- of cerebellar origin. Arch Neurol 42(7):697–8. ological basis and treatment. In: Findley LJ, Koller WC 39 Ammirati M, Mirzai S, Samii M. 1989. Transient (eds) Handbook of tremor disorders. Marcel Dekker, mutism following removal of a cerebellar tumor. New York. A case report and review of the literature. Childs Nerv 56 Grimaldi G, Manto M. 2008. Tremor: from pathogen- Syst 5(1):12–14. esis to treatment. Morgan and Claypool Publishers. 40 Dietze DD Jr, Mickle JP. 1990–1991. Cerebellar mut- 57 Holmes G. 1939. The cerebellum of man. The ism after posterior fossa surgery. Pediatr Neurosurg Hughlings Jackson memorial lecture. Brain 62:1–30. 16(1):25–31. 58 Chase RA, Cullen JK Jr, Sullivan SA, Ommaya AK. 41 Ferrante L, Mastronardi L, Acqui M, Fortuna A 1990. 1965. Modification of intention tremor in man. Nature Mutism after posterior fossa surgery in children. 206(983):485–7. Report of three cases. J Neurosurg 72(6):959–63. 59 Hewer RL, Cooper R, Morgan MH. 1972. An investi- 42 van Dongen HR, Catsman-Berrevoets CE, van Mourik gation into the value of treating intention tremor by M. 1994. The syndrome of ‘cerebellar’ mutism and weighting the affected limb. Brain 95:579–90. subsequent dysarthria. Neurol 44(11):2040–6. 60 Brown P, Rothwell JC, Stevens JM, et al. 1997. Cerebellar 43 Holmes G. 1917. The symptoms of acute cerebellar axial postural tremor. Mov Disord 12(6):977–84. injuries from gunshot wounds. Brain 40:461–535. 61 Silfverskiöld BP. 1977. A 3 C/sec leg tremor in a “cer- 44 Holmes G. 1992. Clinical symptoms of cerebellar ebellar” syndrome. Acta Neurol Scand 55(5):385–93. disease and their interpretation. The Croonian lecture 62 Mauritz KH, Dichgans J, Hufschmidt A. 1979. III. Lancet 2:59–65. Quantitative analysis of stance in late cortical cerebel- 45 Gilman S, Dloedel JR, Lechtenberg R. 1981. Disorder lar atrophy of the anterior lobe and other forms of cer- of the cerebellum. Contemporary Neurology Series. ebellar ataxia. Brain 102:461–82. F.A. Davis, Philadelphia. 63 Harayama H, Ohno T, Miyatake T. 1983. Quantitative 46 Manto M, Van Den Braber N, Grimaldi G, Lammertse analysis of stance in ataxic myxoedema. J Neurol P. 2010. A new myohaptic instrument to assess wrist Neurosurg Psychiat 46(6):579–81. motion dynamically. Sensors 10:3180–94. 64 Manto M, Goldman S, Hildebrand J. 1996. Cerebellar 47 Manto M, Godaux E, Jacquy J. 1994. Cerebellar gait ataxia following neuroleptic malignant syndrome. hypermetria is larger when the inertial load is artifi- J Neurol 243(1):101–2. cially increased. Ann Neurol 35:45–52. 65 Flament D, Hore J. 1986. Movement and electromyo- 48 Manto M, Godaux E, Jacquy J. 1995a. Detection of graphic disorders associated with cerebellar dysmetria. silent cerebellar lesions by increasing the inertial load J Neurophysiol 55(6):1221–33. of the moving hand. Ann Neurol 37(3):344–50. 66 Flament D, Hore J. 1988. Comparison of cerebellar 49 Manto M, Jacquy J, Hildebrand J, Godaux E. 1995b. intention tremor under isotonic and isometric condi- Recovery of hypermetria after a cerebellar stroke occurs tions. Brain Res 439(1–2):179–86. as a multistage process. Ann Neurol 38(3):437–45. 67 Grimaldi G, Manto M. 2010. Neurological tremor: 50 Manto M. 2009. Mechanisms of human cerebellar sensors, signal processing and emerging applications. dysmetria: experimental evidence and current Sensors 10:1399–1422 conceptual bases. J Neuroeng Rehab 6:10. 68 Topka H, Konczak J, Schneider K, et al. 1998. 51 Hore J, Wild B, Diener HC. 1991. Cerebellar dysmetria Multijoint arm movements in cerebellar ataxia: abnor- at the elbow, wrist and fingers. J Neurophysiol mal control of movement dynamics. Exp Brain Res 65:563–71. 119(4):493–503.

Albanese_c17.indd 276 12/24/2011 5:40:59 PM Clinical and Pathophysiological Features of Cerebellar Dysfunction 277

69 Topka H, Massaquoi S. 2002. Pathophysiology of 85 Gerwig M, Kolb FP, Timmann D. 2007. The involve- clinical cerebellar signs. In: Manto MU Pandolfo M ment of the human cerebellum in eyeblink condition- (eds) The Cerebellum and its Disorders. Cambridge ing. Cerebellum 6:38–57. University Press, Cambridge, pp 121–35. 86 Doyon J, Penhune V, Ungerleider LG. 2003. Distinct 70 Stewart TG, Holmes G. 1904. Symptomatology of cere- contribution of the cortico-striatal and cortico- bellar tumors: A study of forty cases. Brain 27:522–91. cerebellar systems to motor skill learning. 71 Sprague JM, Chambers WW. 1953. Regulation of posture Neuropsychologia 41(3):252–62. in intact and decerebrate cat. I. Cerebellum, reticular for- 87 Morton SM, Bastian AJ 2004. Prism adaptation during mation, vestibular nuclei. J Neurophysiol 16(5):451–63. walking generalizes to reaching and requires the 72 Harvey AS, Jayakar P, Duchowny M, et al. 1996. cerebellum. J Neurophysiol 92(4):2497–509 Hemifacial seizures and cerebellar ganglioglioma: an 88 Boyden ES, Katoh A, Raymond JL. 2004. Cerebellum- epilepsy syndrome of infancy with seizures of cerebel- dependent learning: the role of multiple plasticity lar origin. Ann Neurol 40:91–8. mechanisms. Ann Rev Neurosci 27:581–609. 73 Chae JH, Kim SK, Wang KC, et al. 2001. Hemifacial 89 Hallett M, Grafman J. 1997. Executive function and seizure of cerebellar ganglioglioma origin: seizure motor skin learning. In: J. Schmahmann (ed) The control by tumor resection. Epilepsia 42(9):1204–7. cerebellum and cognition. Academic Press, San Diego, 74 Horak FB, Diener HC. 1994. Cerebellar control of pos- pp 297–323. tural scaling and central set in stance. J Neurophysiol 90 Danckert J, Ferber S, Goodale MA 2008. Direct effects 72:479–93. of prismatic lenses on visuomotor control: an event- 75 Amarenco P, Roullet E, Hommel M, et al. 1990. related functional MRI study. Eur J Neurosci Infarction in the territory of the medial branch of the 28(8):1696–704. posterior inferior cerebellar artery. J Neurol Neurosurg 91 Solomon PR, Stowe GT, Pendlbeury WW. 1989. Psychiatry 53(9):731–5. Disrupted eyelid conditioning in a patient with damage 76 Diener HC, Dichgans J, Bacher M, Gompf B. 1984. to cerebellar afferents. Behav Neurosci 103:898–902. Quantification of postural sway in normals and 92 Gerwig M, Dimitrova A, Kolb FP, et al. 2003. patients with cerebellar diseases. Electroencephalogr Comparison of eyeblink conditioning in patients with Clin Neurophysiol 57(2):134–42. superior and posterior inferior cerebellar lesions. 77 Dichgans J, Fetter M. 1993. Compartmentalized Brain 126:71–94. cerebellar functions upon the stabilization of body 93 Andreasen NC, O’Leary DS, Cizadlo T, et al. 1996. posture. Rev Neurol (Paris) 149:654–64. Schizophrenia and cognitive dysmetria: a positron- 78 Bastian AJ, Morton S. 2007. Mechanisms of cerebellar emission tomography study of dysfunctional gait ataxia. Cerebellum 6(1):79–86. prefrontal-thalamic-cerebellar circuitry. Proc Natl 79 Friedemann HH, Noth J, Diener HC, Bacher M. 1987. Acad Sci (USA) 93:9985–90. Long latency EMG responses in hand and leg muscles: 94 Schmahmann JD, Sherman JC. 1998. The cerebellar cerebellar disorders. J Neurol Neurosurg Psychiatry cognitive affective syndrome. Brain 121(Pt 4):561–79. 50(1):71–7. 95 Schalling, E, Hammarberg B, Hartelius L. 2008. A lon- 80 Jacobs JV, Horak FB. 2007. Cortical control of postural gitudinal study of dysarthria in spinocerebellar ataxia responses. J Neural Transm 114(10):1339–48. aspects of articulation, prosody and voice. Journal of 81 Manto M, Van Den Braber N, Grimaldi G, Lammertse Medical Speech-Language-Pathology 16(2):103–17. P. 2010. A new myohaptic instrument to assess wrist 96 Schutter DJLG, van Honk J. 2005. The cerebellum on motion dynamically. Sensors 10:3180–94. the rise of human emotion. Cerebellum 4:290–4. 82 Bastian AJ, Mink JW, Kaufman BA, Thach WT. 1998. 97 Schmahmann JD, Weilburg JB, Sherman JC. 2007. Posterior vermal split syndrome. Ann Neurol The neuropsychiatry of the cerebellum – insights from 44:601–10. the clinic. Cerebellum 6(3):254–67. 83 Ilg W, Giese MA, Gizewski ER, et al. 2008. The 98 Nagahama Y, Fukuyama H, Yamauchi H, et al. 1996. influence of focal cerebellar lesions on the control and Cerebral activation during performance of a card sort- adaptation of gait. Brain 131(Pt 11):2913–27. ing test. Brain 119(Pt 5):1667–75. 84 Pascual-Leone A, Grafman J, Clark K, et al. 1993. 99 Heath RG. 1977. Modulation of emotion with a brain Procedural learning in Parkinson’s disease and pacemaker: treatment for intractable psychiatric cerebellar degeneration. Ann Neurol 34(4):594–602. illness. J Nerv Ment Dis 165:300–17.

Albanese_c17.indd 277 12/24/2011 5:40:59 PM 278 Chapter 17

100 Levisohn L, Cronin-Golomb A, Schmahmann JD. 116 Yarom Y, Cohen D. 2002. The olivocerebellar system 2000. Neuropsychological consequences of cerebel- as a generator of temporal patterns. Ann N Y Acad lar tumour resection in children: cerebellar cognitive Sci 978:122–34. affective syndrome in a paediatric population. Brain 117 Aso K, Hanakawa T, Aso T, Fukuyama H. 2010. 123:1041–50. Cerebro-cerebellar Interactions Underlying Temporal 101 Koziol LF, Budding DE. 2009. Subcortical structures Information Processing. J Cogn Neurosci. [Epub and cognition. Implications for neuropsychological ahead of print.] assessment. Springer, New York. 118 Sainburg RL, Ghez C, Kalakanis D 1999. 102 Riva D, Giorgi C. 2000. The cerebellum contributes Intersegmental dynamics are controlled by sequen- to higher functions during development: evidence tial anticipatory, error correction and postural from a series of children surgically treated for poste- mechanisms. J Neurophysiol 81:1045–56. rior fossa tumors. Brain 123(Pt 5):1051–61. 119 Wolpert DM, Miall RC. 1996. Forward models for 103 Gao JH, Parsons LM, Bower JM, et al. 1996. Cerebellum physiological motor control. Neural Networks implicated in sensory acquisition and discrimination 9:1265–79. rather than motor control. Science 26:545–7. 120 Nowak DA, Topka H, TimmannD, et al. 2007. The 104 Manzoni D. 2007. The cerebellum and sensorymotor role of the cerebellum for predictive control of grasp- coupling: looking at the problem from the perspec- ing. Cerebellum 6:7–17. tive of vestibular reflexes. Cerebellum 6:24–37. 121 Ramnani N. 2006. The primate cortico-cerebellar 105 Pellionisz A, Llinas R. 1980. Tensorial approach to system: anatomy and function. Nat Rev Neurosci the geometry of brain function:cerebellar coordina- 7:511–22. tion via a metric tensor. Neuroscience 5:1125–38. 122 Manto M, Bastian A. 2007. Cerebellum and the 106 Middleton FA, Strick PL. 1997. Cerebellar output deciphering of motor coding. Cerebellum 6:3–6. channels. In: Schmahmann JD (ed) The Cerebellum 123 Ioffe ME, Chernikova LA, Ustinova KI. 2007. Role of and Cognition. Academic Press. San Diego, pp 61–82. cerebellum in learning postural tasks. Cerebellum 107 Butz M, Timmermann L, Gross J, et al. 2006. 6:87–94. Oscillatory coupling in writing and writer’s cramp. 124 Roitman AV, Pasalar S, Johnson MT, Ebner TJ. 2005. J Physiol Paris 99:14–20. Position, direction of movement, and speed tuning 108 Soteropoulus DS, Baker SN. 2006. Cortico-cerebellar of cerebellar Purkinje cells during circular manual coherence during a precision grip task in the monkey. tracking in monkey. J Neurosci 25:9244–57. J Neurophysiol 95:1194–1206. 125 Ito M. 2006. Cerebellar circuitry as a neuronal 109 Bower JM. 1997. Control of sensory data acquisition. machine. Prog Neurobiol 78:272–303. Int Rev Neurobiol 41:489–513. 126 Rothganger FH, Anastasio TJ. 2009. Using input 110 Fujita M. 1982. Adaptive filter model of the cerebel- minimization to train a cerebellar model to simulate lum. Biol Cybern 45:195–206. regulation of smooth pursuit. Biol Cybern 111 Braintenberg V. 1967. Is the cerebellar cortex a 101(5–6):339–59. biological clock in the millisecond range? Prog Brain 127 Maschke M, Gomez CM, Ebner TJ, Konczak J. 2004. Res 25:334–6. Hereditary cerebellar ataxia progressively impairs 112 Ivry RB, Spencer RM. 2004. The neural representa- force adaptation during goal-directed arm move- tion of time. Curr Opin Neurobiol 14:225–32. ments. J Neurophysiol 91:230–8. 113 Oulad Ben Taib N, Manto M. 2008. Effects of trains of 128 Shidara M, Kawano K, Gomi H, Kawato M. 1993. high-frequency stimulation of the premotor/supple- Inverse-dynamics model eye movement control by mentary motor area on conditioned corticomotor Purkinje cells in the cerebellum. Nature 365:50–2. responses in hemicerebellectomized rats. Exp Neurol 129 Pasalar S, Roitman AV, Durfee WK, Ebner TJ. 2006. 212:157–65. Force field effects on cerebellar Purkinje cell dis- 114 Wolpert DM, Miall RC, Kawato M. 1998. Internal charge with implications for internal models. Nat models in the cerebellum. Trends Cogn Sci 2:338–347. Neurosci 9:1404–11. 115 Ivry RB, Keele SW, Diener HC. 1988. Dissociation of 130 Ito M. 2008. Control of mental activities by internal the lateral and medial cerebellum in movement timing models in the cerebellum. Nat Rev Neurosci and movement execution. Exp Brain Res 73:167–80. 9(4):304–13.

Albanese_c17.indd 278 12/24/2011 5:40:59 PM CHAPTER 18 Inherited and Sporadic Ataxias Hélio A.G. Teive,1 Renato P. Munhoz,1 and Tetsuo Ashizawa2 1 Neurology Service, Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil 2 Department of Neurology, University of Florida, Gainesville, FL, USA

Introduction Video 18.1 Ataxia phenomenology Ataxic gait (wide base, awkward turning, inability to Ataxia is a broad term, commonly referring to perform tandem gait), abnormal standing (astasia; able motor incoordination [1]. Ataxias may be classified to stand with normal stance and toes together but not as (i) cerebellar, when the cerebellum and its with feet in the tandem position), normal sitting, mild afferent or efferent projections are affected; dysarthria, dysmetria on the finger chase test, intention (ii) sensory, when the proprioceptive pathways are tremor on the nose-finger test, and abnormal heel-to- shin test. affected; (iii) frontal, a form related to cerebello- frontal disruption; (iv) thalamic, due to cerebello- thalamo-cortical loop damage; and (v) vestibular, due to labyrinthine dysfunction. Patients with cerebellar ataxia commonly show unbalanced gait and station, dystasia, dysmetria, intention tremor, dysdiadochokinesia, dyssynergia, decomposition of the movement and scanning dysarthria (see Video http://bit.ly/uc53ar 18.1). Additionally, they may show titubation, hypotonia, pendular reflexes, loss of check, nystagmus and saccadic and pursuit disorders of adoption may present as sporadic cerebellar ataxias. oculomotor movements, and cerebellar cognitive However, most sporadic cerebellar ataxias remain affective syndrome [2, 3]. as idiopathic degenerative cerebellar ataxias, Cerebellar ataxias can be classified into heredi- which include the cerebellar form of multiple tary, sporadic and symptomatic (secondary) system atrophy (MSA-C), and sporadic adult-onset varieties. Hereditary cerebellar ataxias are further cerebellar ataxia of unknown etiology (SAOA; also classified into disorders of autosomal recessive known as idiopathic late onset cerebellar ataxias (ARCA), autosomal dominant (ADCA), X-linked or idiopathic sporadic cerebellar ataxia) [3–5]. and mitochondrial inheritance. Sporadic cerebellar Symptomatic (secondary) cerebellar ataxias are ataxias are those without identifiable heritability of caused by acquired disorders, such as vascular, the disease. Thus, recessive disorders, mitochon- toxic, neoplastic, paraneoplastic, immune-mediated, drial disorders, and other hereditary cases with de nutritional, infectious, traumatic, and endocrine novo mutations, non-paternity or unrecognized disorders [1].

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Some patients with idiopathic cerebellar ataxias Video 18.2 Friedreich ataxia have congenital disorders with no progression of the disease after birth. These patients may have This patients is affected by Friedreich ataxia (GAA trinucleotide repeat expansion in the FXN gene). some forms of cerebral palsy or other developmen- Hypermetric saccadic movements are visible. [Video tal disorders. In this chapter we focus on progres- courtesy of Alberto Albanese, MD, Milan, Italy] sive cerebellar ataxias of non-congenital onset. The OMIM number in Tables 18.1 and 18.2 links each disease to an extensive genetic, phenotypic and mechanistic description of the disease in the Online Mendelian Inheritance in Man database of the National Center for Biological Information (NCBI).1

Readers should also visit the NCBI GeneReview http://bit.ly/vXYkxR database2 for information. diagnosis and treatment. The GeneReview site also links to GeneTest, which provides information regarding where and how DNA testing of hereditary ataxias can be obtained. Descriptions of ataxic disorders that are not refer- 2–4/100,000 [9]. In FA, the defective upright insta- enced in this chapter can be found in these bility is primarily attributable to sensory ataxia due databases. to the degeneration of dorsal root ganglia, dorsal column and spinocerebellar tract. Although signs of Autosomal Recessive Cerebellar cerebellar ataxia are clinically detectable, cerebellar Ataxias (ARCAs) atrophy is not prominent on MRI. The genetic and clinical description on FA is summarized in Table 18.1. Square wave jerks on oculomotor ARCAs are typically characterized by cerebellar and examination3 often provides a diagnostic clue. spinal cord degeneration with a relatively early age Although ataxia and hyporeflexia have been tradi- at onset (Table 18.1) [6, 7]. The pathogenesis of tionally thought to be the clinical hallmarks of FA, ARCAs most commonly involve “loss of function” many patients with documented FA have hyperre- of proteins related to mitochondrial function, DNA flexia, spasticity and a variety of hyperkinetic repair, cerebellar or brain stem development, movement disorders including tremor, myoclonus, structural maintenance, or cell cycle and homeo- chorea and dystonia [9A]. stasis [8]. Frataxin is a mitochondrial protein whose loss ARCA due to mitochondrial due to the intronic expansion of the GAA repeat dysfunction leads to excess free radical production, disrupted These are disorders caused by nuclear genes encod- iron-sulfur clusters and mitochondrial iron ing mitochondrial proteins (see “Mitochondrial accumulation. [10, 11]. Antioxidants, such as ide- ataxias” below). benone (Coenzyme Q10 analogue), pioglitazone (PPAR gamma ligand), A0001 (alpha-tocopherolqui- Friedreich ataxia none), iron chelators, such as desferrioxamine and Friedreich ataxia (FA), described in 1863 by deferiprone, and, carbamylated erythropoietin have Nicholaus Friedreich, is the most common form of been already in clinical trials (www.clinicaltrials. ARCA in Caucasians, with the prevalence of gov). Histone deacetylase (HDAC) inhibitors have

1 (http://www.ncbi.nlm.nih.gov/omim). 2 (http://www.ncbi.nlm.nih.gov/sites/GeneTests/review? 3 (http://video.google.com/videoplay?docid= db=GeneTests) 5998952712276825620#)

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Table 18.1 Autosomal recessive cerebellar ataxias (ARCAs).

ARCA OMIM # Gene, Locus Mutated protein/mutation Age at onset (years) Phenotype description

Friedreich’s Ataxia #229300 FTX, 9q13–21 Frataxin/ 90–1300 GAAs Typically <25, later Ataxia (sensory ataxia and cerebellar ataxia); hypo-or (FA) (FRDA2, 9p23–p11) (normal 6–36); 5% of FA in late onset FA areflexia, (reflexes retained in FARR); sensory loss with axonal patients are compound (LOFA) neuropathy; square wave jerks on oculomotor exam; heterozygotes with an pyramidal weakness with extensor plantar reflexes - often expansion on one allele and accompanies cardiomyopahty, diabetes mellitus, pes cavus, a point mutation on the scoliosis, sensorineural deafness and optic atrophy. other. (Protein and mutation unknown for FRDA2) Ataxia Telangiectasia #208900 ATM, 11q22–23 Phosphatidylinositol Ataxia at 2–4, Loss Ataxia, conjunctival telangiectasias (Figure 1), oculomotor (AT) 3-kinase-type enzyme of ambulation <10 apraxia, hyperkinesia, hyporeflexia, malignancies, reduced levels of IgA, IgE, and IgG, elevated serum α-fetoprotein, and gray hair and skin keratoses. Ataxia with #208920 APTX, 9p13.3 Aprataxin 2–6 Ataxia followed by oculomotor apraxia, distal muscle oculomotor apraxia 1 weakness and atrophy, and proprioceptive sensory loss, (AOA1) occasional dystonia, hypomimia and mental retardation. Ataxia with #606002 SEXT, 9q34 Senataxin 10–22 Ataxia, hyperkinesia, peripheral neuropathy and areflexia. oculomotor apraxia 2 Oculomotor apraxia in ~20% of cases. Skeletal and foot (AOA2) deformities. Elevated α-fetoprotein, gamma-globulin, and creatine kinase levels in the serum. Spinocerebellar ataxia #607250 TDP1, 14q31 Tyrosyl-DNA Early childhood Ataxia, axonal neuropathy with distal amyotrophy, pes cavus, with axonal phosphodiesterase-1 mild hypercholesterolemia and hypoalbuminemia. neuropathy (SCAN1) Abetalipoproteinemia #200100 MTP, 4q22–24 Microsomal triglyceride 6–12 Ataxia, areflexia, distal amyotrophy and loss of transfer protein proprioception, with lipid malabsorption, acanthocytosis, retinopathy. Ataxia with primary #277460 α-TTP, 8q13 α-tocopherol-transporter- Typically <25 Similar to FA without cardiomyopathy or impaired glucose vitamin E deficiency protein metabolism. Titubation may be present in 1/3 of cases. (AVED) Plasma vitamin E level <10% of normal. Cayman cerebellar #601238 ATCAY, 19p13.3 Caytaxin At birth Hypotonia, mental and physical retardation, non-progressive ataxia ataxia. Spastic ataxia of #270550 SACS, 13q11 Sacsin <13 Ataxia and spasticity with distal muscle wasting, finger/foot 22/0172:8AM 7:26:28 12/24/2011 7:26:28AM Charlevoix-Saguenay deformities and hypermyelination of retinal nerve fibers.

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Table 18.1 (cont’d).

ARCA OMIM # Gene, Locus Mutated protein/mutation Age at onset (years) Phenotype description

Marinesco-Sjögren #248800 SIL1, 5q31 18qter SIL1 Unknown gene or <1 Ataxia, congenital cataracts, short statue and mental syndrome unknown, protein for this 2nd locus retardation with neuromuscular disorders (demyelinating polyneuropathy and recurrent rhabdomyolysis. Refsum disease #266500 PHYH, 10pter–p11 Phytanoyl-CoA hydroxylase Early childhood-50s Ataxia, retinitis pigmentosa (night blindness polyneuropathy, high cerebrospinal fluid protein without pleocytosis, and elevated phytanic acid. Infantile Refsum #266510 PEX1 7q21–q22 Peroxin 1(peroxisome <1 A phenotype similar to adult-onset Refsum disease; atypical disease PEX2 8q21.1 biogenesis factor 1) Peroxin retinitis pigmentosa, peripheral neuropathy and cerebellar PEX26 22q11.21 2 (peroxisomal assembly ataxia with elevated phytanic acid but associated with severe factor 1) Peroxin 26 deafness, mental and growth retardation, facial dysmorphism and hepatomegaly with elevated very long chain fatty acids (VLCFA). Cerebrotendinous #213700 CYP27, 2q33-qter Sterol 27-hydroxylase <10 Diarrhea, jaundice, hepatitis, cataracts, optic disk pallor, and xanthomatosis premature retinal senescence with retinal vessel sclerosis and hypermyelinated retinal nerve fibers in the first decade of life, xanthomas on tendons and neurological signs with mental retardation, dementia, hyperkinesias, and cerebellar ataxia in 2nd and 3rd decades. Posterior column %609033 unknown, 1q31 Unknown Childhood (ataxia A ring scotoma gradually leading to blindness, sensory ataxia and retinitis in the 2nd decade) ataxia, proprioceptive sensory loss, amyottrophy, weakness pigmentosa (AXPC1) and areflexia. Ataxia of the Beauce #610743 SYNE1, 6q25 Synaptic nuclear envelope 1 Typically middle Pure cerebellar ataxia with occasional lower limb age hyperreflexia. SeSAME syndrome #612780 KCNJ10, 1q23.2–q23.3 Inwardly rectifying <1 Seizures, sensorineural deafness, ataxia, mental retardation potassium channel and electrolyte imbalance. 22/0172:8AM 7:26:28 12/24/2011 7:26:28AM Inherited and Sporadic Ataxias 283

been proposed to reduce the mitochondrial iron overload. Idebenone has been suggested to show a dose-related neurologic benefit in a phase II trial. However, the current clinical management of patients with FA largely depends on symptomatic and supportive treatments although the management of cardiomyopathy, diabetes and dysphagia may be of particular importance.

ARCA due to coenzyme Q10 deficiency Coenzyme Q10 (CoQ10), or ubiquinone, is a mobile lipophilic electron carrier critical for electron transfer in the mitochondria. While primary CoQ10 Figure 18.1 Telangiectasia in the sclera in ataxia deficiency has variable phenotypes, the ataxic form telangiectasia. (See color plate 18.1) is characterized by childhood-onset and cerebellar atrophy, reduced levels of muscle CoQ10, lactic Ataxia with oculomotor apraxia academia, elevated serum creatine kinase (CK) and Ataxia with oculomotor apraxia 1 episodic myoglobulinemia. Additional features Clinical and genetic characteristics of AOA1 [15] include seizures, myoclonus, mental retardation, are summarized in Table 18.1. AOA1 often muscle weakness, fatigability, hyporeflexia and accompanies axonal neuropathy, cerebellar and pyramidal signs. Oral high-dose CoQ10 may brainstem atrophy, hypoalbuminemia and hyper- dramatically improve the clinical manifestations cholesterolemia. AOA1 is the most frequent reces- [12]. Primary CoQ10 deficiency is cause by muta- sive ataxia in Japan, while it is the second most tions in the decaprenyl diphosphate synthase common, after FRDA, in Portugal. subunit–2 (PDSS2), PDSS1, CABC1, COQ2 and COQ9, and possibly, APTX genes [13]. Ataxia with oculomotor apraxia 2 Ataxia with oculomotor apraxia type 2 (AOA2) ARCA due to DNA repair defects [15] represents ∼8% of non-FA ARCA. Clinical and Ataxia telangiectasia genetic features are summarized in Table 18.1. Ataxia telangiectasia (AT), described in 1941 by Additionally, cerebellar atrophy and axonal sensory Louis-Bar, is the second most common cause of neuropathy are often found. Senataxin possibly progressive cerebellar ataxia in childhood, after acts in the DNA repair pathway and splicing FRDA, with a prevalence of 1 in 105 live births [14]. machinery. Dominant mutations in SETX gene Clinical manifestations, including telangiectasia cause ALS4, an autosomal dominant form of (Figure 18.1), are summarized in Table 18.1. Brain amyotrophic lateral sclerosis. imaging shows cerebellar atrophy. Most patients die by 20, usually from bronchopneumonia or Spinocerebellar ataxia with axonal malignancy. Treatment with conventional dosages neuropathy (SCAN1) of radiation can be fatal in AT patients. Patients See reference [16] and Table 18.2. with “variant” AT have an extended lifespan with a milder disease. ARCA due to vitamin E deficiency The ATM gene encodes a nuclear phosphoprotein and related disorders (phosphatidylinositol 3-kinase-type enzyme) that Vitamin E is an antioxidant, which scavenges acts in DNA-damage checkpoint processes and peroxyl radicals in cell membranes. Of various forms repair. The precise pathogenic role of ATM for ataxia of vitamin E, α-tocopherol has the highest biological is unknown. activity. In the liver, the α-tocopherol-transfer-protein

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(TTPA) incorporates α-tocopherol in the very-low In a single gigantic exon spanning 12,794 bp of density lipoproteins (VLDL). the SACS gene, 29 different mutations have been Deficiency of vitamin E may also be a consequence found in Quebec, Turkey, Tunisia, Italy, Spain, of lipid malabsorption, abetalipoproteinemia (ABL), Japan, Belgium, and Holland. or primary vitamin E deficiency. In these conditions, ataxia is usually part of a multisystem disorder Marinesco-Sjögren syndrome (MSS) caused by multiple defects of other lipid-soluble MSS was described in 1931 by Marinesco, vitamins and essential factors, such as vitamin A in Draganesco, and Vasiliu’. In addition to core ABL. Early treatment with high-dose vitamin E features described in Table 18.1 [19, 20], patients and other supplements can delay THE disease show often laboratory abnormalities, including sus- progression or even prevent the onset of tained or episodic elevation of serum creatine neurological deficits [17]. kinase and hypergonadotropic hypogonadism. Treatment is symptomatic, and cataractectomy and Abetalipoproteinemia hormonal replacement therapy may be needed. (Bassen Kornzweig disease) Patients survive to old age with varying disability. See Table 18.2. Other ARCAs with known mutations Other ARCAs with known mutations include Ataxia with primary vitamin E Refsum disease, cerebrotendinous xanthomatosis, deficiency (AVED) SeSAME syndrome (seizures, sensorineural deaf- AVED was first described by Burck in 1981 in cases ness, ataxia, mental retardation, and electrolyte with a phenotype similar to FA. The disease is fre- imbalance), recessive ataxia of the Beauce (SYNE1 quent in North-Africans and other Mediterranean ataxia), and posterior column ataxia with retinitis populations with distinct nonsense mutations. pigmentosa (Table 18.1; also see OMIM4 and Plasma vitamin E levels are usually less than 10% GeneReview5). of normal values, and daily supplementation with high dosage of vitamin E is necessary and Other autosomal recessive ataxias effective. with unknown genetic loci There are many autosomal recessive ataxias in Cayman cerebellar ataxia which neither genetic loci nor mutations are Cayman cerebellar ataxia (CCA) was identified in known. Among them, some disorders appear to be an isolated population from Grand Cayman islands. phenotypically distinct but they are almost certainly Caytaxin, the protein mutated in Cayman cerebel- genetically heterogeneous. lar ataxia, contains a CRAL-TRIO domain, which is also present in TTPA [17]. Hyperkinetic movement disorders in ARCAs ARCA due to chaperon protein Chorea, dystonia, myoclonus, and tremor are often deficiency seen as extrapyramidal signs of ARCAs. Patients Spastic ataxia of Charlevoix-Saguenay with FA may show generalized or primarily upper Autosomal recessive spastic ataxia of Charlevoix- body chorea – in some cases even without cerebel- Saguenay (ARSACS, see Table 18.1) [18] was lar signs. Some patients with FA may also show described by Bouchard in 1978 in the Charlevoix- dystonia, myoclonus, and head tremor. Chorea is Saguenay-Lac-Saint-Jean region of Quebec (carrier frequency, 1 in 22 individuals). Main pathological findings comprise atrophy of the upper vermis and 4 http://www.ncbi.nlm.nih.gov/omim loss of Purkinje cells in the cerebellum. Rare 5 http://www.ncbi.nlm.nih.gov/sites/GeneTests/review? patients with ARSACS lack spasticity. db=GeneTests

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Table 18.2 Autosomal dominant cerebellar ataxias (ADCAs).

ADCA OMIM # Gene, Locus Primary Pathogenic Gene Harding’s ADCA Age at Phenotype Description Product Mutation type/Anticipation Onset (years)

SCA1 #164400 ATXN1, 6p23 Ataxin-1 40–82 CAGs (normal ADCA 1 5–70 Ataxia, spasticity, dysarthria, ophthalmoplegia, 6–44; CAT interruptions in large Anticipation (+) hypermetric saccades, nystagmus, optic atrophy, normal alleles) pyramidal tract signs; rare extrapyramidal; signs; some have dementia; neuropathy and slow saccades occur late SCA2 #183090 ATXN2, 12q24 Ataxin-2 33–64 CAGs (normal ADCA 1 9–44 Ataxia, dysarthria, muscle cramps; slow saccades/ 14–31, intermediate 34–35 with Anticipation (+) ophthalmoplegia; peripheral neuropathy, CAA interruptions) hyporeflexia, dementia in some; no pyramidal or extrapyramidal features except for dopa- responsive parkinsonism at young ages with a small CAG expansion. An infantile form suggested. SCA3 or #109150 ATXN3, 14q24.3–q31 Josephin (Ataxin-3) 52–86 CAGs ADCA 1 17–72 Ataxia, dysarthria, ophthalmoplegia; type I onset Machado-Joseph (normal 12–44, intermediate Anticipation (+) in mid 20s with facial-lingual myokymia, disease, 45–51 with reduced penetrance) pyramidal and extrapyramidal features; type II onset in 40s; type III onset in mid 40s with peripheral neuropathy (weakness and atrophy) SCA4 %600223 Gene 16q22.1 (same ADCA 1 or 3 19–72 Pure ataxia in some cases, most have sensory unknown, region as axonal neuropathy; deafness in some #117210 below) SCA5 #600224 SPTBN2, 11p13 Spectrin beta chain, brain 2 ADCA 3 10–68 Downbeat nystagmus; ataxia, dysarthria, Anticipation has impaired smooth pursuit, and gaze-evoked been reported nystagmus; slow progression; both vermian and hemispheric cerebellar atrophy, normal life expectancy SCA6 #183086 CACNA1A, 19p13 Voltage-dependent P/Q-type Ca+2 ADCA 3 22–71 Ataxia, dysarthria, nystagmus, distal sensory channel alpha-1a subunit 19–33 Anticipation (−) loss, normal life expectancy CAGs (normal 4–18) SCA7 #164500 ATXN7, 3p21.1–p12 Ataxin-7 37–300+ CAGs (normal ADCA 2 0–50 Pigmentary retinal degeneration, ataxia, 4–27, intermediate 28–35) Anticipation (+) dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signs SCA8 #608768 ATXN8OS, 13q21 ATXN8OS RNA 3’UTR (CUG)n and ADCA 3 20s–70s Ataxia, dysarthria, nystagmus, impaired smooth opposite-strand PolyQ 107–250 Anticipation (−) pursuit

22/0172:9AM 7:26:29 12/24/2011 7:26:29AM CTG/CAG (normal 16–91)

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Table 18.2 (cont’d).

ADCA OMIM # Gene, Locus Primary Pathogenic Gene Harding’s ADCA Age at Phenotype Description Product Mutation type/Anticipation Onset (years)

SCA9 Unassigned Unassigned category category SCA10 +603516 ATXN10, 22q13 Ataxin-10 intron RNA 850–4500 ADCA 3 10–50 Ataxia, dysarthria, nystagmus, epileptic ATTCTs (normal 10–29; reduced Anticipation (+) seizures; to date only found in Mexican and penetrance 280–850) Argentinean families SCA11 %604432 SCA11, Tau-tubulin kinase 2 ADCA 3 20–40 Ataxia, dysarthria, nystagmus 15q14–q21.3 Anticipation (−) SCA12 #604326 PPP2R2B, 5q31–q33 Ser/thr protein phosphatase 2A, ADCA 1 8–55 Upper extremity and head tremor, gait ataxia, 55-kd regulatory subunit B, beta Anticipation (−) ophthalmoplegia, hyperreflexia, bradykinesia, isoform 55–78 CAGs in 5’UTR dementia (normal 7–32) SCA13 #605259 KCNC3, 19q13.3–q13.4 Voltage-gated K+ channel, ADCA 3 4–82 Ataxia, dysarthria, mental retardation; slow subfamily C member 3 Anticipation (−) progression, seizures SCA14 #605361 PRKCG, 19q13.4 Kinase C, gamma type; ADCA 3 Child to 60 Ataxia, dysarthria, nystagmus; younger patients Anticipation (−) (<27 y) also had intermittent axial myoclonus prior to ataxia SCA15 SCA16 %606658 ITPR1, 3p26.1–p25.3 Inositol 1,4,5-triphosphate ADCA 3 10–66 Slowly progressive pure cerebellar ataxia, receptor type 1 Large deletion Anticipation (−) dysarthria, tremor; may have head titubation, nystagmus, oculovestibular reflex abnormalities, mild hyperreflexia SCA17 #607136 TBP, 6q27 TATA-box–binding protein 47–63 ADCA 1 7–49 Ataxia, pyramidal, extrapyramidal, and, possibly CAGs (normal 25–44, 46–47 with Anticipation (+) autonomic dysfunctions; dementia, psychosis, reduced penetrance); CAA degeneration of caudate, putamen, thalamus, interruptions frontal cortex, temporal cortex, and cerebellum SCA18 %607458 SCA18, 7q22–q32 Unknown; IFRD1 has been a ADCA 1 20s–30s Sensorimotor axonal neuropathy with ataxia; candidate Anticipation (−) gait abnormality, dysmetria, hyporeflexia, muscle weakness and atrophy, decreased vibratory and proprioceptive sense SCA19 SCA22 %607346 1p21–q21 Unknown IDCA 3 12–40 Ataxia, hyporeflexia, dysphagia, dysarthria, and Anticipation has gaze-evoked horizontal nystagmus; cerebellar been reported atrophy on MRIs SCA20 %608687 SCA20 Unknown IDCA 1 or 3 19–64 Dysarthria, gait and upper limb ataxia, slow −

22/0172:9AM 7:26:29 12/24/2011 7:26:29AM 11p13–q11 Anticipation ( ) progression; more variable features are mild pyramidal signs, hypermetric saccades, nystagmus, palatal tremor, slow cognitive decline; CT scan shows dentate calcification laeec8id 287 Albanese_c18.indd 287

SCA21 %607454 SCA21, 7p21–15 Unknown ADCA 1 6–30 Cerebellar ataxia, limb ataxia and akinesia, Anticipation (−) dysarthria, dysgraphia, hyporeflexia, postural tremor, resting tremor, rigidity, cognitive impairment, cerebellar atrophy SCA23 %610245 20p13–12.3 Unknown ADCA 1 40s–50s Slow progression; gait and limb ataxia, Anticipation (−) dysarthria (varies), slow saccades and ocular dysmetria, decreased vibratory sense, pyramidal signs; severe cerebellar atrophy SCA25 %608703 SCA25, 2p21–p13 Unknown ADCA 1 1–39 Invariable features are cerebellar ataxia; Anticipation (−) variable features are lower limb areflexia, peripheral sensory neuropathy, nystagmus, decreased visual acuity, facial tics, extensor plantar responses, urinary urgency, and gastrointestinal symptoms SCA26 %609306 19p13.3 Unknown ADCA 3 26–60 Pure cerebellar signs, including ataxia of the Anticipation (−) trunk and limbs, dysarthria, and irregular visual pursuit movements; intelligence normal; MRI shows atrophy of cerebellum, sparing pons and medulla SCA27 #609307 FGF14, 13q34 Fibroblast growth factor 14 ADCA 1 12–20 Cerebellar ataxia, tremor, low IQ, aggressive Anticipation (−) behavior, eye movement abnormalities are nystagmus, cerebellar dysarthria, head tremor, orofacial dyskinesias, cerebellar atrophy, pes cavus, axonal sensory neuropathy, neuronal loss in cerebral cortex, amygdala, and basal ganglia SCA28 %610246 AFG3L2, 18p11.22–q11.2 AFG3-like protein 2 ADCA 1 12–36 Imbalance and mild gait incoordination; Anticipation (−) gaze-evoked nystagmus, slow saccades, ophthalmoparesis, and, often, ptosis; frequently lower limb hyporeflexia SCA29 %117360 3p26 Genetic Unknown ADCA 3 Birth Non-progressive cerebellar ataxia heteroge- Anticipation (−) neity? SCA30 %613371 4q34.3–q35.1 Unknown ADCA 3 45–76 Slowly progressive gait and appendicular Anticipation (−) cerebellar ataxia, hypermetric saccades, some with hyperreflexia SCA31 #117210 BEAN, 16q21–q22 Brain-expressed associated with ADCA 3 45–72 Pan-cerebellar ataxia, decreased muscle tone, NEDD4 2.5–3.8 kb insertion Anticipation (−) horizontal gaze nystagmus

22/0172:0AM 7:26:30 12/24/2011 7:26:30AM containing pentanucleotide repeat including (TGGAA)n

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Table 18.2 (cont’d).

ADCA OMIM # Gene, Locus Primary Pathogenic Gene Harding’s ADCA Age at Phenotype Description Product Mutation type/Anticipation Onset (years)

Dentatorubral- #125370 DRPLA, 12p13.31 Atropin-1–related protein 49–88 ADCA 1 1–70 Myoclonic epilepsy, dementia, ataxia, pallidoluysian CAGs (normal 3–36) Anticipation (+) choreoathetosis, degeneration of dentatorubral atrophy (DRPLA) and pallidoluysian systems Episodic ataxia #160120 KCNA1, 12p13 K+1 voltage-gated channel (A1) Episodic ataxia Early Continuous muscle movement (myokymia) and type 1, EA1 Anticipation (−) child-hood periodic ataxia Episodic ataxia #108500 CACNA1A, 19p13 Voltage-dependent P/Q-type Ca+2 Episodic ataxia Before 10 Ataxia, downbeating nystagmus dizziness type 2, EA2 channel alpha-1A subunit Anticipation (−) treated with acetazolamide; no progression after childhood; cerebellar atrophy Episodic ataxia %606554 1q42 Unknown Episodic ataxia 1–42 Vestibular ataxia, vertigo, tinnitus, interictal type 3, EA3 Anticipation (−) myokymia Episodic ataxia %606552 Unknown Unknown Episodic ataxia 20s–50s Recurrent attacks of vertigo, diplopia, and type 4, EA4 Anticipation (−) ataxia; some with slowly progressive cerebellar ataxia with defective smooth pursuit and gaze-evoked nystagmus Episodic ataxia +601949 CACNB4, 2q22–q23 Voltage-dependent L-type Episodic ataxia 20–30 Ataxia similar to EA-2; severe episodic lasting type 5, EA5 calcium beta-4 subunit Anticipation (−) hours to weeks; interictal gait and truncal ataxia with mild dysarthria; nystagmus (downbeat, spontaneous, gaze evoked); seizures Choreo-athetosis %601042 12p13 Unknown Episodic ataxia 2–15 Paroxysmal choreoathetosis with episodic spasticity Anticipation (−) ataxia and spasticity episodic, CSE Autosomal %108600 SAX1, 12p13 Unknown ADCA 3 10–20 Lower limb spasticity, generalized ataxia, dominant spastic Anticipation (−) impaired ocular movements, gait ataxia, SPAX1 abnormalities; brain and cord MRIs normal; neuropathology shows midbrain neuronal loss 22/0172:0AM 7:26:30 12/24/2011 7:26:30AM Inherited and Sporadic Ataxias 289

the most frequent extrapyramidal sign in AT; in an advanced stage. These hyperkinetic movement however, early-onset dystonia and myoclonus have disorders in SCA7, SCA17, and DRPLA resemble also been found in AT. Patients with AOA1 typically those of Huntington disease although cerebellar show chorea in addition to ataxia; however, dysto- ataxia is a key feature in these diseases, and visual nia, myoclonus, and tremor seem to be rare. In loss distinguishes SCA7 from others. Upper limb contrast, about 15% of patients with AOA2 show action tremor is frequently seen in patients with tremor and dystonia, but chorea is less common in SCA2, SCA12, SCA21, and Japanese patients with AOA2 than in AOA1. In AVED head tremor and SCA15 although less prominent tremor may be dystonia are most common extrapyramidal signs. detected in other SCAs. Patients with SCA12 may Palatal myoclonus, tremor, and dystonia may be show dystonia in addition to tremor. Isolated cases found in some patients with cerebrotendinous of SCA8, SCA10 and, SCA14, which belong to xanthomatosis. ADCA type 3, have been reported with dystonia. Chorea may also be a rare sign of SCA14. In SCA20, palatal tremor and myoclonus may be prominent Autosomal dominant cerebellar features in some family. ataxias (ADCAs) Genetic classification ADCAs constitute a large, complex, group of and nomenclature of ADCAs heterogeneous autosomal dominant diseases of the In Human Genome Organization (HUGO) database, cerebellum and its afferent and efferent connec- the nomenclature of spinocerebellar ataxia (SCA) is tions, which may be accompanied by extracerebel- reserved for ADCAs whose locus has been mapped; lar signs such as ophthalmoplegia, pyramidal the number following “SCA” has been given signs, movement disorders (including parkinson- primarily in the order of identification of the locus, ism, dystonia, myoclonus, and chorea), dementia, hence SCA1 is the first one mapped. Currently, the epilepsy, visual disorders (including pigmentary number is up to 31, and specific genetic mutations retinopathy), lower motor neuron disease, and have been identified in SCAs types 1–3, 5–8, 10–17, peripheral neuropathy. There have been many 27, and 31. For the remaining types – SCAs 4, excellent reviews on ADCAs but the most recent 18–26, 28, 29 and 30 – the disease locus is defined reviews are by Durr [21] and Teive [5]. but the genes and mutations associated with them have not been identified. While SCA9 and SCA24 Harding’s classification of ADCAs were recessive ataxias and have been removed Harding classified progressive neurodegenerative from the SCA group, dentatorubral pallidoluysian ADCAs into four basic types [22]: atrophy (DRPLA) is usually counted as a SCA. • Type 1: ADCA with extracerebellar signs such as Mutations for SCAs 1–3, 6–8, 10, 12, 17, 31, and ophthalmoplegia, dementia, amyotrophy. and DRPLA involve short-tandem repeats (also known extrapyramidal signs. as microsatellite repeats), whereas SCAs 5, 11, • Type 2: ADCA with retinal degeneration and can 13–16, and 27 are caused by point mutations. SCA be accompanied by other extracerebellar signs. 16 has been identified as being identical to SC15. • Type 3: ADCA with “pure” cerebellar ataxia. SCAs 29 and 15, and SCAs 22 and 19, may repre- • Type 4: ADCA with deafness and myoclonus. sent different allelic forms of the same gene [5, 21].

Hyperkinetic movement disorders Epidemiology of SCAs in ADCAs The prevalence of SCAs has been estimated as 1 to Chorea, dystonia and myoclonus are seen in 5 per 100,000. SCA3 is the most common world- patients with ADCA type 1, most commonly in wide; SCAs 1, 2, 6, 7, and 8 have greatly varying SCA7, SCA17, and DRPLA but also in SCA1, 2, 3, prevalence depending on the ethnic background of especially in patients with an early-onset disease or the population [5, 21]. SCAs 12 and 17 are relatively

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Box18. 1 ALGORITHM FOR ASSESSING Video 18.3 SCA2 ataxia PATIENTS WITH SPINOCEREBELLAR This video shows two patients with SCA2 (expanded CAG ATAXIA (SCA): trinucleotide repeat in the ataxin-2 gene). The finger-to- nose maneuver reveals dysmetria and trunk instability. I – AUTOSOMAL DOMINANT CEREBELLAR ATAXIA + Ocular movements are slowed in all directions. Gait is SPECIFIC CLINICAL DATA (A to Q): wide-based with instability and tandem gait is not A- EPISODIC ATAXIA (EA): EA1,2,3,4,5,6 and 7. possible without holding the handrail. [Video courtesy B- SENSORY ATAXIA: SCA4. of Alberto Albanese, MD, Milan, Italy] C- VISUAL LOSS: SCA7. D- EPILEPSY: SCA10 and 13. E- MYOCLONUS + CHOREA + DEMENTIA: DRPLA and SCA17. F- OCULOMOTOR SIGNS: GO TO PART II – SCA1,2,3. G- MENTAL RETARDATION: SCA13. H- AXIAL MYOCLONUS: SCA14. I- HEAD TREMOR: SCA12 and 16. J- DEMENTIA + PARKINSONISM: SCA17 and 21. http://bit.ly/taBqOz K- PERIPHERAL NEUROPATHY: SCA2,3,4,10,18,24, and 25 L- POSTURAL TREMOR + MYOCLONUS: SCA19. M- PALATAL TREMOR + SPASMODIC DYSPHONIA: SCA20. Video 18.4 SCA3 ataxia + N- MYOCLONUS SACCADIC INTRUSIONS: SCA24. The phenomenology of ataxia is shown in this patient + O- POSTURAL TEMOR DYSKINESIAS: SCA17. affected by SCA3. He sits in a chair as is unable to walk P- PALPEBRAL PTOSIS: SCA28. or stand autonomously. The following features are Q- PURE CEREBELLAR ATAXIA: SCA 5,6,8,10,11,12,14, illustrated: mixed scanning and spastic dysarthria, 16,22,23,26,30 and 31. abnormal finger-to-nose and heel-to-sheen, intention II – OCULOMOTOR SIGNS (R, S, and T): tremor, dysmetric finger chase, slowing of pronation- R- NYSTAGMUS + HYPERMETRIC SACCADES supination alternating movements. (Associated to pyramidal signs): SCA type 1. S- SLOWED SACCADIC EYE MOVEMENTS + HYPOREFLEXIA: SCA type 2. T- NYSTAGMUS + OPHTHALMOPLEGIA + PHENOTYPIC VARIATION IN THE FAMILY (WITHOUT DEMENTIA, AND WITH OTHER SIGNS: PYRAMIDAL SIGNS + DYSTONIA + PARKINSONISM + PERIPHERAL NEUROPATHY + AMYOTROPHY http://bit.ly/tir8Bb + “BULGING EYES” + FACIAL FASCICULATIONS): SCA type 3 (With different subphenotypes). = DRPLA Dentatorubral-Pallidoluysian Atrophy. sensitivity of these findings can accurately determine the SCA type. Genotype determination by rare, and most patients with SCA12 have been seen DNA testing offers accurate and economical diagno- in India. SCAs 10 and 31 are rare but may be the sis when the result is positive. The DNA testing may second most common SCA in the Latin America identify SCA types in ∼60% of patients with an and Japan, respectively. SCAs 4, 5, 11, 13–15, autosomal dominant family history and ∼5% of 18–23, and 25–30 are very rare. patients with no family history. Table 18.2 summarizes core clinical features, genetic loci, mutations, Clinical and genetic diagnosis of SCAs and proteins of SCAs. Readers may wish to examine Diagnosing specific SCA types based on clinical the clinical diagnostic algorithms (Box 18.1) [23]. findings alone is a difficult task. There are some use- Some supplemental information is described below. ful clues for clinically diagnosing some of these SCAs. However, they are often overlapping with Clinical and genetic characteristics SCAs each other, and neither the specificity nor the See Table 18.1.

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Normal ADCA-III ADCA-I & II

Figure 18.2 Brain MRI of a normal subject (left), a patient with ADCA-III, and a patient with ADCA-I.

Neuroimaging studies polyglutamine tract causes neurodegeneration by a Neuroimaging, particularly magnetic resonance gain of toxic function [24]. imaging, reveals cerebellar atrophy (Figure 18.2), with or without brainstem involvement, roughly ADCA caused by expansion or insertion corresponding to Harding’s classification. Cerebral of non-coding short tandem repeats cortical atrophy may be seen in cases in which A second group of SCAs, which includes SCAs 8, dementia is a part of the SCA phenotype. 10, 12, and 31, is caused by an expansion of a non-coding microsatellite repeat [21, 25]. Clinical Pathogenic mechanisms of ADCAs and genetic characteristics of these SCAs are ADCAs caused by expanded polyglutamine- summarized in Table 18.2. SCA8, 10, and 31 coding CAG repeats cause the disease by producing toxic RNA with SCAs 1, 2, 3, 6, 7, and 17 and DRPLA are known as expanded untranslated CTG and ATTCT repeats polyglutamine expansion diseases and share some transcribed from their respective genes, although clinical, histopathological and molecular features the pathogenic mechanism of SCA8 may also with each other and with Huntington disease, involve the polyglutamine tract expansion which is also caused by an expansion of a CAG derived from the complementary strand (see repeat encoding a polyglutamine repeat (“polyQ”) GeneReview). In addition to ataxia, SCA8 may be tract. The CAG repeat size inversely correlates with associated with myoclonus and migraine head- the age of onset and generally correlates with the aches [25A]. In SCA12, an expansion of 5’UTR severity of the disease. Expanded mutant alleles are CAG appears to deregulate the activity of protein mostly unstable with tendency to further expand in phosphatase 2 (PP2), an enzyme that has an successive generations, causing anticipation, i.e. important function in Purkinje cells. the progressively earlier onset with increasingly severe disease in successive generations in affected ADCA caused by point mutations families. Existing evidence suggests that the This group of SCAs (SCA5, 11, 13, 14, 15, and 27) mutant protein product containing an expanded involves changes in the amino acid composition of

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the following proteins: βIII spectrin in SCA5, tau Mitochondrial ataxias tubulin kinase (TTBK2) in SCA11, potassium channels (KCNC3) in SCA13, protein kinase C gamma Mitochondrial ataxias usually combine cerebellar (PRKCG) in SCA14, inositol 1,4,5-triphosphate and sensory ataxia, among other features, due to receptor, type 1 (ITPR1) in SCA15, and fibroblast abnormalities of the mitochondrial DNA. They are growth factor 14 (FGF14) in SCA27. Most, if not maternally inherited ataxias due to point mutations all, of these diseases are caused by a loss-of-function in genes coding for RNAs, respiratory chain subu- of the respective genes [21]. nits or deletions/duplications of the mitochondrial DNA. This group includes myoclonic epilepsy asso- Hereditary episodic ataxias ciated with ragged-red fibers (MERRF), neuropathy, Hereditary episodic ataxias (EAs) are character- ataxia and retinitis pigmentosa (NARP), KSS, ized by recurrent episodes of ataxia and vertigo, as mitochondrial myopathy, encephalopathy, lactic well as progressive CA. To date, seven forms of EA acidosis, and stroke-like episodes (MELAS), have been identified, the most common been type infantile-onset spinocerebellar ataxia (IOSCA), and 1 (EA1) and type 2 (EA2), which are both second- mitochondrial recessive ataxia syndrome (MIRAS). ary to genetic mutations coding for membrane MIRAS is caused by the mutation in the mitochon- proteins that constitute ion channels and drial DNA polymerase gamma (POLG) [28]. transporters. Clinically, EAs are characterized by childhood-onset episodes of ataxia, lasting from seconds to minutes, triggered by physical exertion Sporadic ataxias and stress, and interictal myokymia. EA2 is an allelic disorder of familial hemiplegic migraine Sporadic ataxias with adult onset represent a type 1 and SCA6, which are all caused by muta- challenging group of acquired ataxias and idio- tions in the CACNA1A gene. EA2 is characterized pathic degenerative ataxias. Autosomal recessive, by episodes of ataxia (lasting hours to days), X-linked, and mitochondrial ataxias may be and interictal nystagmus, with childhood or presented as sporadic cases. Even in autosomal adolescence onset [26]. dominant ataxias, non-paternity, unrecognized adoption, reduced penetrance and de novo mutation may result in apparent sporadic cases. About 5% of X-Linked ataxias adult-onset ataxias without positive family history may have positive genetic testing for one of the The most clinically relevant and common form is SCAs. Conversely, phenocopies have been found the fragile X/tremor/ataxia syndrome (FXTAS) when an individual with ataxia shows a negative described by Hagerman in 2001 [27]. The syndrome genetic testing while his/her affected family occurs predominantly in males, over 50 years of members have documented SCA by genetic testing. age, and is characterized by the presence of action Among acquired ataxias, there are rare but treata- tremor with prominent kinetic component, cere- ble causes, which should not be missed. bellar ataxia, cognitive dysfunction, and occasionally parkinsonism and autonomic dysfunction. Acquired ataxias MRI shows increased T2 signal intensity in the Among the acquired or secondary cerebellar middle cerebellar peduncles in the majority of ataxias, it should be stressed that neuroimaging patients. FXTAS is caused by intermediate expan- studies, especially using MRI, are of capital impor- sions (between 50 and −200 repeats) of a CGG tance in defining focal lesions of the cerebellum trinucleotide in the fragile X mental retardation 1 and its connections, including neoplastic, inflam- (FMR1) gene, the same gene that causes fragile X matory, demyelinating, and vascular disorders. syndrome [27]. Hypothyroidism and Hashimoto encephalopathy

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(with elevated serum thyroperoxidase antibodies), form (64.7%) [28C]. In Brazil, in a follow-up study drugs, such as alcohol (alcoholic cerebellar of 15 years with 55 patients, 64% had SAOA and degeneration) [28A], chemotherapeutic agents the remaining 36% were diagnosed with MSA-C, (fluorocytosine arabinoside sp?), phenytoin, SCAs, FA, and acquired ataxias [1, 5, 29]. mercury, lead, thalium, lithium, solvents, several infectious disorders (HIV associated ataxia, mumps Multiple system atrophy (MSA) virus, infectious mononucleosis virus – Epstein- MSA is a sporadic and progressive neurodegenera- Barr virus – syphilis, Lyme disease, Whipple disease) tive disease characterized by parkinsonism, cerebel- and dietary deficiency of vitamins, such as thiamine, lar ataxia, and autonomic failure [29]. There is no tocopherol, and B12 can cause cerebellar, or etiology known and neuropathologically MSA is a sensory ataxia should be considered [1]. sinucleinopathy, with the presence of argyrophilic Miller Fisher syndrome, a Guillain-Barré filamentous glial cytoplasmic inclusions (GCIs). In syndrome variant and paraneoplastic cerebellar most Western populations, the clinical picture degeneration (PCD) are immune-mediated cerebel- showed a predominance of parkinsonian features lar disorders. In PCD there are several types of (defined as MSA-P) whereas the remaining MSA autoantibodies directed against neuronal antigens, patients had cerebellar ataxia as the main motor the most common being anti-Yo (PCA–1), associ- disorder (defined as MSA-C). However, in Japan, ated with breast and gynecological cancer; anti-Hu there is a predominance of MSA-C (83.8%). (ANNA–1) associated with small-cell lung cancer, and anti-Tr (Hodgkin’s lymphoma), among others. Sporadic adult-onset cerebellar Antibodies against glutamic acid decarboxylase ataxia (SAOA) (GAD), which are originally described in patients The original definition of SAOA is a non-hereditary with stiff-person syndrome but may also be found degenerative adult-onset (after 20 years of age) in insulin-dependent diabetes mellitus and thyroid ataxia disorder distinct from MSA. Clinically, how- diseases. Also antigliadin antibodies have been ever, most patients with SAOA exhibit slowly pro- associated with ataxia and celiac disease [28B]. gressive pure cerebellar ataxia, with onset after the Anti-GAD ataxia, Miller Fisher syndrome, and PCD age of 50 years although subtle non-cerebellar signs, are variably responsive to intravenous immuno- such as chorea, pyramidal, and sensory signs, can be globulins and steroids. Gluten ataxia, in which the found. Thus, in practice, SAOA resembles a disorder antigliadin antibody is positive in 100% of the previously known as cerebello-olivary degeneration patients, responds to gluten-free diet. Finally, prion or pure cerebello-olivary degeneration of Marie, diseases, such as Creutzfeldt–Jakob disease Foix, and Alajouanine. The diagnosis is one of (sporadic or hereditary), Gerstmann–Sträussler– exclusion, after acquired/secondary, genetic ataxias Scheinker (familial), fatal familial insomnia, and and MSA have been investigated [1]. variant Creutzfeldt–Jakob disease also cause cerebellar ataxia [1]. Sporadic olivopontocerebellar atrophy (sporadic OPCA) Non-genetic degenerative ataxias The nomenclature of OPCA is confusing [29A]. The Idiopathic cerebellar degeneration includes a group diagnosis of OPCA has been used for some of the of disorders of unknown etiology, such as MSA-C genetic ataxias while it has also been given to and SAOA. In a series of 112 sporadic ataxia patients with MSA-C. However, as MSA-C and patients from Germany, 29% had MSA-C, 58% SAOA has become relatively well-defined entities, had SAOA, while FA and SCAs (SCA1, 3, and 6) the diagnosis of Sporadic OPCA may be given to were found respectively in 4 and 9%. In Japan, a patients with sporadic cerebellar ataxia associated population-based epidemiological study of sporadic with prominent clinical extracerebellar features and ataxias showed that OPCA is the most common atrophy of the cerebellum and brainstem on imag-

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ing studies in the absence of autonomic failure or muscle coenzyme Q10 deficiency. Neurol 62: parkinsonism. However, the original definition of 818–20. SAOA includes such a disorder. Furthermore, some 13 Pineda M, Montero R, Aracil A, et al. 2010. Coenzyme of these patients may turn out to have MSA-C as Q(10)-responsive ataxia: 2-year-treatment follow- they develop autonomic failure later in the course up. Mov Disord 25:1262–8. 14 Ahmad SI. 2009. Molecular mechanisms of ataxia of the disease. It should be noted that genetic OPCA telangiectasia. Landes Bioscience, Austin, TX. largely overlaps with the SCAs of the ADCA type 1 15 Liu W, Narayanan V. 2008. Ataxia with oculomotor phenotype although some recessive and X-linked apraxia. Semin Pediatr Neurol 15:216–20. disorders have also been classified as OPCA [1]. 16 Hirano R, Interthal H, Huang C, et al. 2007. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? References Embo J 26:4732–43. 17 Di Donato I, Bianchi S, Federico A. 2010. Ataxia 1 Klockgether T. 2010. Sporadic ataxia with adult onset: with vitamin E deficiency: update of molecular classification and diagnostic criteria. Lancet Neurol diagnosis. Neurol Sci 31:511–15. 9:94–104. 18 Baets J, Deconinck T, Smets K, et al. 2010. Mutations 2 Perlman SL. 2003. Diagnostic evaluation of ataxic in SACS cause atypical and late-onset forms of patients. In: Pulst SM (ed), Genetics of movement dis- ARSACS. Neurol 75:1181–8. orders. Academic Press, Amsterdam. pp 254–72. 19 Anttonen AK, Mahjneh I, Hamalainen RH, et al. 3 Soong BW, Paulson HL. 2007. Spinocerebellar ataxias: 2005. The gene disrupted in Marinesco-Sjogren syn- an update. Curr Opin Neurol 20:438–46. drome encodes SIL1, an HSPA5 cochaperone. Nat 4 Schols L, Bauer P, Schmidt T, et al. 2004. Autosomal Genet 37:1309–11. dominant cerebellar ataxias: clinical features, genet- 20 Senderek J, Krieger M, Stendel C et al. 2005. ics, and pathogenesis. Lancet Neurol 3:291–304. Mutations in SIL1 cause Marinesco-Sjogren syn- 5 Teive HA. 2009. Spinocerebellar ataxias. Arq drome, a cerebellar ataxia with cataract and Neuropsiquiatr 67:1133–42. myopathy. Nat Genet 37:1312–14. 6 Rosa AL, Ashizawa T. 2002. Genetic ataxia. Neurol 21 Durr A. 2010. Autosomal dominant cerebellar Clinic 20:727–57. ataxias: polyglutamine expansions and beyond. 7 Gasser T, Bressman S, Durr A, et al. 2003. State of Lancet Neurol 9:885–94. the art review: molecular diagnosis of inherited 22 Harding AE. 1993. Clinical features and classification movement disorders. Movement Disorders Society of inherited ataxias. Adv Neurol 61:1–14. task force on molecular diagnosis. Mov Disord 23 Tan EK, Ashizawa T. 2001. Genetic testing in 18:3–18. spinocerebellar ataxias: defining a clinical role. Arch 8 Di Donato S, Gellera C, Mariotti C. 2001. The com- Neurol 58:191–5. plex clinical and genetic classification of inherited 24 Ashizawa T, Wells RD. 2006. Genetic instabilities and ataxias. II. Autosomal recessive ataxias. Neurol Sci neurological disorders (2nd edn). Elsevier, 22:219–28. Burlington. 9 Pandolfo M. 2009. Friedreich ataxia: the clinical 25 White MC, Gao R, Xu W, et al. 2010. Inactivation of picture. J Neurol 256(Suppl 1):3–8. hnRNP K by expanded intronic AUUCU repeat 9A Hou J-G, Jankovic J. Movement disorders in induces apoptosis via translocation of PKCdelta to Friedreich’s ataxia. J Neurol Sci 2003; 206:59–64. mitochondria in spinocerebellar ataxia 10. PLoS 10 Pandolfo M, Pastore A. 2009. The pathogenesis of Genet 6:e1000984. Friedreich ataxia and the structure and function of 25A Gupta A, Jankovic J. 2009. Spinocerebellar ataxia 8: frataxin. J Neurol 256(Suppl 1):9–17. variable phenotype and unique pathogenesis. 11 Schmucker S, Puccio H. 2010. Understanding the Parkinsonism Relat Disord 15:621–6. molecular mechanisms of Friedreich’s ataxia to 26 Jen JC. 2008. Hereditary episodic ataxias. Ann N Y develop therapeutic approaches. Hum Mol Genet Acad Sci 1142:250–3. 19:R103–10. 27 Hagerman PJ, Hagerman RJ. 2004. Fragile 12 Gironi M, Lamperti C, Nemni R, et al. 2004. Late- X-associated tremor/ataxia syndrome (FXTAS). onset cerebellar ataxia with hypogonadism and Ment Retard Dev Disabil Res Rev 10:25–30.

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28 Finsterer J. 2009. Mitochondrial ataxias. Can J Japan-a population-based epidemiological study. Neurol Sci 36:543–53. Cerebellum 2008; 7:189–97. 28A Mostile G, Jankovic J. Alcohol in essential tremor 29 Stefanova N, Bucke P, Duerr S, Wenning GK. 2009. and other movement disorders. Mov Disord 2010 Multiple system atrophy: an update. Lancet Neurol Oct; 25:2274–84. 8:1172–8. 28B Oertel W. Neurological symptoms in patients with 29A Berciano J, Boesch S, Perez-Ramos JM, Wenning biopsy proven celiac disease. Mov Disord 2009 Dec GK. Olivopontocerebellar atrophy: toward a better 15; 24(16):2358–62. nosological definition. Mov Disord 2006; 28C Tsuji S, Onodera O, Goto J, Nishizawa M; Study 21:1607–13. Group on Ataxic Diseases. Sporadic ataxias in

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Albanese_p07.indd 297 12/24/2011 7:28:02 AM CHAPTER 19 Dyskinesias in Parkinsonian Syndromes S. Elizabeth Zauber1 and Christopher G. Goetz2 1 Department of Neurology, Indiana University School Medicine, Indianapolis, IN, USA 2 The Parkinson Disease and Movement Disorder Center, Rush University Medical Center, Chicago, IL, USA

Introduction four signs: rigidity, bradykinesia, tremor, postural instability. By far, the most common cause of Dyskinesia is an involuntary hyperkinetic primary parkinsonism is PD which is usually char- movement disorder that includes chorea, dystonia, acterized by an asymmetric onset of parkinsonism tics, myoclonus, stereotypies, and mixed move- and a slow progression of disability over many ments with both choreic and dystonic components, years. Patients with PD typically have a good termed choreoathetosis [1]. In rare instances, the response to levodopa and other dopaminergic movements can be large amplitude and ballistic in drugs, but often develop drug-associated dyskine- character. This chapter will discuss the variety of sias after years of treatment. Whereas these dyski- dyskinesias associated with primary or idiopathic nesias were formerly known as Levodopa-Induced Parkinson disease (PD) as these types of involuntary Dyskinesias or LID, dyskinesias can occur with movements are much less likely to be encountered dopamine agonists as well and can be exacerbated in secondary or atypical forms of parkinsonism. by agents such as monoamine oxidase inhibitors Dyskinesias may occur as a feature of the underlying or catechol-O-methyl transferase inhibitors disease or as an effect of drug treatment for the (COMTI) when used with levodopa. Although the disease. The chapter is organized to deal with PD term “LID” is still historically used by some first and to discuss dyskinesias that occur as part of authors to cover all dyskinesias associated with PD itself and then to discuss the larger topic of any dopaminergic agent, the terminology for dyskinesias encountered in the context of drug these dyskinesias that will be used throughout treatment. The second part of the chapter will this chapter will be “dopaminergic drug-associated address the other parkinsonian syndromes, again dyskinesias.” dealing first with dyskinesias seen as part of the core It is important to recognize the different forms disease and second the dyskinesias that can develop of dyskinesias in parkinsonian disorders, because during drug treatment. Chapter 20 focuses on drug- the different forms require different treatment induced dyskinesia in non-parkinsonian patients strategies. Further, some forms of dyskinesia are treated with antipsychotic or dopamine receptor more typical of the non-PD parkinsonian syndromes blocking medications. than PD, and the presence of these special forms of Parkinsonism is a hypokinetic movement dyskinesia may help in establishing a solid diagnosis. disorder, consisting of at least two of the following The pathophysiology of dyskinesias likely differs

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among the different parkinsonian syndromes, and treatment strategies need to be tailored to the type Phenomenology of dopaminergic of dyskinesia and the underlying parkinsonian drug-associated dyskinesias in PD syndrome. Peak-dose dyskinesia occurs when dopaminergic activity levels are high and when patients are Parkinson disease experiencing good clinical benefit from levodopa. This type of dyskinesia is usually stereotypic Dyskinesia as a manifestation of PD or choreic (random, flowing, dance-like Dystonia may appear in early, untreated PD. movements), although it can be dystonic, or a In young patients, foot dystonia is particularly combination of chorea and dystonia during the common. In this case, the foot cramps and the high-peak phase. As such, lip-smacking, neck usual dystonic posture is foot inversion with jerking, and random movements of the extremities hyperextension of the big toe [2]. Some patients are highly typical of the choreic dyskinesias at develop calf spasms with minor foot twisting in peak dose, whereas neck twisting of a more the early morning before or immediately after sustained nature (torticollis) or foot inversion rising from bed. The involved dystonic foot is on may occur as dystonic forms of peak-dose the same side of the predominant parkinsonian dyskinesia. These movements occur at rest, but signs of bradykinesia, tremor and rigidity [3]. are exacerbated by mental stress, speaking, and Some patients experience additional or isolated some voluntary movements. Peak-dose dyskinesia exercise induced dystonia, also called kinesiogenic tends to affect the upper body, and usually is most foot dystonia. Whereas foot dystonia is often marked on the side of the body more affected by present in the context of other demonstrable PD symptoms (Figure 19.1). parkinsonian signs, sometimes the foot cramping Diphasic dyskinesia occurs when dopaminergic develops months or even years prior to the onset drug activity is rising or descending relative to the of other motor symptoms [4]. Since idiopathic peak medication effect. These movements typically dystonia in adults usually affects the head, neck, involve lower extremities and trunk, and may or upper extremities, a presentation of leg coexist with mild OFF symptoms (parkinsonism), dystonia in an adult should raise the suspicion because the patient is in a transition phase between for early PD [3]. full ON and full OFF. As such, patients with diphasic dyskinesia often complain of movements immediately after taking the dose of dopaminergic Dopaminergic drug-associated drug and at the very end of the dose cycle. In dyskinesia in PD As PD progresses, brain dopamine levels decline, and dopamine cells become markedly reduced in quantity. Consequently, patients become more Video 19.1 Peak dose dyskinesia dependent on exogenous dopamine and its smooth This man has peak dose dyskinesia. There are delivery for normal motor function [5]. Motor involuntary choreic movements of his hands, neck, and fluctuations or an irregular response to medication legs at rest. Movements are present on both sides, but over a given medication cycle include wearing-off are more marked on his right side. of benefit near the end of a drug cycle and drug- induced-dyskinesia. With wearing off, patients find that they alternate between periods of good response to medicine with little PD related disability called the ON state, and periods when symptoms of parkinsonism return, called OFF state. Dyskinesias can occur in both ON or OFF http://bit.ly/rUwQTN states, as described below.

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Diphasic Diphasic dyskinesia dyskinesia Peak dose dyskinesia

Levodopa level On-Off threshold

Motor response Time Figure 19.1 Type of dyskinesia varies in relationship to timing of dopaminergic medicine.

Table 19.1 Clinical characteristics of dopaminergic drug-associated dyskinesia in Parkinson disease.

Type Distribution Movement Timing

Levodopa induced Upper body Stereotypy > chorea Peak-dose effect dyskineisia > dystonia when parkinsonism is maximally treated Diphasic dyskinesia Lower body Flinging leg and Beginning and end of dose truncal jerking cycle when patient is in between ON and OFF Off dystonia Foot Dystonic End of dose or before first morning dose: Patient is OFF and parkinsonian

between these two periods, the same patient Video 19.2 Diphasic dyskinesia often has peak-dose dyskinesia, but the move ments In the first half of this video the patient is ON with peak switch from trunk and leg distribution of diphasic dose dyskinesia, characterized by involuntary dyskinesias to head, shoulder and upper extremities movements of her arms and face. In the second half of during the peak-dose abnormal movements. the video she is at the end of her dopaminergic dose OFF dyskinesia occurs when levodopa or other cycle. She has marked lower extremity movements consistent with diphasic dyskinesia. dopaminergic activity is low. This type of dyskinesia is usually dystonic, and affects the foot of the more affected side, often causing painful toe extension [6]. Run-away dyskinesias after neurotransplantation. A particular form of dyskinesia has also been reported after fetal mesencephalic cell transplanta- http://bit.ly/v2LA9o tion, and this topic is discussed later in the chapter.

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hormone replacement therapy and menopause Video 19.3 Off dyskinesia remain undefined. One study suggests that estro- Off dyskinesia is visible in her left foot. This is a gen replacement in postmenopausal women less- dystonic dyskinesia causing internal rotation of the ens dyskinesia [13]. Whereas most dopaminergic foot. Right hand rest tremor is also noted, consistent with her OFF state. drug-associated dyskinesias are increased by movement, excitement, and stress, no studies have focused on interventions related to altering these environmental factors.

Clinical impact

http://bit.ly/v7M0nH The clinical impact of dyskinesia is variable. When mild, dyskinesia may be unnoticed by patients [14]. Epidemiology When more marked, it can adversely impact activities of daily living and cause spilling, imbalance and Risk factors for dyskinesia include age at PD onset, falls, Additionally, dyskinesias can lead to fatigue, PD severity, levodopa dose, and duration of treat- pain, and clinically pertinent social isolation. In ment. Because several of these risk factors are spite of disabling dyskinesias, however, most linked, the relative importance of individual fac- patients prefer to be ON even with severe dyskine- tors, such as the influence of PD severity and sia rather than to be OFF and experiencing parkin- duration versus levodopa dose and treatment dura- sonian symptoms [14]. Quality of life studies have tion, have been disputed. Evidence that disease confirmed these clinical observations, so that when severity, not levodopa dose or treatment duration, dyskinesia is mild and non-disabling, it is not is most important comes from observations that generally associated with reduced quality of life patients with a long duration of untreated disease [15]. However, when it is more severe or painful, have a short latency to onset of dopaminergic drug- associated dyskinesias [7]. Other evidence for the role of disease severity Video 19.4 On-state dyskinesia comes from the observation that time to onset of This patient is 65 years old. At age 45 she developed dyskinesia is related to stage of disease. In one postural instability and rigidity of the right upper limb. study, patients with early PD (stage I) had a median Later she developed akinetic rigid features and a diagnosis of Parkinson’s disease was made. A levodopa time to dopaminergic drug-associated dyskinesias therapy was started. At age 55 she started to have of 66 months compared to more advanced patients wearing off episodes, and later, about two years ago, (stage III) who developed dyskinesias after 14 she developed evident peak-dose dyskinesias. The months of treatment [8]. Younger patients are videotape shows on-period dystonic and choreic more likely to develop dopaminergic drug- dyskinesias. Counting backwards stresses the patient and increases dyskinetic movements. She cannot stand associated dyskinesias than elderly PD subjects [9, still, but walks efficiently. 10]. After 5 years of drug treatment, dyskinesia occurs in 50% of patients with PD onset at age 40–59, compared with only 16% of PD patients whose disease onset occurred after age 70 [11]. Women are more likely to develop dyskinesias during the course of the disease than men [12]. Specific hormonal influences have not been http://bit.ly/sBnWXO studied, and the influence of menstrual fluctuations,

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dyskinesia is associated with poor quality of life and The goal of objective measures is to provide increased cost of care [16]. Many clinicians under unbiased, sensitive ways to quantitate dyskinesia. dose dopaminergic medicine out of fear of inducing Several techniques have been studied, including, dyskinesias, but when those patients are compared analysis of digitized spiral drawings [23], use of to patients with adequate benefit from levodopa accelerometers [24], force transducers [25]. These even with dyskinesia, the later group has better measures can be cumbersome, carry the risk of quality of life scores [17]. One study showed including tremor movements within the dyskinesia that while 59% of patients have dyskinesia after registration, and may fail to accurately capture the 10 years of drug treatment, less than half of the complicated phenomenology and variability of dyskinetic patients required medication adjustment dyskinesia. If small and portable, however, they to reduce dyskinesias [18]. may have the advantage of collecting data over long epochs and even 24 hours [26].

Rating scales Pathophysiology Dopaminergic drug-associated dyskinesia is notoriously difficult to measure. Several different More than dopamine approaches have been used to quantify dyskinesia. The development and persistence of dyskinesia Clinical rating scales aim to estimate the severity depends on a variety of pathophysiological of dyskinesia based on examiner observations. changes at several levels in the dopaminergic However, many scales are of limited clinical utility and cortico-subcortical pathways. Dyskinesia is because they only capture certain aspects of not solely a hyperdopaminerigic phenomenon; dyskinesia, and therefore lack sensitivity [19]. For instead, a combination of effects likely occurs example, individual scales focus on either the related to an increase in synaptic dopamine, intensity, anatomical distribution, phenomenology, changes in cortico-subcortical loops, the under- or disability, but do not provide an accurate measure lying dopaminergic deinnervation of PD, and a of the diversity of dyskinetic movements. The new progressive development of intermittent rather version of the Unified Parkinson Disease Rating Scale, than continuous dopaminergic stimulation. developed by the Movement Disorder Society (MDS- Together, these alterations cause downstream UPDRS), includes several items designed to capture changes in gene/protein expression in post- levodopa-related motor complications [20]. Recently, synaptic cells [6]. Nigral degeneration is required the Unified Dyskinesia Rating Scale (UDysRS) has for the occurrence of dyskinesia. Patients on been designed to assess and quantify the diverse chronic levodopa therapy for dopa responsive nature of dyskinetic movements and to incorporate dystonia, as well as normal controls exposed to patient perceptions of disability from dyskinesia [21]. levodopa, do not develop dyskinesia [6]. The Patients’ self evaluation diaries are sometimes occurrence of dyskinesia is not a simple reflection used in clinical studies to record the amount of time of dopaminergic levels being too high, as increas- that dyskinesia is present during the day. Because ing doses of levodopa prolong dyskinesia dura- this methodology relies on patient’s self report, tion, but do not change the quality of the ON some have challenged the accuracy of these diary- state or severity of dyskinesia [27, 28]. based tools. However, accuracy can be improved with patient training, and data from these diaries Dopamine transporter changes are accepted by the Food and Drug Administration Early in PD, the expression of the dopamine (FDA) as a clinical end point [22]. transporter (DAT) is down-regulated as a result of In addition to clinical rating scales, objective loss of nigrostriatal terminals and as a compensatory measures are used to help quantify dyskinesia. mechanism for low presynaptic dopamine. This

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allows the synaptic dopamine to stay in the synapse polymorphism developed LID earlier in the course longer. PET (positron emission tomography) studies of dopaminergic treatment for PD. of DAT show that patients with dyskinesia have a lower ratio of DAT to dopaminergic nerve terminals Differing mechanisms for different than patients without dyskinesia [29]. This finding dyskinesias suggests that patients with the most robust compen- Several pharmacological observations suggest that satory mechanisms are the most likely to develop distinct mechanisms may be at play in different dyskinesia. Other PET studies show that patients types of dyskinesia. For instance, histamine H3 with dopaminergic drug associated dyskinesias have agonists reduce peak dose dyskinesia but not greater change in synaptic dopamine release in dystonia, cannabinoid CB1 agonists reduce diphasic response to levodopa than patients without dyski- dyskinesia of an antiparkinsonian dose of levodopa, nesia [30]. Whereas synaptic levels of dopamine are but not peak-dose dyskinesia, while α-2 adrenergic not higher in dyskinetic patients compared to non- antagonists reduce dopaminergic drug associated dyskinetic subjects, this observation suggests that peak-dose dyskinesia but not dyskinesia elicited by dyskinetic patients have a larger change in dopa- apomorphine [37]. These differences suggest that mine levels induced by levodopa. antidyskinetic drugs may need to be tailored to the Animal models show an upregulation of the type of dyskinesia that most disables any individual D3 receptor in dopaminergic drug associated patient (Figure 19.2). dyskinesia [31]. Whereas D3 antagonists cause parkinsonism, a D3 partial agonist, reduced dyskinesia without worsening parkinsonism in a Treatment primate model of PD [32]. The most important aspect of treating dopaminergic Non-dopaminergic influences drug-associated dyskinesia is correct recognition of A large body of evidence suggests that other the type of dyskinesia (timing in relationship to neurotransmitter systems besides dopaminergic medicine), as different treatment approaches are function are important to the development of required for each type of dyskinesia. dyskinesia. Multiple neurotransmitter systems Painful OFF-period dystonia can improve with have been implicated, such as changes in the same therapeutic measures used for motor fluc- N-methyl-D-aspartic acid (NMDA) and (α-amino- tuations when the therapeutic emphasis is the 3-hydroxyl-5-methyl-4-isoxazole-propionate reduction of OFF time. Examples include changes (AMPA) glutamergic receptors, adenosine, and in the dosage or in the frequency of administration opiate receptors. The glutamatergic system, in of levodopa preparations, the addition of oral particular the NMDA receptor, has been the focus dopamine agonists, the adjunctive treatment with of antidyskinetic drug development, since the most COMT inhibitors [38] and monoamine oxidase effective antidyskinetic drug to date, amantadine, (MAO)-B inhibitors (selegiline, rasagiline) [39] are likely acts by antagonizing the NMDA receptor [33]. common therapeutic approaches to reduce OFF Alterations in the A2a adenosine receptor and time. Sustained release levodopa given at bedtime opiate receptors have been well described, but may be useful to treat nocturnal akinesia and early- to date pharmacological modification of these morning dystonia [40]. In some cases, the injec- receptors have not improved dyskinesia [34, 35]. tions of botulinum toxin may alleviate prolonged Brain derived neurotropic factor (BDNF) has a painful foot dystonia [41]. Subcutaneous injections role in synaptic plasticity, and has a modulatory of apomorphine may also be used to treat sudden, effect on D1, D3, NMDA, and γ-Aminobutyric acid unexpected off period dystonia [42]. (GABA)ergic receptors. A common BDNF polymor- The first step in treating peak-dose dyskinesias phism (vall66met) has been associated with is to reduce individual levodopa doses temporally LID [36]. Patients who are homozygous for this associated with dyskinesia. Reduction of the

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Dyskinesia

Type of dyskinesia Off dystonia Peak-dose Diphasic

Treatment Give morning Smaller more frequent doses options dose early Increase individual doses Change CR to regular release

Decrease or discontinue Add COMT or MAO Add agonist COMT or MAO

Add amantadine Hourly liquid levodopa Add CR at bedtime

Surgical treatment

Figure 19.2 Treatment algorithm for different types of dyskinesia in Parkinson disease.

amount of an individual dose, however, may placebo-controlled studies performed in parkin- decrease the duration of clinical benefit and can sonian patients with motor fluctuations and dyski- result in more severe OFF periods. As a result, nesias have documented that oral amantadine patients with peak-dose dyskinesias typically need reduces dyskinesia severity and decreases the per- more frequent levodopa doses in order to maintain centage of time patients experience dyskinesias, ON time without prominent dyskinesia. Peak-dose without reducing ON time [44–46]. Amantadine is dyskinesia can often be lessened by changing commonly used at doses of 200 to 300 mg/day. sustained release levodopa to standard levodopa. Elderly patients, or those with reduced renal The sustained release formulation often causes a function are particularly susceptible to the side cumulative effective such that dyskinesia peaks late effects which include: confusion, worsening of in the day, after several doses. Similarly, treatment hallucinations, edema of the feet and livedo reticu- of peak-dose dyskinesia may require discontinua- laris. Amantadine is currently the only drug tion of COMT or MAO-B inhibitors. considered efficacious in the treatment of dyskinesia Diphasic dyskinesia are the most difficult to treat. by evidence-based review techniques [47]. Its Higher individual doses of levodopa, may be of antidyskinetic effect in PD gives support to the benefit [43]. glutamatergic hypothesis as a pathogenic mechanism of dopaminergic drug-associated dyskinesias. Antidyskinetic drugs Clozapine has been reported to reduce the sever- Amantadine is a glutamate antagonist that is active ity of dyskinesia in some open studies and in one at NMDA receptors and has shown antidyskinetic randomized, double-blind, parallel-group, placebo- effects in patients with PD. Small, randomized, controlled multicenter study. In the latter [48],

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50 parkinsonian patients were treated with a mean of dyskinesias, induced by bilateral DBS of STN dose of 39 mg/day of clozapine for 10 weeks. The may last up to 5 years [57, 58]. mean daily ON time without dyskinesias increased Bilateral stimulation of the internal globus palli- 1.7 hours. Potential adverse effects of clozapine are dus (GPi) has been explored as a treatment for LID. agranulocytosis (white cell count monitoring is There was an overall improvement of dyskinesia needed), somnolence, seizures, myocarditis, and severity by 41 to 87% [59] with a significant orthostatic hypotension. At present, there is insuf- increase in ON time without dyskinesia [60]. ficient evidence to support or refute the efficacy of A recent multi-center study showed similar efficacy clozapine in reducing LID [49]. of STN DBS when compared to GPi DBS for the A variety of other drugs have been reported to treatment of PD [61]. reduce LID but lack evidence from double-blind, The mechanism of action by which each surgical randomized, controlled trials. These drugs include: target reduces dyskinesia is likely to be quite differ- dextromethorphan, riluzole, istradefylline, meman- ent. STN DBS allows for about at 50% reduction in tine, remacemide, and propranolol [50]. Sarizotan, levodopa dose, and this dose reduction is thought a dopamine agonist that also binds to 5-hydroxy- to account for the reduction in dyskinesia. In con-

tryptamine1A receptors, showed promise in early trast, patients who undergo GPi DBS do not have studies, but two large studies failed to demonstrate a significant reduction in levodopa dose post antidyskinetic properties [51]. operatively, but still have a reduction in dyskinesia. This improvement appears to be due to direct anti- Stereotactic surgery dyskinetic effects of GPi stimulation [58, 60]. Pallidotomy was the first major surgical target Adverse effects related to DBS of STN include intervention for dyskinesias. Unilateral pallidotomy intracranial hemorrhage that can appear in 4% reduces dyskinesia severity by 75% in the con- of patients and infections in 1.5%. Device malfunc- tralateral limbs [52], and a mean increase of 2.8 tion, migration, and fracture of leads are also hours in daily ON time without dyskinesias [53]. reported, and other side effects directly related to Bilateral pallidotomy often results in side effects the stimulation such as dysarthria, diplopia, pares- such as dysarthria, dysphagia, cognitive changes, thesias, weight gain, and psychiatric and cognitive and falls. Therefore deep brain stimulation surgery symptoms can occur [62]. (DBS) has largely replaced lesional therapies in the treatment of PD. Bilateral DBS of the subthalamic nucleus (STN) Runaway dyskinesia after is currently the most commonly performed surgi- transplantation cal procedure in patients with PD and severe motor complications that include dyskinesias Dyskinesia has proven not only to be a troublesome [54]. Reviews of the large number of uncon- side effect of drug treatment in advanced PD, but to trolled studies and the few randomized, double- be a severe complication of fetal nigral transplanta- blind crossover trials [55] have found that tion for PD. bilateral DBS of STN increases ON time without Dyskinetic movements developed in 50% of dyskinesias, reduces OFF time, and improves all patients who received transplants. They occurred clinical patterns of dyskinesias (OFF period dysto- in both the ON and OFF states. ON dyskinesias nia, peak-dose and diphasic dyskinesias). In addi- were choreic, while OFF dyskinesias affected the tion, DBS of STN allows a reduction in lower extremities, suggesting its mechanism may antiparkinsonian medication, which in part may be similar to that of diphasic dyskinesia. Patients contribute to dyskinesias improvement. The aver- who were most sensitive to levodopa’s beneficial age reduction in dyskinesias severity following and adverse effects preoperatively, were the surgery is estimated to be 70% [56]. Further, the most likely to develop this post transplant OFF- clinical motor improvement, including reduction dyskinesia [63].

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Based on electrophysiological recordings, the About half of patients with blepharospasm have pathophysiology of post- transplantation dyskine- coexistent apraxia of eye lid opening. Blepharospasm sias is likely to differ from that of dopaminergic can render a patient functionally blind, but should drug-associated dyskinesia under normal condi- not go unrecognized, as it often treatable. tions, firing rates in the GPi decrease in the ON Dystonia and myoclonus occur commonly in state, and with dyskinesia. However, in patients CBD. In this disorder, limb dystonia usually involves with post-transplant OFF dyskinesia, firing rates one upper extremity and over time leads to a were not reduced and were typical of a PD patient painful, fisted hand that can eventually develop in the OFF state [64]. Therapeutically, DBS of the contractures. In one published series, more than GPi, but not STN has been effective at treating half of the patients developed dystonia [71]. these dyskinesias [65]. Dyskinesia in association with drug treatment in non-PD parkinsonism Non-PD parkinsonian syndromes By definition, atypical parkinsonian disorders have a minimal or an unsustained clinical improvement Dyskinesia as part of the primary with dopaminergic treatment. As such, in late disease, parkinsonian syndrome most patients with these disorders (PSP, MSA, CBD) Cervical dystonia, specifically anterocollis is are either not treated with dopaminergic medication considered a clinical hallmark of multiple system doses or only receive small daily doses. In the early atrophy (MSA). The exact etiology of this abnormal and mid-phases of the diseases, however, clinicians posture is not fully understood, although it probably may prescribe high doses of these drugs in order to represents a combination of dystonia and rigidity maximize a clinical response. In this instance, drug- rather than extensor myopathy [66, 67]. In a cohort associated dyskinesia can develop. For instance, while of clinically diagnosed MSA patients, as many as anterocollis can be a manifestation of untreated MSA, 46% had dystonia prior to the onset of treatment, it may also occur in response to treatment. Several most commonly limb dystonia or anterocollis [68]. authors have reported patients who developed Tongue movements have occasionally been anterocollis after treatment with a dopamine agonist observed in untreated MSA as well [69]. that resolved after stopping the drug [72]. Most drug- Dystonia is also a common feature of untreated induced dyskinesia in MSA is confined to face, lips, progressive supranuclear palsy (PSP). In a and neck [68]. Drug-induced dyskinesia can also retrospective study of clinically diagnosed PSP occur in patients with PSP, and there are rare reports patients, 46% had dystonia during their illness: of oromandibular dystonia induced by levodopa, 27% limb, 24% blepharospasm, 17% retrocollis. which resolved off levodopa [73]. Limb dystonia, often occurs early in the disease and is either hemidystonia, or involves a single limb (usually arm). Patients who present with arm Future perspectives dystonia, may be mistaken for corticobasal degeneration (CBD), and indeed a minority in the Certainly, more pharmacological treatments are study had coexistent CBD or vascular pathology at needed that can reduce dyskinesia severity without autopsy. Retrocollis is the most commonly reported worsening parkinsonism. There are several reasons and recognized dystonic feature of PSP. Some why such drug discovery has remained elusive. First, argue, however, that the neck rigidity and the underlying mechanism of dyskinesia likely retrocollic posture do not represent dystonia, as the involves multiple interconnected subcortical path- neck is not mobile, and lacks a sensory trick or ways, and neurochemical substrates. Second, dyski- other features typical of dystonia. Blepharospasm, a nesia is notoriously difficult to quantify, and more focal dystonia causing involuntary eye closure, is refined measurement tools may allow for better effi- usually a late disease manifestation of PSP [70]. cacy documentation. As such, considerable research

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is currently targeted at developing more sensitive 8 Kostic VS, Marinkovic J, Svetel M, et al. The effect of and reliable measures of dyskinesia. Lastly, recent stage of Parkinson’s disease at the onset of levodopa research has shown a placebo-induced improvement therapy on development of motor complications. Eur in dyskinesia during double-blind placebo controlled J Neurol 2002 Jan; 9(1):9–14. trials. Therefore, open-label studies of antidyskinetic 9 Sharma JC, Bachmann CG, Linazasoro G. Classifying risk factors for dyskinesia in Parkinson’s disease. drugs often produce misleadingly positive results, as Parkinsonism Relat Disord 2010 Jun 30; 16(8):490–7. was the case with sarizotan [74, 75]. 10 Ku S, Glass GA. Age of Parkinson’s disease onset as a Recent PD research has focused non-motor predictor for the development of dyskinesia. Mov symptoms such as autonomic dysfunction, cognitive Disord 2010 Jul 15; 25(9):1177–82. and behavioral changes. Some of the behavioral 11 Kumar N, Van Gerpen JA, Bower JH, Ahlskog JE. changes associated with chronic dopaminergic drugs Levodopa-dyskinesia incidence by age of Parkinson’s include dopamine dysregulation disorder and disease onset. Mov Disord 2005 Mar; 20(3):342–4. punding. Punding describes purposeless, repetitive 12 Lyons KE, Hubble JP, Troster AI, et al. Gender differ- behaviors such as arranging or disassembling and ences in Parkinson’s disease. Clin Neuropharmacol reassembling objects. There is some evidence that 1998 Mar-Apr; 21(2):118–21. some of these behavioral changes may be comorbid 13 Nicoletti A, Arabia G, Pugliese P, et al. Hormonal replacement therapy in women with Parkinson with dyskinesia, and may share some of the same disease and levodopa-induced dyskinesia: a crossover underlying pathophysiology. Patients with punding trial. Clin Neuropharmacol 2007 Sep-Oct; 30(5): have more severe dyskinesia than those without 276–80. punding, and the severity of punding correlated with 14 xHung SW, Adeli GM, Arenovich T, et al. Patient severity of dyskinesia, even after controlling for med- perception of dyskinesia in Parkinson’s disease. ication dose [76]. It is expected that a better under- J Neurol Neurosurg Psychiat 2010 Jul 28. standing of both the behavioral and motor changes 15 Marras C, Lang A, Krahn M, et al. Quality of life in in advanced PD will lead to new treatments for PD. early Parkinson’s disease: impact of dyskinesias and motor fluctuations. Mov Disord 2004 Jan; 19(1):22–8. References 16 Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life 1 Jankovic J. Treatment of hyperkinetic movement and health-related costs: a prospective European disorders. Lancet Neurol 2009 Sep;8(9):844–56. study. Eur J Neurol 2005 Dec; 12(12):956–63. 2 Tolosa E, Compta Y. Dystonia in Parkinson’s disease. 17 Schrag A, Quinn N. Dyskinesias and motor fluctua- J Neurol 2006 Dec; 253(Suppl 7):7–13. tions in Parkinson’s disease. A community-based 3 McKeon A, Matsumoto JY, Bower JH, Ahlskog JE. The study. Brain 2000 Nov; 123(Pt 11):2297–305. spectrum of disorders presenting as adult-onset focal 18 Van Gerpen JA, Kumar N, Bower JH, et al. Levodopa- lower extremity dystonia. Parkinsonism Relat Disord associated dyskinesia risk among Parkinson disease 2008 Dec; 14(8):613–9. patients in Olmsted County, Minnesota, 1976–1990. 4 xLees AJ, Hardie RJ, Stern GM. Kinesigenic foot dysto- Arch Neurol 2006 Feb; 63(2):205–9. nia as a presenting feature of Parkinson’s disease. 19 Colosimo C, Martinez-Martin P, Fabbrini G, et al. Task J Neurol Neurosurg Psychiat 1984 Aug; 47(8):885. force report on scales to assess dyskinesia in Parkinson’s 5 Schapira AH, Emre M, Jenner P, Poewe W. Levodopa in disease: critique and recommendations. Mov Disord the treatment of Parkinson’s disease. Eur J Neurol 2009 2010 Jul 15; 25(9):1131–42. Sep; 16(9):982–9. 20 Goetz CG, Tilley BC, Shaftman SR, et al. Movement 6 Del Sorbo F, Albanese A. Levodopa-induced dyski- Disorder Society-sponsored revision of the Unified nesias and their management. J Neurol 2008 Aug; Parkinson’s Disease Rating Scale (MDS-UPDRS): scale 255(Suppl 4):32–41. presentation and clinimetric testing results. Mov 7 Cabassa JC AK, Shulman LM. Early Onset of Motor Disord 2008 Nov 15; 23(15):2129–70. Fluctuations and Dyskinesias after 10 years of 21 Goetz CG, Nutt JG, Stebbins GT. The Unified Undiagnosed Parkinson’s Disease. Mov Disord 2009; Dyskinesia Rating Scale: presentation and clinimetric 24:1875. profile. Mov Disord 2008 Dec 15; 23(16):2398–403.

Albanese_c19.indd 308 12/24/2011 7:29:16 AM Dyskinesias in Parkinsonian Syndromes 309

22 Hauser RA, Deckers F, Lehert P. Parkinson’s disease 36 Foltynie T, Cheeran B, Williams-Gray CH, et al. BDNF home diary: further validation and implications for val66met influences time to onset of levodopa induced clinical trials. Mov Disord 2004 Dec; 19(12):1409–13. dyskinesia in Parkinson’s disease. J Neurol Neurosurg 23 Liu X, Carroll CB, Wang SY, et al. Quantifying drug- Psychiat 2009 Feb; 80(2):141–4. induced dyskinesias in the arms using digitised 37 Brotchie JM. Nondopaminergic mechanisms in spiral-drawing tasks. J Neurosci Methods 2005 May levodopa-induced dyskinesia. Mov Disord 2005 Aug; 15; 144(1):47–52. 20(8):919–31. 24 Keijsers NL, Horstink MW, van Hilten JJ, et al. Detect- 38 Widnell KL, Comella C. Role of COMT inhibitors and ion and assessment of the severity of levodopa-induced dopamine agonists in the treatment of motor fluctua- dyskinesia in patients with Parkinson’s disease by neural tions. Mov Disord 2005; 20(Suppl 11):S30–7. networks. Mov Disord 2000 Nov; 15(6):1104–11. 39 Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as 25 Wenzelburger R, Zhang BR, Pohle S, et al. Force over- an adjunct to levodopa in patients with Parkinson’s flow and levodopa-induced dyskinesias in Parkinson’s disease and motor fluctuations (LARGO, Lasting effect disease. Brain 2002 Apr; 125(Pt 4):871–9. in Adjunct therapy with Rasagiline Given Once daily, 26 SE Z. Dyskinesia monitoring with electronic data gath- study): a randomised, double-blind, parallel-group ering apparatus. [Master’s thesis]. In press 2010. trial. Lancet 2005 Mar 12–18; 365(9463):947–54. 27 Metman LV, van den Munckhof P, Klaassen AA, et al 40 Grandas F, Martinez-Martin P, Linazasoro G. Quality Effects of supra-threshold levodopa doses on dyskine- of life in patients with Parkinson’s disease who trans- sias in advanced Parkinson’s disease. Neurol 1997 Sep; fer from standard levodopa to Sinemet CR: the STAR 49(3):711–3. Study. The STAR Multicenter Study Group. J Neurol 28 Nutt JG, Chung KA, Holford NH. Dyskinesia and 1998 May; 245(Suppl 1):S31–3. the antiparkinsonian response always temporally 41 Singer C, Papapetropoulos S. Adult-onset primary coincide: a retrospective study. Neurol 2010 Apr 13; focal foot dystonia. Parkinsonism Relat Disord 2006 74(15):1191–7. Jan; 12(1):57–60. 29 Troiano AR, de la Fuente-Fernandez R, Sossi V, et al. 42 Stocchi F. Use of apomorphine in Parkinson’s disease. PET demonstrates reduced dopamine transporter Neurol Sci 2008 Dec; 29(Suppl 5):S383–6. expression in PD with dyskinesias. Neurol 2009 Apr 7; 43 Waters C. Other pharmacological treatments for motor 72(14):1211–16. complications and dyskinesias. Mov Disord 2005; 30 de la Fuente-Fernandez R, Sossi V, Huang Z, et al. 20(Suppl 11):S38–44. Levodopa-induced changes in synaptic dopamine 44 Snow BJ, Macdonald L, McAuley D, Wallis W. The effect levels increase with progression of Parkinson’s disease: of amantadine on levodopa-induced dyskinesias in implications for dyskinesias. Brain 2004 Dec; 127 Parkinson’s disease: a double-blind, placebo-controlled (Pt 12):2747–54. study. Clin Neuropharmacol 2000 Mar-Apr; 23(2):82–5. 31 Berthet A, Bezard E. Dopamine receptors and 45 Thomas A, Iacono D, Luciano AL, et al. Duration of L-dopa-induced dyskinesia. Parkinsonism Relat Disord amantadine benefit on dyskinesia of severe Parkinson’s 2009 Dec; 15(Suppl 4):S8–12. disease. J Neurol Neurosurg Psychiat 2004 Jan; 32 Bezard E, Ferry S, Mach U, et al. Attenuation of 75(1):141–3. levodopa-induced dyskinesia by normalizing dopamine 46 Wolf E, Seppi K, Katzenschlager R, et al. Long-term D3 receptor function. Nat Med 2003 Jun; 9(6):762–7. antidyskinetic efficacy of amantadine in Parkinson’s 33 Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa- disease. Mov Disord 2010 Jul 30; 25(10):1357–63. induced dyskinesias. Mov Disord 2007 Jul 30; 47 Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence- 22(10):1379–89; quiz 523. based medical review update: pharmacological and 34 LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine surgical treatments of Parkinson’s disease: 2001 to A2A receptor antagonist istradefylline (KW–6002) 2004. Mov Disord 2005 May; 20(5):523–39. reduces “off” time in Parkinson’s disease: a double-blind, 48 Durif F, Debilly B, Galitzky M, et al. Clozapine randomized, multicenter clinical trial (6002-US–005). improves dyskinesias in Parkinson disease: a Ann Neurol 2008 Mar; 63(3):295–302. double-blind, placebo-controlled study. Neurol 2004 35 Stacy M, Silver D, Mendis T, et al. A 12-week, Feb 10; 62(3):381–8. placebo-controlled study (6002-US–006) of istradefyl- 49 Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, line in Parkinson disease. Neurol 2008 Jun 3; Bronte-Stewart H, et al. Practice Parameter: treatment 70(23):2233–40. of Parkinson disease with motor fluctuations and

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dyskinesia (an evidence-based review): report of the 62 Kenney C, Simpson R, Hunter C, et al. Short-term and Quality Standards Subcommittee of the American long-term safety of deep brain stimulation in the Academy of Neurology. Neurol 2006 Apr 11; treatment of movement disorders. J Neurosurg 2007 66(7):983–95. Apr; 106(4):621–5. 50 Mizuno Y, Hasegawa K, Kondo T, et al. Clinical effi- 63 Olanow CW, Gracies JM, Goetz CG, et al. Clinical cacy of istradefylline (KW–6002) in Parkinson’s dis- pattern and risk factors for dyskinesias following fetal ease: a randomized, controlled study. Mov Disord nigral transplantation in Parkinson’s disease: a double 2010 Jul 30; 25(10):1437–43. blind video-based analysis. Mov Disord 2009 Feb 15; 51 Rascol O, Damier P, Goetz CG. A large phase III study 24(3):336–43. to evaluate the safety and efficacy of sarizotan in the 64 Graff-Radford J, Foote KD, Rodriguez RL, Deep brain treatment of L-dopa-induced dyskinesia associated stimulation of the internal segment of the globus with PD: the paddy–1 study. Mov Disord 2006; pallidus in delayed runaway dyskinesia. Arch Neurol 21:S492–S3. 2006 Aug; 63(8):1181–4. 52 Vitek JL, Bakay RA, Freeman A, et al. Randomized trial 65 Herzog J, Pogarell O, Pinsker MO, et al. Deep brain of pallidotomy versus medical therapy for Parkinson’s stimulation in Parkinson’s disease following fetal disease. Ann Neurol 2003 May; 53(5):558–69. nigral transplantation. Mov Disord 2008 Jul 15; 53 de Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral 23(9):1293–6. pallidotomy in Parkinson’s disease: a randomised, 66 Jankovic J. Camptocormia, head drop and other single-blind, multicentre trial. Lancet 1999 Nov 13; bent spine syndromes: heterogeneous etiology and 354(9191):1665–9. pathogenesis of Parkinsonian deformities. Mov Disord 54 Metman LV, O’Leary ST. Role of surgery in the 2010 Apr 15; 25(5):527–8. treatment of motor complications. Mov Disord 2005; 67 Lava NS, Factor SA. Focal myopathy as a cause of 20(Suppl 11):S45–56. anterocollis in Parkinsonism. Mov Disord 2001 55 Kleiner-Fisman G, Herzog J, Fisman DN, et al. Jul; 16(4):754–6. Subthalamic nucleus deep brain stimulation: sum- 68 Boesch SM, Wenning GK, Ransmayr G, Poewe mary and meta-analysis of outcomes. Mov Disord W. Dystonia in multiple system atrophy. J Neurol 2006 Jun; 21(Suppl 14):S290–304. Neurosurg Psychiat 2002 Mar; 72(3):300–3. 56 Deuschl G, Schade-Brittinger C, Krack P, et al. A ran- 69 Sheehy SH, Lawrence T, Thevathasan AW. Serpentine domized trial of deep-brain stimulation for Parkinson’s tongue: A lingual dyskinesia. Neurology 2008 May 20; disease. N Engl J Med 2006 Aug 31; 355(9):896–908. 70(21):e87. 57 Krack P, Batir A, Van Blercom N, et al. Five-year 70 Barclay CL, Lang AE. Dystonia in progressive follow-up of bilateral stimulation of the subthalamic supranuclear palsy. J Neurol Neurosurg Psychiat 1997 nucleus in advanced Parkinson’s disease. N Engl Apr; 62(4):352–6. J Med 2003 Nov 13; 349(20):1925–34. 71 Vanek Z, Jankovic J. Dystonia in corticobasal degen- 58 Romito LM, Contarino MF, Vanacore N, Replacement eration. Mov Disord 2001 Mar; 16(2):252–7. of dopaminergic medication with subthalamic nucleus 72 Prakash KM, Lang AE. Reversible dopamine agonist stimulation in Parkinson’s disease: long-term observa- induced anterocollis in a multiple system atrophy tion. Mov Disord 2009 Mar 15; 24(4):557–63. patient. Mov Disord 2007 Nov 15; 22(15):2292–3. 59 Burchiel KJ, Anderson VC, Favre J, Hammerstad JP. 73 Tan EK, Chan LL, Wong MC. Levodopa-induced Comparison of pallidal and subthalamic nucleus deep oromandibular dystonia in progressive supranuclear brain stimulation for advanced Parkinson’s disease: palsy. Clin Neurol Neurosurg 2003 Apr; 105(2):132–4. results of a randomized, blinded pilot study. Neurosurgery 74 Goetz CG, Laska E, Hicking C, et al. Placebo influences 1999 Dec; 45(6):1375–82; discussion 82–4. on dyskinesia in Parkinson’s disease. Mov Disord 2008 60 Deep-brain stimulation of the subthalamic nucleus Apr 15; 23(5):700–7. or the pars interna of the globus pallidus in 75 Muller T, Olanow CW, Nutt J. The paddy–2 study: the Parkinson’s disease. N Engl J Med 2001 Sep 27; evaluation of sarizotan for treatment-associated dyski- 345(13):956–63. nesia in PD patients. Mov Disord 2006; 21:S591. 61 Follett KA, Weaver FM, Stern M, et al. Pallidal versus 76 Silveira-Moriyama L, Evans AH, Katzenschlager subthalamic deep-brain stimulation for Parkinson’s R, Lees AJ. Punding and dyskinesias. Mov Disord 2006 disease. N Engl J Med 2010 Jun 3; 362(22):2077–91. Dec; 21(12):2214–17.

Albanese_c19.indd 310 12/24/2011 7:29:17 AM CHAPTER 20 Restless Legs Syndrome Pamela Hamilton-Stubbs1 and Arthur S. Walters2 1 Sleep Clinic for Children and Adults, Richmond, VA, USA 2 Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA

Historical background Disorders: Diagnostic and Coding Manual (ICSD) In the early 1990s a group of interested physicians and Restless legs syndrome (RLS), formerly termed researchers formed the International RLS Study Ekbom syndrome, is a sensorimotor disorder first Group (IRLSSG), which published the original described by Thomas Willis in the 17th century [1]. consensus definition of RLS in 1995 [6]. In 2003 the Initially thought to be a form of neurosis, in 1923, definition was updated for better clarity [7]. Oppenheim suggested the condition could be a Although all of the important clinical features of RLS genetic neurological disorder [2]. In 1945 Ekbom were documented by Ekbom, except for “Nocturnal coined the term “Restless Legs” and reported the Myoclonus” later termed “Periodic Limb Movements findings of a large number of patients in a doctoral in Sleep” [8], he did not make an attempt to divide thesis entitled “Restless legs: a clinical study of a the clinical features into essential and non-essential hitherto overlooked disease in the legs character- criteria. Neither the 1979 nor the 1990 version of ized by peculiar paresthesias and occurring in two the ICSD listed all four of the current minimal main forms, asthenia crurum paraesthetica and criteria as essential. In addition, the 1979 and 1990 asthenia crurum dolorosa” [3]. In his publication versions included some criteria as essential that are he described previously published similar cases by currently considered non-essential. The 2003 Wittmack in 1861, Bing in 1913, Code and Allen in definition by the International RLS Study Group 1936 and Allison in 1943 when various descriptive was soon adopted by the new ICSD in 2005 [7]. This terms were used such as anxietas tibiarum and leg updated definition has been universally accepted jitters [3]) Prior to his use of the term “Restless and a severity scale that was validated by the IRLSSG Legs,” Ekbom himself had previously used the term in 2003 was instrumental in the development of “irritable legs” [4]. In 1974 Karl Ekbom Jr and FDA-approved medications for RLS [7, 9]. K.A. Ekbom reported a previously overlooked case of restless legs syndrome described by Magnus Huss in Huss’s extensive writings on chronic alcoholism, Clinical features published in 1849 [5]. In 1979 and 1990 The Diagnostic Classification RLS typically involves the lower limbs but can Steering Committee of the American Association of involve the upper limbs, trunk, and occasionally Sleep Medicine developed RLS diagnostic criteria. the face. If sensory symptoms are present, which is The criteria were published in two respective true in the majority of cases, patients describe the versions of the International Classification of Sleep sensory sensations by various terms and phrases

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such as ants crawling in my legs, heebie jeebies, Video 20.1 Periodic limb movements painful, etc. The symptoms are experienced as in sleep coming from deep within the legs and not as superficial [3]) Large parts of the calves, thighs, or both The patient is lying on her stomach and flexing her left leg at the knee in a periodic fashion. Three periodic are usually affected [3]. Although this description is limb movements in sleep are shown. typical of familial/idiopathic RLS, we have observed that RLS associated with peripheral neuropathy or radiculopathy may not always follow this pattern and may involve smaller parts of the thighs or calves and may sometimes be felt as superficial rather than deep. The onset of discomfort follows a circadian pattern with discomfort beginning or http://bit.ly/rEUHul worsening in the evening or just before bedtime and resolving or absent in the morning. With increasing severity, sensations may lose the circa- other conditions, i.e. peripheral neuropathy or dian pattern and occur earlier in the day [9, 10]) radiculopathy [7] (Box 20.1). In patients older than 12 years of age, the diag- A periodic limb movement is defined as a limb nosis of RLS requires the presence of four essential movement of at least 0.5 second duration and a features [7]: (1) an urge to move the legs, usually maximum duration of 10 seconds. In addition, accompanied or caused by uncomfortable and Periodic Limb Movements require the occurrence of unpleasant sensations in the legs; (2) the urge to a minimum series of four limb movements with a move, or the unpleasant sensations, may begin or period of between 5 and 90 seconds. In addition, worsen during periods of rest or inactivity such as limb movements must be associated with an increase lying or sitting; (3) the urge to move, or the in electromyogram (EMG) amplitude of a minimum unpleasant sensations, may be partially or totally of 8 μV above the baseline EMG (Figure 20.1) [12]. relieved by movement, such as walking or stretch- Nearly 90% of patients with RLS have periodic ing, at least as long as the activity continues; and limb movements during sleep with two nights of (4) the urge to move, or the unpleasant sensations, polysomnographic recording [13]. Periodic limb may worsen, or only occur in the evening or night. movements (PLMs) can occur during sleep and When the diagnosis is questionable, the presence of wakefulness. PLMs occurring during wakefulness supportive clinical features may resolve uncer- are strongly associated with RLS. tainty. Supportive clinical features include: positive If the patient is cognitively impaired, RLS cannot family history of RLS, a positive therapeutic effect be definitively diagnosed. The patient is diagnosed to very low doses of dopaminergic medications, and with “probable RLS” in the presence of five criteria: periodic limb movements [7]. When the diagnosis (1) signs of leg discomfort such as rubbing or knead- is in doubt, associated features are also helpful ing the legs and groaning while holding the lower when confirming the diagnosis. Features associated extremities; (2) excessive motor activity in the with RLS include: lower extremities such as pacing, fidgeting, repeti- (1) The natural clinical history. When the onset of tive kicking, tossing, and turning in bed, slapping RLS occurs in patients under 50 years, the onset is the legs on the mattress, cycling movements, foot often insidious. In patients older than 50 years, tapping, rubbing the feet together, and an inability symptoms often occur abruptly. to remain seated; (3) signs of leg discomfort are (2) Sleep disturbance. exclusively present or worsen during periods of rest (3) The medical evaluation/physical examination. or inactivity; (4) signs of leg discomfort decrease The physical examination is generally normal and with activity; and (5) criteria (1) or (2) occur only does not contribute to the diagnosis except for in the evening or night or are more severe than those cases where RLS may be co-morbid with during the day [7] (Box 20.1).

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Box 20.1 RLS diagnostic criteria Restless Legs Syndrome Study Group. Movement Disorders, 10, 634–42. Allen,R., Picchietti, D. Hening,W, A. Adults and children 13 years of age and older Trenkwalder, C., Walters, A., Montplaisi, J. (2003). Restless Essential features legs syndrome: diagnostic criteria, special considerations, 1. Urge to move the legs, usually accompanied or and epidemiology A report from the restless legs caused by uncomfortable and unpleasant sensations syndrome diagnosis and epidemiology workshop at the 2. Symptoms begin or worsen during periods of rest or National Institutes of Health. Sleep Medicine, 4, 101–119. inactivity 3. Symptoms are partially or totally relieved by movement, walking or stretching, at least as long as Children 2 to 12 years of age can be diagnosed the activity continues with RLS when all four adult criteria are present 4. Symptoms are worse or only occur in the evening or and the child relates a description in his or her night own words that is consistent with leg discomfort.

Supportive clinical features If the child meets all four adult criteria but is una- 1. Positive family history of RLS ble to describe the symptoms in his/her own 2. Positive therapeutic effect to very low doses of words, the child must have at least two of the fol- dopaminergic medications lowing: a sleep disturbance greater than expected 3. Presence of periodic limb movements for his or her age, immediate biological relative with RLS, or a periodic limb movement Associated features 1. The natural clinical history index of five or more during sleep documented by polysomnography [7]. As in the case of adults, 2. Sleep disturbance when the essential diagnostic criteria cannot be 3. Normal physical examination except with co-morbidity clearly identified in children, supportive criteria can be useful and definitions for probable and B. Probable RLS diagnostic criteria in cognitively possible RLS in children have been defined [7] impaired adults (Box 20.1). 1. Signs of leg discomfort RLS is classified as either primary or secondary. 2. Excessive motor activity in the lower extremities RLS is classified as primary if a precipitating medi- 3. Rest or inactivity is associated with onset or cal illness, neurological disorder or medication side worsening of symptoms effect cannot be identified and is considered 4. Activity improves or eliminates symptoms at least secondary if such an association can be identified. temporarily Although primary RLS can occur sporadically, is 5. Criteria 1 & 2 are more severe or occur only in the most probably genetic when it occurs at a young evening or night age, and there is a family history of RLS. C. Children 2 to 12 years of age Secondary RLS is associated with an underlying 1. All four adult essential criteria are present medical disorder, neurological abnormality, or 2. Child relates a description in his/her own words medication side effect (1) Any medical condition consistent with leg discomfort associated with iron deficiency can precipitate sec- Children unable to meet criteria #2 must have at least ondary RLS (2) Peripheral neuropathy and radicu- two of the following: lopathy are in the differential diagnosis of RLS but 1. sleep disturbance greater than expected for age they may also occur with RLS (3) Use of antidepres- 2. immediate biological relative with RLS sant medications, such as selective serotonin reup- 3. a periodic limb movement index of five or more take inhibitors (SSRIs), may also aggravate and during sleep documented by polysomnography sometimes be the sole apparent cause of RLS (4) Supportive and associated features may help clarify the RLS occurs in pregnancy but disappears after deliv- diagnosis ery (5) RLS can be more frequently comorbid with 1. Adapted from Walters, A. (1995). Toward a better fibromyalgia, diabetes, uremia, rheumatoid arthri- definition of the restless legs syndrome. The International tis, multiple sclerosis, hypertension, heart disease,

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Figure 20.1 Periodic Limb Movements. A limb with an intermovement interval between 5 and 90 movement of at least 0.5 second duration and a seconds. Limb movements must be associated with an maximum duration of 10 seconds, requires the increase in electromyograph (EMG) amplitude of a occurrence of a minimum series of four limb movements minimum of 8 μV above the baseline EMG.

attention deficit hyperactivity disorder, anxiety, and Box 20.2 RLS Mimics depression [7]. In the case of the more frequent association of anxiety or depression with RLS, we Positional discomfort Restlessness related to habit or anxiety assume that the reverse is true – i.e. the RLS leads Leg cramps to anxiety and depression, and not vice versa. Local leg injury Restless legs syndrome must be differentiated Arthritis from conditions that mimic RLS as certain conditions unrelated to RLS may occasionally satisfy all RLS diagnostic criteria. As an example, patients pain may be localized to a small area and relieved by with leg cramps or positional leg discomfort may a brief simple shift of position. This is quite different meet all four RLS diagnostic criteria but do not have from idiopathic RLS where large parts of the thighs, RLS [14] (Box 20.2) In leg cramps the legs go into calves, or both are usually involved. RLS is different an actual spasm that is usually brief and relieved by from both positional discomfort and leg cramps in dorsiflexion of the foot on the floor. This is not true that walking or other activities to relieve leg dis- of RLS patients even if they complain of a cramp- comfort is more prolonged in RLS. Restlessness like sensation, as is sometimes the case. In positional related to habit or anxiety may mimic RLS but is discomfort, e.g. due to pain from hip discomfort, the less likely to be worse at night.

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Italian population. In this community-based study Video 20.2 Restless leg syndrome of subjects 50–89 years of age the prevalence of This 49 year old woman has a life-long history of RLS was 10.6% and more than twice as frequent extremely severe restless legs syndrome (RLS) that could in women compared to men [16]. not be controlled with medications, including dopamine agonists, intravenous iron, and methadone, but she In a study by Tison and colleagues of 10,000 obtained moderate improvement with thalamic deep French subjects, among all subjects, RLS had a brain stimulation. [Video courtesy of Joseph Jankovic, prevalence of 8.5%. The prevalence was 10.8% MD, Houston, Texas] among women [17]. Previously the prevalence of RLS among African-Americans was thought to be rare but a recent study suggests that it the same as the prevalence among Caucasians [18]. In Asian countries the prevalence of RLS is 1–2%. In 2000, Rothdach et al. studied the prevalence of RLS among German subjects 65–83 years of age. The http://bit.ly/tXuie9 prevalence of RLS was 6.1% among men and 13.9% among women [19]. The prevalence of clinically significant RLS, defined as symptoms occurring at least twice per week that are moderate or Peripheral neuropathy and radiculopathy are in severely distressing, is 2.7% [20]. The prevalence of the differential diagnosis of RLS if the patient does RLS decreases in older men but remains stable in not meet the criteria for RLS. If a patient with older women. peripheral neuropathy or radiculopathy meets the diagnostic criteria for RLS, the patient is considered to have RLS associated with peripheral Hypertension, heart disease, neuropathy or radiculopathy. Sleep transitional and stroke movements, which includes hypnic jerks, are in RLS may be associated with an increase preva- the differential diagnosis of the periodic move- lence of stroke [21]. It has been shown that PLMs ments during wakefulness that is sometimes seen are a manifestation of sympathetic activation. in RLS. Heightened sympathetic activity is associated with elevations in pulse rate and blood pressure. Changes in sympathetic activation occurring in Epidemiology RLS and associated PLMs may be a risk factor for stroke [21]. In 1945 Ekbom reported a 5.2% prevalence of RLS The relationship of RLS to hypertension is in a study population of Swedish subjects. unclear. Some researchers report a relationship Prevalence was slightly higher among women [2]. between RLS and hypertension [21]. Högl did not In 2002, Ohayon and Roth studied the prevalence find a relationship between RLS and hyperten- of Periodic Limb Movement Disorder (PLMD) sion [16]. Studies by Winkelman demonstrate an and RLS in 18,980 subjects from 15 to 100 years of association between RLS and cardiovascular dis- age living in five countries: United Kingdom, ease but not hypertension [22, 23]. A review of Germany, Italy, Portugal, and Spain. Using specific the Wisconsin Sleep Cohort study by Winkelman diagnostic criteria from the International Classi- et al. found that persons with daily RLS symp- fication of Sleep Disorders: Diagnostic and Coding toms were more likely to have a history of cardio- Manual (1990 edition), the researchers found a vascular disease [22]. This finding was confirmed prevalence of 5.5% for RLS and 3.9% for PLMD in a later study by Winkelman et al. using the [15]. Högl et al. reported a prevalence of RLS International RLS Study Group diagnostic criteria among residences of Bruneck, an “entirely white” for RLS [23].

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Childhood restless legs syndrome Etiology and attention deficit hyperactivity disorder Genetics Brenning performed the first study documenting a The etiology of RLS is unknown but primary RLS is relationship between childhood “growing pains thought to be genetic. Linkage studies in RLS fami- and RLS-like symptoms” [24]. The Peds REST study lies identified eight loci: chromosomes 12q (RLS1), examined the prevalence and impact of restless legs 14q (RLS2), 9p (RLS3), 20p (RLS4), 2q (RLS5), 4q, syndrome in children using data collected from 17p, and 19p [34]. In 2007 genome-wide associa- 10,523 families. Moderate or severe RLS occurred tion studies completed by two different groups of in 0.5% of children 8–11 years of age and 1.0% in researchers identified a common variant in an intron children 12–17 years of age [25]. Eighty percent of of BTBD9 on chromosome 6p [35, 36]. In addition, children with RLS in this study presented with Winkelman et al. identified genomic regions: MEIS1 growing pains [25]. on chromosome 2p and a region on chromosome Attention deficit hyperactivity disorder (ADHD) 15q containing MAP2K5 and LBXCOR1 [36]. The occurs more commonly in children and adults with MEIS1 gene is believed to be related to limb devel- RLS and vice versa. Kotagal and Silber reported that opment [37]. Schormair et al. identified an associa- 8 of 25 children with RLS demonstrated inattentive- tion between RLS and protein tyrosine phosphatase ness [26]. In 2005 Cortese et al. reported that up to receptor type delta (PTPRD) at 9p23–24 [38]. 44% of children with ADHD have RLS or symptoms A gene promoter region favoring monoamine of RLS [27]. Zak et al. studied 30 adults with ADHD oxidase A activity, which would cause more rapid and found a 20% prevalence of RLS [28]. elimination of dopamine from the synapse, is associated with RLS in women but not men [39]. This Iron deficiency latter observation is consistent with the hypodopa- Secondary RLS (symptomatic RLS) has been linked minergic hypotheses of RLS and the observation to conditions causing iron deficiency such as preg- that RLS is more common in women than men. nancy and blood donation [29, 30]. Pathophysiology Gastrointestinal disease RLS has been linked to gastrointestinal disease. In Iron and dopamine 2009, Weinstock et al. studied 85 patients with The pathophysiology of RLS is unknown but celiac disease. The incidence of RLS among patients appears to involve the central nervous system with celiac disease was 35% and prevalence was metabolism of iron, the neurotransmitter dopamine 25% [31]. Restless Legs Syndrome has been (DA), and genetic factors. There is up regulation of described as an extra-intestinal manifestation of tyrosine hydroxylase and down regulation of D2 Crohn’s disease. In a multicenter study of 272 receptors [40]. subjects from outpatient gastrointestinal clinics the Ultrasound studies demonstrate hypoechogenic- incidence of RLS in patients with Crohn’s disease ity in the substantia nigra of patients with RLS was 43% (93 of 218 patients) The prevalence of consistent with decreased iron content [41]. Using RLS in patients with Crohn’s disease was 30% (82 a special MRI measurement (R2) to assess brain of 272 patients) [32]. iron content, Allen et al. found a significant decrease in brain iron within the substantia nigra, and a End stage renal disease (ESRD) somewhat less significant reduction in the puta- Studies estimate the prevalence of RLS among men, both in proportion to RLS severity [42]. This dialysis patient from 6.6 to 21.5%. Nearly 20% of may indicate iron deficiency. dialysis patients discontinue dialysis due to RLS As to iron metabolism, iron is stored in the body symptoms [33]. by ferritin and transported within the body by

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transferrin. Transferrin is manufactured in the liver Endogenous opioid system and brain. Peripheral transferrin does not cross the We have recently completed a preliminary autopsy blood–brain barrier. When CSF levels of iron, fer- study of RLS patients showing decrements in the ritin, and transferrin of patients with RLS are com- endogenous opioids beta-endorphin and meten- pared to normal controls, patients with RLS have kephalin in the thalamus of RLS patients versus lower CSF ferritin and iron levels and higher trans- controls suggesting that hypofunctioning of the ferrin levels [42–44]. When symptoms occur in endogenous opioids system may be pathogenetic patients 45 years of age and younger, there is a cor- to RLS [47]. relation between the age of symptom onset and ferritin level. The earlier the age of onset, the lower Immunity and inflammation the ferritin level [45]. Most recently we have noted that RLS patients Iron is essential to the production and utilization have an increased prevalence of Irritable Bowel of DA. Iron is a cofactor to tyrosine hydroxylase, Syndrome (IBS) and an increased prevalence of the rate-limiting enzyme in the transformation of Small Intestinal Bacterial Overgrowth (SIBO) tyrosine to levodopa. Levodopa is a precursor to compared to controls [48]. This led us to review the dopamine. It is possible that defective acquisition or 40 or so secondary causes of RLS. Independent of utilization of iron within brain cells leads to RLS, the vast majority of these secondary causes dopamine deficits in patients with RLS. Researchers, are associated with either iron deficiency, SIBO, or studying the neuropathological changes of 7 brains inflammatory/immune abnormalities. This suggests from individuals with RLS and 5 age-matched that inflammation and immune attacks on the controls without RLS, found a reduction in iron peripheral or central nervous system in RLS could and H-ferritin staining in the substantia nigra. Cells be pathogenetic to RLS [48]. An alternate explana- staining for L-ferritin were morphologically tion is that inflammation may lead to iron defi- different from the cells of the controls. Transferrin ciency which may in turn lead to RLS. receptor staining on neuromelanin-containing cells There is a significant association between RLS was decreased in the RLS brains compared to and multiple sclerosis (MS) In a study of 164 normal. The researchers concluded that RLS may patients with MS, 19% had symptoms of RLS at be a functional disorder secondary to impaired iron least twice per week. It is hypothesized that inflam- acquisition by neuromelanin cells [46]. matory damage associated with MS may trigger Several researchers posit that a diencepalospinal RLS [49]. Interestingly, idiopathic RLS in the pathway is involved in RLS. The diencephalospinal absence of MS or any other autoimmune disease pathway originates in the A11 dopaminergic cell responds to steroids under double-blind conditions group of the hypothalamus and terminates in the [50] and RLS may undergo remissions just like intermediolateral cell column of the spinal cord. MS [7, 8]. The intermediolateral cells of the spinal cord are RLS has also been associated with rheumatoid also innervated by excitatory neurons descending arthritis. Salih et al. studied patients with osteoar- from the serotonergic dorsal raphe. When dopa- thritis and rheumatoid arthritis. RLS was associ- mine is reduced, sympathetic tone is increased ated with rheumatoid arthritis but there was no because of the relative increase of serotonergic acti- significant association with osteoarthritis. The vation. One hypothesis is that this leads to over researchers posited that RLS was secondary to iron stimulation of skeletal muscles and irritation of deficiency due to anemia of a chronic disease muscle spindles. The increased input to the muscle which occurs with rheumatoid arthritis but the spindle would lead to increased activation of nearby autoimmunity associated with rheumatoid arthri- sensory fibers which project to the spinal cord. The tis, and not osteoarthritis, is a possible pathogenic nociceptive input to the spinal cord would then be risk factor [51]. referred to the cortex where it might be perceived as An overall approach to the management of RLS the abnormal sensations associated with RLS [21]. is listed in Box 20.3 and Figure 20.2.

Albanese_c20.indd 317 12/24/2011 7:30:53 AM Box 20.3 A Step Approach to the pharmacologic management of patients meeting RLS diagnostic criteria Step 1. Classification of symptoms Intermittent: Frequency of symptoms does not warrant daily medication. However, when present, symptoms are troublesome enough to justify treatment. Daily: Symptoms occur more than 14 days per month Refractory (Malignant RLS): Daily RLS treated with a dopamine agonist with one or more of the following outcomes: 1. Inadequate response to appropriate medication dosage 2. Loss of control of symptoms despite increasing amounts of medication 3. Presence of unacceptable adverse affects 4. Uncontrollable augmentation Step 2. Review medications for drugs that contribute to RLS symptoms: antidepressants, neuroleptics agents, dopamine -blocking antiemetics, sedating antihistamine. Prudently consider discontinuation of medications that contribute to RLS symptoms. Step 3. Identify co-morbid conditions that interfere with response to RLS therapy 1. Ferritin level less than 50ug/mL (investigate etiology) 2. Neuropathies (may benefit from gabapentin or pregabalin) 3. Renal disease (may respond to clonidine) Step 4. Initiate nonpharmacologic therapy to all patients and simultaneously initiate pharmacological therapy Step 5. Selection of pharmacologic agent

(A) Intermittent RLS Ferritin level less than 50 ug/mL

Yes No

Ferrous sulfate + Vitamin C

1.Look for etiology of low ferritin level 2. Continue iron therapy of three months then re-evaluate

Symptoms resolved

Yes No Initiate one of the following: Nonpharmacologic strategies 1. Carbidopa/levodopa 2. DA 3. Low-potency opioids 4. Tramadol 5. Benzodiazepine 6. Anticonvulsant 7. Transcutaneous electrical nerve stimulation/pneumatic compression device 8. Valerian root Figure 20.2 (cont’d).

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(B) Daily RLS Ferritin level less than 50 ug/mL

Yes No

Ferrous sulfate + Vitamin C

1. Look for etiology of low ferritin level 2. Continue iron therapy of three months then re-evaluate 3. Simultaneously initiate additional therapy

Levodopa or dopamine agonists

Symptoms controlled

Yes No

Continue therapy Change to another DA

Symptoms controlled

No Yes

Continue therapy Add or change to alternative therapy which includes: Gabapentin, Pregabalin, low-potency opiates, benzodiazepine

Symptoms controlled

Yes No Continue therapy see Refractory RLS

Figure 20.2 (cont’d).

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(C) Refractory RLS Combination therapy: DA plus one additional agent from one or two of the other classes of medications used to treat RLS:

1. Benzodiazepine 2. High potency opioid 3. Anticonvulsant Symptoms controlled

Yes No

Continue therapy Trial of intravenous iron

Or change medication to methadone

Symptoms controlled

Yes No

Continue therapy Consider 1. Intrathecal morphine 2. Intravenous iron therapy

*Abrupt discontinuation of levodopa and or DA is not recommended

Figure 20.2 (cont’d)(A) Intermittent RLS. For intermittent RLS medication is administered as needed usually 45 minutes before engaging in activities known to precipitate RLS such as long plane rides sitting down for extended periods of time such long plane flights going to the theater (B) Daily RLS (C) Refractory RLS. [Adapted from: Silber et al. (2004) An algorithm for the management of Restless Legs Syndrome. Mayo Clinic Procedings, 79:916–22, with permission.]

Treatment sants, neuroleptics, dopamine-blocking antiemetics, or sedating antihistamines [52]. For some individuals, Non-pharmacologic strategies may resolve mild or working in the afternoon or night shift can be helpful intermittent symptoms and possibly reduce when activity can suppress the symptoms at a time symptoms in other patients. All patients should be when the symptoms are most likely to occur. encouraged to use non-pharmacologic strategies. The serum ferritin level should be evaluated in A non-pharmacologic approach includes: use of all patients with RLS. A serum ferritin level less alerting mental activities such as games, crossword than 50 micrograms/L is often associated with RLS puzzles, or playing a musical instrument; abstinence symptoms and should be treated simultaneously from caffeine, nicotine, and alcohol; and, when med- with the initiation of more definitive therapy ically possible, discontinuing medications known to [53, 54]. We recommend ferrous sulfate 325 mg tid exacerbate RLS symptoms such as certain antidepres- with Vitamin C 500 mg tid to aid absorption. The

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etiology of iron deficiency should be investigated. and increased to 0.5 mg after an additional 4–7 days Patients with neurologic findings of peripheral if needed. The usual prescribed dose is 0.5 mg per neuropathy or radiculopathy and symptoms of RLS day but we have used doses up to 3 mg/day in should be evaluated by electromyography and divided dosages over the evening time [57]. nerve conduction studies [54]. Levodopa/carbidopa, has a relatively short half-life Of the pharmacologic agents used to treat RLS, and, as such, may be used to control mild symp- only pramipexole and ropinirole are approved by toms that occur only in association with prolonged the United States Federal Drug Administration sitting or intermittently. The routine night-time (FDA) All medications used to treat RLS should be dosing of levodopa/carbidopa, however, should be started at the lowest dose and increased as needed avoided as it can lead to gradual loss of efficacy and to the maximum dose (see Table 20.1). augmentation and rebound (see below). Cabergoline is an ergot-derived long-acting D2 Dopaminergics agonist seldom used in the United States due to cost In 2004, the Standards of Practice Committee of and side effects. In a meta-analysis of randomized The American Academy of Sleep Medicine pub- clinical trials of dopaminergic agents (DA) used to lished guidelines for the use of dopaminergics in treat RLS, Zintzaras et al. reported that cabergoline the treatment of RLS. Levodopa with decarboxy- and pergolide had greater efficacy than non-ergot lase inhibitor, pramipexole and ropinirole are all dopaminergics [58]. effective treatments. The only FDA approved medi- All dopaminergics are potentially associated cations for treatment of RLS are the non-ergot with augmentation and rebound. Augmentation is dopamine agonists ropinirole and pramipexole [2]. defined by the presence of an increase in the fre- We have reviewed the dopaminergic therapy of quency or severity of symptoms, slightly earlier RLS elsewhere in detail [2]. onset of symptoms or the onset of symptoms in pre- The ergot dopamine agonists, bromocriptine and viously uninvolved body areas, but the earlier onset pergolide, are also effective but because of their of symptoms is the key feature [59]. Augmentation association with pleuropulmonary fibrosis and is associated with daily administration of levodopa cardiac valvulopathy, are no longer recommended. or administration of 300 mg per day or more. Rotigotine is a non-ergot dopamine receptor ago- Augmentation occurs less often with dopamine nist with strong affinity to D3, D2, and D1 receptors agonists than L-Dopa but is still a significant clinical and lesser affinity to D5 and D4 receptors [55]. problem with dopamine agonists. Rebound is a Previously available in the United States as a silicon withdrawal symptom and occurs when the medica- transdermal patch, Rotigotine effectively reduced tion is wearing off at a time that is compatible with RLS symptoms. Due to problems with crystalliza- the half-life of the drug. Rebound may lead to the tion, Rotigotine is currently unavailable in the emergence of symptoms during early morning United States but is available in Europe. hours after the administration of night-time medi- Ropinirole should be started at 0.25 mg adminis- cations [60]. Rebound must be distinguished from tered 1–3 hours before bedtime or 90–120 minutes augmentation because treatment of these phenom- before the onset of symptoms. Ropinirole can be ena differs. In augmentation the symptoms appear increased by 0.5 mg every 7 days as needed to a at a time incompatible with the half-life of the drug maximum dose of 4 mg per day. The therapeutic when medications are long out of the blood stream. range is 0.25 mg to 4 mg per day. The mean dose is For example, if symptoms previously began at 6 pm 2 mg per day. Syncope, sometimes associated with and were treated at 5 pm with a dopaminergic agent bradycardia, hypotension, and hallucinations, are with a 6 hour half-life, the symptoms may start to reported side effects [56]. begin at 4 pm as a side effect of the drug itself. With Pramipexole should be started at 0.125 mg. If mild augmentation an earlier dose of medication symptoms are not controlled in 4–7 days, prami- may sometimes be helpful. However, with recurrent pexole can be increased to 0.25 mg after 4–7 days augmentation the medication should be reduced or

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Table 20.1 Behavioral manifestations of dopamine dysregulation syndrome in RLS patients.

Behavior* Definition Diagnostic Criteria

Compulsive gambling The presence of five or more of the following in a persistent DSM IV (Pathological gambling) and recurrent maladaptive behavior:

1. Preoccupation with gambling 2. to maintain level of excitement, gambles with increasing amounts of money 3. repeated unsuccessful attempts to control, reduce or stop gambling 4. attempts to reduce or stop gambling are associated with restlessness or irritability 5. uses gambling to escape from problems or to elevate mood 6. attempts to recoup gambling losses by returning on another day to get even 7. conceals extend of gambling 8. engages in illegal acts such as forgery, fraud, theft or embezzlement to finance gambling 9. risk loosing or has lost a significant relationship, job or educational or career opportunity due to gambling 10. depends on others for money to elevate dire financial problems caused by gambling B. gambling behavior is not better accounted for by a Manic Episode. Hypersexuality Disturbance in the processes of one or more of the phases of the sexual DSM IV (Sexual Dysfunction) response cycle (desire, excitement, orgasm, resolutions) or by pain associated with sexual intercourse. Punding Complex prolonged, purposeless stereotyped behavior associated with Rylander central stimulants. Often involves repetitive handling of objects. Drug hoarding Fear of discarding something useful or that may become useful in the Winsberg et al. future Shopping Traveling

*Patients may develop more than one type of impulsive behavior.

discontinued. Rebound can be treated by increasing hyperphagia, traveling, punding, and hypersexuality the medication dosage at bedtime or changing to an (see Table 20.1) extended release form of medication. DDS is thought to be secondary to excessive stimulation of the central dopamine reward Dopamine dysregulation syndrome system [63]. DDS has been reported in patients Dopamine dysregulation syndrome (DDS), also treated with pramipexole, ropinirole, pergolide, bro- known as hedonistic homeostatic dysregulation, is mocriptine, and levodopa monotherapy [61–66]. an iatrogenic neurobehavioral disorder thought to Initially thought to only occur in association with be secondary to excessive stimulation of the central large doses of dopaminergic agents such as those dopamine reward pathway [61]. Behaviors used to treat Parkinson disease [61], DDS has been observed in DDS are similar to behaviors observed reported in patients taking low doses of levodopa in patients who abuse central stimulants such as and dopaminergic agents to control RLS symptoms. amphetamines and cocaine. Behaviors associated In 2007, Quickfall et al. and Tippman-Peikert et al. with DDS include pathological gambling, shopping, reported the onset of compulsive gambling in 4 RLS

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patients treated with pramipexole (0.125 to 0.75 mg/ DDS is treated by decreasing the dosage or day) and ropinirole (0.5 mg/day) [65, 66]. In 2010, discontinuing dopamine or dopamine agonists. Kolla et al. reported two additional cases of new Therapy is then continued with off label medications. onset compulsive behavior disorder in 2 patients with RLS treated with dopamine agonists. One Iron therapy patient experienced hypersexuality and the other The most common cause of secondary RLS is iron case was complicated by the patient’s suicide deficiency [29, 30]. Any condition associated with attempt due to an inability to control gambling [67]. iron deficiency may trigger RLS symptoms in Salas et al. reported the onset of drug hoarding as patients predisposed to RLS. Serum ferritin and an atypical manifestation of DDS in a patient with iron levels should be evaluated in all patients with RLS [68]. Increased shopping and traveling around RLS. Unless iron is contraindicated for other rea- the country were reported by Ondo and Lai [69]. sons, patients with a ferritin level less than 50 mcg /L should be given supplemental iron [41]. We rec- Punding ommend 325 mg of ferrous sulfate administered “Punding” is a term coined by Rylander to describe orally with 500 mg of vitamin C three times per day the automatic behaviors associated with high doses for three months. Ferritin and iron levels should be of central stimulant drugs [70]. Punding is complex, determined again after three months of therapy. An prolonged, purposeless stereotyped behavior first attempt to determine the etiology of iron defi- observed in chronic amphetamine users. Rylander ciency is indicated. Oral iron therapy will not work observed that the behavior is generally something immediately and is dependent on raising iron that the patient is accustomed to doing or something stores. Because iron crosses the blood brain barrier that the patient enjoys. Examples of punding poorly this may take a few months and for severe behavior include manipulation of technical patients concomitant therapy with medications is equipment such a radios or engines, repetitive recommended. cleaning of a room or object, and excessive Intravenous iron therapy may be helpful in attention to personal hygiene [70]. Initially patients with refractory RLS who are unable to reported as a side effect in patients taking high tolerate oral iron. After intravenous administration doses of amphetamines, punding has been reported of high molecular weight iron dextran, Ondo noted in patients taking dopaminergic agents. In 2009, improvement in patients with refractory RLS symp- Evan et al. described punding in a 65-year-old toms. The clinical effect of intravenous iron is female with RLS and a familial history of RLS. The delayed by approximately three days. Intravenous patient was initially prescribed pergolide 0.10 mg iron must be given with caution due to the risk of per night. Over a period of 6 years the medication anaphylaxis [72] (Box 20.4). was increased to 1.5 mg three times per day. Approximately 6 months after starting pergolide Second line treatments the patient voluntarily terminated employment Opioids and began gambling. She later developed The opioid oxycodone decreased RLS symptoms hypersexuality and punding. Punding behavior and PLMs in a double-blind study [76]. Opioids are consisted of spending many hours attending to her effective long-term therapy [77]. The mechanism garden, painting her house, often the same room of opioid effectiveness in RLS is thought to be multiple times, and engaging in aimless repetitive opiate receptor specific as the opiate receptor cleaning such as polishing furniture more often blocker naloxone reverses the therapeutic benefit than necessary. The dose of pergolide was reduced of the opioids [78]. Methadone has been used and the patient was given a trial of cabergoline to for refractory RLS and in patients unable to toler- no avail. Punding, hypersexuality, and gambling ate dopaminergics [79]. In addition to its effect stopped abruptly with the discontinuation of all upon the mu opiate receptor subtype, metha- dopaminergic agents [71]. done uniquely antagonizes N-methyl-D-aspartate

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Benzodiazepines Box 20.4 Pharmacologic agents for Long-acting benzodiazepines, such as clonazepam, treatment of RLS reduce RLS symptoms and frequency of periodic Classification and Name of medication limb movements and promote sleep because of Dopaminergic agents Carbamazepine their hypnosedative properties [85]. Short-acting Ropinirole Valproic acid benzodiazepines (such as triazolam) or intermedi- Pramipexole Benzodiazepines ate acting benzodiazepines (such as temazepam) Levodopa/carbidopa Clonazepam Cabergoline Oxazepam are less likely to be effective [86]. There are reports Rotigotine Temazepam of benzodiazepines precipitating sleep apnea. Bromocriptine Diazepam Benzodiazepines, taken in low to moderate doses, Pergolide Antihypertensives have sustained efficacy with low risk for adverse Opioids Clonidine effects, dosage escalation or abuse in sleep disorder Codeine Herbal Preparations Hydrocodone patients without a previous history of addiction Valerian Methadone [87]. Oxycodone Minerals and Oxycodone XR Supplements Third line treatment Propoxyphene Iron (oral) Clonidine Tramadol Iron (intravenous) Morphine (Intrathecal) Magnesium Clonidine is a centrally acting alpha adrenergic ago- Only ropinirole and Anticonvulsants nist. Clonidine 0.1–0.3 mg at bedtime can be used pramipexole are FDA Gabapentin to reduce sleep latency. Clonidine relieves the leg approved for treatment Pregabalin discomfort of RLS but does not reduce periodic limb of RLS Lamotrigine movements [88].

Alternative therapies receptors in the spinal cord [80]. Patients on opioids Herbal therapy must be monitored for the onset of sleep apnea [77]. When allopathic therapies do not relieve symp- When patients with severe RLS symptoms do not toms, 67% of patients with RLS try complementary respond to other forms of therapy, these patients and alternative medical therapies (CAM) [89]. In a may benefit from intrathecal morphine [73–75]. blinded pilot study of 48 patients with RLS, Cuellar reported that RLS symptom severity decreased and Anticonvulsants sleep quality improved in patients given 800 mg of Patients not responding to dopaminergics may Valerian an hour before bedtime for 8 weeks. improve with gabapentin or pregabalin. Gabapentin Valerian is thought to be a safe herbal product asso- and pregabalin are ligands for the α-2-δ subunit of ciated with few side effects. Reported side effects calcium channels [81]. Unlike dopaminergic agents, include gastrointestinal disturbances, fatigue/men- gabapentin and pregabalin are not associated with tal sluggishness, vivid dreams, agitation/restless- augmentation or rebound. ness, headache, dizziness, and rash [90]. Gabapentin decreases RLS symptoms, improves sleep architecture, and decreases PLMs [82]. Acupuncture Gabapentin has an interpatient variable rate of In 2007 Cui et al,, reviewed the Cochrane Central absorption making the effective dose difficult to Register of Controlled Trials, Medline, EMBASE, determine. Gabapentin enacarbil is an extended several Chinese databases and a Korean database release form of gabapentin and overcomes interpatient for evidence of effectiveness of acupuncture for variable absorption. Clinical trials show gabapentin RLS (91) There is limited data on the use of the enacarbil improves RLS symptoms [83]. Pregabalin various acupuncture methods in the treatment of administered as a minimum dose of 150 mg per day RLS. The authors found case reports and small effectively reduces RLS symptoms [84]. studies that support effectiveness of acupuncture

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for RLS, but no reports of acupuncture being more associated with a variety of pain syndromes effective than allopathic therapy including FDA- including failed-back syndrome, neuropathic pain, approved medications. They concluded “there is radiculopathic pain, phantom limb and ischemic insufficient evidence to support the hypothesis that leg pain [97]. There is limited information available acupuncture is more effective in the treatment of regarding the use of SCS for RLS. Jakobsson and RLS than no treatment or other therapies. There Ruuth reported failure of SCS to improve RLS are insufficient well-designed randomized con- symptoms in a 52-year-old woman with refractory trolled trials and the safety of acupuncture methods RLS [73]. for RLS is unknown” [70]. In 2009 Stanislao et al. reported the results of a retrospective case study of Deep brain stimulation (DBS) 30 Italian adults with RLS. Most had some benefit, and pallidotomy and some had relief of symptoms for up to 6 months In 1999, Rye reported a patient with RLS and PD after 10–12 acupuncture sessions [92]. who experienced resolution of RLS symptoms after The effectiveness of acupuncture is complex pallidotomy for severe symptoms of Parkinson dis- because there are several methods of acupuncture. ease [98]. Okun et al. described eliminating RLS Methods of acupuncture include body acupunc- symptoms in a patient with dystonia and comorbid ture, auricular acupuncture, scalp acupuncture, RLS after bilateral internal segment of the globus electro-acupuncture, laser acupuncture, acupres- pallidus (GPi) deep brain stimulation (DBS) [99]. In sure, and acupoint injection therapy, which is the a study by Ondo, involving patients with essential injection of medication into acupoints. tremor and RLS, stimulation of the ventralis intermedius nucleus (VIM) of the thalamus did not Transcutaneous electrical nerve improve the RLS symptoms [100]. stimulation In 2004 Kedin et al. reported the emergence of In 1990, Krueger reported that transcutaneous RLS in 11 patients with Parkinson disease treated electric nerve stimulation may be beneficial [93]. by subthalamic DBS and a reduction in dopaminer- There is, however, limited literature on treating RLS gic therapy. The authors concluded that their with transcutaneous electric nerve stimulation. unmasking of the RLS symptoms was due to a reduction in dopaminergic medications [101]. Enhanced external counter pulsation A similar study by Driver-Dunckley et al. reported Enhanced external counter pulsation (EECP) contradicting results. They found an improvement increases collateral circulation to the legs and other in RLS symptoms post-subthalamic stimulation, body parts and has been used in the treatment of and attributed the positive benefit to a slower taper angina. In an open label study, 6 patients with RLS of dopaminergic therapy, a longer post-operative were treated with EECP [94]. Changes in severity period of observation and different programming of RLS symptoms were measure by the International parameters of the stimulators [102]. RLS Study Group severity scale. The patients’ score on the severity scale decreased and EECP appeared Infrared light to be a promising treatment. The open label study Mitchell et al. evaluated the effectiveness of mono- was followed by a parallel double-blind placebo- chromatic near-infrared light treatment in decreas- controlled study with long-term subjective following RLS symptoms. Thirty-four subjects with RLS up for 6 months. EECP did not show long-term were randomly assigned to one of two groups: improvement of RLS symptoms [95]. infrared therapy or sham therapy. The legs were exposed to infrared lights or sham lights for 20 Spinal cord stimulation minutes. Therapy was given at the same time on For more than 40 years, spinal cord stimulation Monday, Wednesday, and Friday. If a subject missed (SCS) has been a therapeutic option for treatment a session, the session was made up on another day of chronic pain [96]. SCS alleviates or reduces pain of the week. Response to therapy was monitored

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by the RLS severity rating scale developed by the degradation of ferroportin. Ferroportin is the only International Restless Legs Syndrome Study Group. known mechanism for the export of intracellular Subjects treated by infrared therapy showed signifi- non-heme-associated iron, and ferroportin and cant improvement compared to subjects receiving hepcidin are critical to iron homeostasis [110]. The sham therapy [103]. degradation of ferroportin leads to iron deficiency. The association between iron deficiency and RLS is Supplements and vitamins well established [42–45]. Magnesium In 1998 Hornyak reported findings from an open Pneumatic compression devices trial study of 10 patients with RLS and or PLM. Pneumatic compression devices work on a principle Patients were administered 12.4 mmol (approxi- distinct from the EECP mentioned above. In EECP mately 300 mg) magnesium each evening for 4–6 leg devices compress and decompress in relation- weeks. Polysomnography documented a reduction ship to cardiac cycles, whereas with pneumatic in PLMs and patients reported improvement in RLS compression devices this is not the case. In a symptoms [104]. Magnesium decreases smooth double-blind study where 35 subjects were enrolled, muscle contraction and dilates blood vessels [105]. true compression was compared to sham compres- Walters et al. measured total serum and CSF mag- sion, and there was a significant improvement in nesium levels in patients with RLS and controls. severity of RLS symptoms, quality of life, and sleep There was no statistical significant difference quality. The devices were applied for at least 1 hour between patients and controls for either serum or prior to the usual onset of symptoms and the CSF magnesium [106]. authors conclude that pneumatic compression devices should be considered as a useful adjunct to Folate pharmacotherapy [111]. Botez et al. described 3 patients with RLS and folate deficiency whose RLS symptoms improved after treatment with folate [107] According to Lee et al. Conclusions a reduction in folate may be associated with RLS symptoms during pregnancy [108]. The expanding body of medical research has redefined RLS from a rare disorder affecting only older Antibiotic treatment persons of European descent, to a common disorder RLS patients with comorbid celiac disease and irri- affecting nearly every ethnic group. The IRLSSG’s table bowel syndrome (IBS) may have a reduction standardization of diagnostic criteria and validation in symptoms after treatment with antibiotics. In a of an RLS severity scale are instrumental to ongoing study by Weinstock, 10 of 13 patients with RLS and research and provide valuable aid to clinicians. IBS treatment with 10 days of rifaximin had a reduction in RLS symptoms [109]. Weinstock et al. propose two hypotheses regarding the relationship References between chronic gastrointestinal infections and RLS. One hypothesis is that RLS may be caused by 1 Willis T (1685) The London Practice of Physick. London: an immunologic mechanism precipitated by infec- Basset T and Crooke W. 2 Hamilton-Stubbs P, Walters A (2010) Restless Legs tion. An alternative hypothesis is that SIBO is a Syndrome. In: Kompoliti K and Metman LV (eds) chronic infection associated with poor gastrointes- Encyclopedia of Movement Disorders. Vol.3, pp 32–7. tinal iron uptake [31]. Volunteers given bacterial Oxford: Academic Press. lipopolyscaccharides, develop elevated cytokine 3 Ekbom KA (1945) Restless legs. Acta Medica Scand levels. Cytokines, such as interleukin-6, up-regulates 158:1–123. hepcidin, a hormone produced by the liver 4 Ekbom KA (1944) Asthenia crurum paraesthetica that regulates iron absorption. Hepcidin induces (irritable legs) Acta Medica Scand 118:197–209.

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5 Ekbom K, Ekbom K (1974) An early Swedish descrip- adults: a nationwide survey. The INSTANT study. tion of restless legs (Huss 1849) Lakartidningen Neurol 65:239–46. 71:2905–6. 18 Lee H, Hening W, Allen R, et al. (2006) Race and rest- 6 Walters A (1995) Toward a better definition of the less legs syndrome symptoms in an adult community restless legs syndrome. The International Restless Legs sample in east Baltimore. Sleep Med 7:642–5. Syndrome Study Group. Mov Disord 10:634–42. 19 Rothdach A, Trenkwalder C, Haberstock J, et al. 7 Allen R, Picchietti D. Hening W, et al. (2003) Restless (2000) Prevalence and risk factors of RLS in an elderly legs syndrome: diagnostic criteria special considera- population: the MEMO study. Memory and Morbidity tions, and epidemiology A report from the restless legs in Augsburg Elderly. Neurol 54:1064–8. syndrome diagnosis and epidemiology workshop at 20 Allen R, Walters A, Montplaisir J, et al. (2005) Restless the National Institutes of Health. Sleep Med legs syndrome prevalence and impact REST general 4:101–19. population study. Arch Intern Med 165:1286–92. 8 Lugaresi E, Coccagna G, Berti Ceroni G, Ambrosetto C 21 Walters A, Rye D (2009) Review of the relationship of (1968) Restless Legs Syndrome and Nocturnal restless legs syndrome and periodic limb movements Myoclonus. In: Gastaut H, Lugaresi E, Berti Ceroni G, in sleep to hypertension, heart disease and stroke. Coccagna G (eds) The Abnormalities of Sleep in Man. Sleep 32:589–97. pp 285–294. Bolgna: Gaggi Editore. 22 Winkelman JW, Finn L, Young T (2006) Prevalence 9 Walters AS (2003) Group Organizer and and correlates of restless legs syndrome symptoms in Correspondent: The International Restless Legs the Wisconsin Sleep Cohort. Sleep Med 7:545–52. Syndrome Study Group. Validation of the International 23 Winkelman JW, Shahar E, Sharief I, Gottlieb DJ Restless Legs Syndrome Study Group Rating Scale for (2008) Association of Restless Leg Syndrome and Restless Legs Syndrome. Sleep Med 4:121–32. cardiovascular disease in the Sleep Heart Health Study. 10 Trenkwalder C, Hening WA, Walters AS, et al. (1999) Neurol 70:35–42. Circadian rhythm of Periodic Limb Movements and 24 Brenning R (1960) Growing pains. Acta Soc Med sensory symptoms of the Restless Legs Syndrome. Upsal 65:185–201. Mov Disord 14:102–10. 25 Picchietti D, Allen R, Walters A, et al. (2007) Restless 11 Hening WA, Walters AS, Wagner M, et al. (1999) legs syndrome: prevalence and impact in children Circadian rhythm of motor restlessness and sensory and adolescents – the Peds REST study. Pediat 120: symptoms in the idiopathic Restless Legs Syndrome. 253–66. Sleep 22:901–12. 26 Kotagal S, Silber M (2005) Childhood-onset restless 12 Iber C, Ancoli-Israel S, Chesson A, Quan S (2007) The legs syndrome. Ann Neurol 56:803–7. AASM Manual for the Scoring of Sleep and Associated 27 Cortese S, Konofal E, Lecendreux M, et al. (2005) Events. Westchester IL: American Academy of Sleep Restless legs Syndrome and attention-deficit/hyperac- Medicine. tivity disorder: a review of the literature. Sleep 13 Montplaisir J, Boucher S, Poirier G, et al. (1997) 28:1007–13. Clinical, polysomnographic, and genetic characteris- 28 Zak R, Fisher B, Couvadelli B, et al. (2009) Preliminary tics of Restless Legs Syndrome: A study of 133 patients study of the prevalence of restless legs syndrome in diagnosed with new standard criteria. Mov Disord adults with attention deficit hyperactivity disorder. 12:61–5. Percep Motor Skills 108:759–63. 14 Hening W, Allen R, Washburn M, et al. (2009) The 29 Manconi M, Govini V, DeVito A, et al. (2009) Restless four diagnostic criteria for restless legs syndrome are Legs Syndrome and Pregnancy. Neurol 63:1065–9. unable to exclude confounding conditions (“mimics”) 30 Ulfberg J, Nystrom B (2004) Restless Legs Syndrome Sleep Med 10:976–81. in blood donors. Sleep Med 5, 115–18. 15 Ohayon M, Roth T (2002) Prevalence of restless les 31 Weinstock L, Walters A, Mullin G, Duntley S (2010) syndrome and periodic limb movement disorder in the Celiac Disease is associated with restless legs syndrome. general population. J Psychosomat Res 53:547–54. Digest Dis Sci 55:1667–73. 16 Högl B, Kiechl S,Willeit J et al. (2005) Restless legs 32 Weinstock L, Bosworth B, Scherl E, et al. (2010) syndrome: a community-based study of prevalence, Crohn’s disease is associated with restless legs severity, and risk factors. Neurol 64:1920–4. syndrome. Inflam Bowel Dis 16:275–9. 17 Tison F, Crochard A, Legér, D, et al. (2005) 33 Moysés de Oliveira M, Conti C, Valbuza J, et al. (2010) Epidemiology of restless legs syndrome in French The pharmacological treatment for uremic Restless

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Legs Syndrome: Evidence-Based Review. Mov Disord 48 Weinstock LB. Walters AS. (n.d.) Increased bacterial 25:1335–42. overgrowth in Restless Legs Syndrome: Is RLS medi- 34 Trenkwalder C, Högl B, Winkelmann J. (2009) Recent ated by inflammation? (Manuscript in preparation). advances in the diagnosis genetics and treatment of 49 Manconi M, Ferini-Strambi L, Filippi M, et al. (2008) restless legs syndrome. J Neurol 256:539–53. Multicenter Case-Control study on Restless Legs 35 Stefansson H, Rye D, Hicks A, et al. (2007) A genetic Syndrome in Multiple Sclerosis: the REMS study. risk factor for periodic limb movements in sleep. New Sleep 31:944–52. England J Med 357:639–47. 50 Hornyak M, Rupp A, Riemann D, et al. (2008) Low 36 Winkelmann J, Schormair B, Lichtner P, et al. (2007) dose hydrocortisone in the evening modulates symp- Genome-wide association study of restless legs syn- tom severity in Restless Legs Syndrome. Neurol drome identifies common variants in three genomic 70:1620–2. regions. Nat Genet 8:1000–6. 51 Salih A, Gray R, Mills K, Webley M (1994) A clinical 37 Mercader N, Leonardo E, Azpiazu N, et al. (1999) serological and neurophysiological study of restless Conserved regulation of proximodistal limb anis legs syndrome in rheumatoid arthritis. Brit J Rheumat development by Meis 1/Hth Nature 402:425–9. 33:60–3. 38 Schormair B, Kemlink D, Roeske D, et al. (2008) 52 Medical Advisory Board of the Restless Legs Syndrome PTPRD (protein tyrosine phosphatase receptor type Foundation (2004) An algorithm for the management delta) is associated with restless legs syndrome. Nat of restless legs syndrome. Mayo Clinic Proc Genet 40:946–948. 79:916–22. 39 Desautels A, Turecki G, Montplaisir J, et al. (2002) 53 O’Keeffe ST, Gavin K, Lavan JN (1994) Iron status and Evidence for a genetic association between monoam- Restless Legs Syndrome in the elderly. Age Ageing ine oxidase A and the Restless legs Syndrome. Neurol 23:200–3. 59:215–19. 54 Trenkwalder C, Paulus W (2010) Restless legs 40 Connor JR Wang XS Allen RP, et al. (2009) Altered syndrome: pathophysiology, clinical presentation and dopaminergic profile in the Putamen and Substantia management. Nat Rev Neurol 6:337–46. Nigra in Restless Legs Syndrome. Brain 132(Pt 9) 55 Kenney C, Jankovic. J (2007) Rotigotine transdermal :2903–12. patch in the treatment of Parkinson’s disease and rest- 41 Schmidauer C, Sojer M, Seppi K, et al. (2005) less legs syndrome. Expert Opin Pharma 8:1329–35. Transcranial ultrasound shows nigral hypoechogenic- 56 http://us.gsk.com/products/assets/us_requip.pdf ity in Restless Legs Syndrome. Ann Neurol 58:630–4. 57 http://bidocs.boehringer-ingelheim.com/BIWebAccess/ 42 Allen R, Barker P, Wehrl R, et al. (2001) MRI meas- ViewServlet.ser?docBaserenetnt&folderPath/ urement of brain iron in patients with restless legs Prescribing+Information/PIs/Mirapex/Mirapex.pdf syndrome. Neurol 56:263–5. 58 Zintaras E, Kitsios G, Papathanasiou A, et al. (2010) 43 Mizuno S, Mihara T, Miyaoka T, et al. (2005) CSF iron Randomized trials of dopamine agonists in restless legs ferritin and transferring levels in restless legs syn- syndrome: a systematic review quality assessment, drome. J Sleep Res 14:43–7. and meta-analysis. Clin Therap 32:221–37. 44 Earley CJ, Connor JR, Beard JL, et al. (2000) 59 Allen R, Earley C (1996) Augmentation of the Restless Abnormalities in CSF concentration of ferritin and trans- Legs Syndrome with carbidopa/levodopa. Sleep ferrin in Restless Legs Syndrome. Neurol 54:1698–1700. 19:205–13. 45 Earley C, Connor J, Beard J, et al. (2005) Ferritin 60 Guilleminault C, Cetel M, Philip P (1993) Dopaminergic levels in the cerebrospinal fluid and restless legs treatment of restless legs and rebound phenomenon. syndrome: effects of different clinical phenotypes. Neurol 43:445. Sleep 28:1069–75. 61 Giovannoni G, O’Sullivan J, Turner K, et al. (2000) 46 Connor J, Boyer P, Menzies S, et al. (2003) Hedonistic homeostatic dysregulation in patients with Neuropathological examination suggests impaired Parkinson’s disease on dopamine replacement thera- brain iron acquisition in restless legs syndrome. Neurol pies. J Neurol Neurosurg Psych 68:423–8. 61:304–9. 62 Sullivan S, Evans A, Lees A (2009) Dopamine dsyreg- 47 Walters AS, Ondo WG, Zhu W, Le W (2009) Does the ulation syndrome An overview of its epidemiology endogenous opiate system play a role in the Restless mechanisms and management CNS Drugs 23:157–70. Legs Syndrome? A pilot post-mortem study. J Neurol 63 Voon V, Fernagut P, Wickens J, et al. (2009) Chronic Sci 279:62–5. dopaminergic stimulation in Parkinson’s disease: from

Albanese_c20.indd 328 12/24/2011 7:30:55 AM Restless Legs Syndrome 329

dyskinesias to impulse control disorders, The Lancet 79 Ondo W (2004) Methadone and restless legs Neurol 8:1140–9. syndrome. Mov Disord 20:345–8. 64 Voon V, Fox S (2007) Medication-related impulse con- 80 Callahan RJ, Au JD, Paul M, et al. (2004) Functional trol and repetitive behaviors in Parkinson Disease. inhibition by methadone of N-methyl-D-aspartate Arch Neurol 64:1089–96. receptors expressed in Xenopus oocytes: stereospecific 65 Tippmann-Peikert M, Park J, Boeve B, et al. (2007) and subunit effects. Anesth Analg 98:653–9. Pathologic gambline in patients with restless legs 81 Tzellos TG, Papazisis G, Toulis KA, et al. (2010) A2 syndrome treated with dopaminergic agonists. Neurol delta ligands gabapentin and pregabalin: Future 68:301–3. implications in daily clinical practice. Hippokratia 66 Quickfall J, Suchowersky O (2007) Pathological 14:71–5. gambling associated with dopamine agonist use in 82 Vignatelli L, Billiard M, Clarenbach D, et al. (2006) restless legs syndrome. Parkin Rel Disord 13:535–6. EFNS guidelines on management of restless legs 67 Kolla B, Mansukhane M, Barraza R, Bostwickm J syndrome and periodic limb movement disorder in (2010) Impact of dopamine agonists on compulsive sleep. Europ J Neurol 13:1049–65. behaviors: A case series of Pramipexole-induced 83 Kushida C, Walters A, Becker P, et al. (2009) A rand- pathological gambling. Psychosomat 51:271–3. omized, double-blind, placebo-controlled, crossover 68 Salas R, Allen R, Earley C, Gamaldo C (2009) Drug study of XP13512/GSK1838262 in the treatment of hoarding: a case of atypical dopamine dysregulation patients with primary restless legs syndrome. Sleep syndrome in a RLS patient. Mov Disord 24:627–8. 32:159–68. 69 Ondo W, Lai D (2008) Predictors of impulsivity and 84 Garcia-Borreguero D, Larrosa O, Williams AM, et al. reward seeking behavior with dopamine agonists. (2010) Treatment of restless legs syndrome with Parkin Rel Disord 14:28–32. pregabalin: a double-blind, placebo-controlled study. 70 Rylander G (1972) Psychoses and the punding and Neurol 74:1897–904. chorieiform syndromes in addiction to central stimu- 85 Horiguchi J, Inami J, Sasaki A, et al. (1992) Periodic lant drugs. Psych Neurol Neurochir 75:203–14. Leg movements in Sleep with Restless Legs Syndrome: 71 Evans A, Katzenschlager R, Paviour D, et al. (2004) Effect of clonazepam treatment. Jap J Psych Neurol Punding in Parkinson’s Disease: Its relation to the 46:727–32. dopamine dysregulation syndrome Mov Disord 86 Mitler M, Browman C, Menn S, et al. (1986) Nocturnal 19:397–405. Myoclonus: Treatment and efficacy of Clonazepam 72 Ondo W (2010) Intravenous iron dextran for severe and Temazepam. Sleep 9:385–92. refractory restless legs syndrome. Sleep Med 11:494–6. 87 Schenck C, Mahowald M (1996) Long-term nightly 73 Jakobsson B, Ruuth K (2002) Successful treatment of benzodiazepine treatment of injurious parasomnias restless legs syndrome with an implanted pump for and other disorders of disrupted nocturnal sleep in intrathecal drug delivery. Acta Anaesth Scand 170 adults. The Amer J Med 100:333–7. 46:114–17. 88 Wagner ML, Walters AS, Coleman RG, et al. (1996) 74 Ross D, Narus M, Nutt J (2008) Control of medically A randomized double-blind placebo controlled study refractory restless legs syndrome with intrathecal of clonidine in restless legs syndrome. Sleep 19:52–8. morphine:Case report. Neurosurg 62:E263. 89 Cueller N, Galper D, Taylor A, et al. (2004) Restless 75 Lindvall P, Ruuth K, Jakobsson NS (0000) Intrathecal legs syndrome. J Alter Comp Med 3:422–3. morphine as a treatment for refractory Restless Legs 90 Cuellar N, Ratcliffe S (2009) Does Valerian improve Syndrome. Neurosurg 63:E1209. sleepiness and symptoms severity in people with 76 Walters AS, Wagner ML, Hening WA, et al. (1993) Restless Legs Syndrome? Alter Therap Health Med Successful treatment of the idiopathic restless legs 15:22–8. syndrome in a randomized double blind trial of oxyco- 91 Cui Y, Wang Y, Liu Z.(2008) Acupuncture for restless done versus placebo. Sleep 16:327–32. legs syndrome. Cochrane database of systematic 77 Walters A, Winkelmann J, Trenkwalder C, et al. reviews 4, CD006457. (2001) Long-term follow-up on restless legs syndrome 92 Stanislao C, Brotzu R, Franconi G (2009) Acupuncture patients treated with opioids. Mov Disord 16:1105–9. for Restless Legs Syndrome: A Retrospective Case 78 Walters A (2002) Review of receptor agonist and Series. Med Acupunct 21:63–5. antagonist studies relevant to the opiate system in 93 Krueger B (1990) Restless legs syndrome and periodic Restless Legs Syndrome. Sleep Med 3, 301–4. movements of sleep. Mayo Clinic Proc 65:999–1006.

Albanese_c20.indd 329 12/24/2011 7:30:55 AM 330 Chapter 20

94 Rajaram S, Shanahan J, Ash C, et al. (2005) 103 Mitchell U, Myrer W, Johnson A, Hilton S (2010) Enhanced external counter pulsation (EECP) as a Restless legs syndrome and near-infrared light: An novel treatment for Restless Legs Syndrome (RLS): alternative treatment option. Physiotherapy Theory A preliminary test of the vascular neurologic hypoth- and Practice Early Online 1–7. esis for RLS. Sleep Med 6,101–6. 104 Hornyak M, Voderholzer U, Hohagen F, et al. (1998) 95 Rajaram S, Rudzinskiy P, Walters A (2006) Enhanced Magnesium Therapy for Periodic Leg Movements- external counter pulsation (EECP) for restless legs related Insomnia and Restless Legs Syndrome: An syndrome (RLS): Preliminary negative results in a open Pilot study. Sleep 2:502–5. parallel double-blind study. Sleep Med 7, 390–1. 105 Fawcett WJ, Haxby EJ, Male DA (1999) Magnesium: 96 Atallah J, Armah F, Wong D, et al. (2008) Use of physiology and pharmacology. Brit J Anesth spinal cord stimulatior for treatment of lumbar radic- 83:302–20. ulopathy in a patient with severe kyphoscoliosis. 106 Walters A, Elin R, Cohen B, et al. (2007) Magnesium Official J Amer Soc Interv Pain Phys 11:555–9. not likely to play a major role in the pathogenesis of 97 Matarazzo A, Giodano A, Sassi O, et al. (2002) Spinal Restless legs syndrome: Serum and cerebrospinal cord electric stimulation. Treatment of serious fluid studies. Sleep Med 8:186–7. chronic ischemic syndromes of the limbs. Minerva 107 Botez M, Cadotte M, Beaulieu R, et al. (1976) Cardioan 50:691–4. Neurologic disorders responsive to folic acid therapy. 98 Rye D, DeLong M (1999) Amelioration of sensory Can Med Assoc J 115:217–23. limb discomfort of restless legs syndrome by pallidot- 108 Lee KA, Zaffke ME, Baratte-Beebe K (2001) Restless omy. Ann Neurol 46:800–1. Legs Syndrome and Sleep disturbance during preg- 99 Okun A, Fernandez H, Foote K (2004) Deep brain nancy: The role of folate and iron. J Women’s Hlth & stimulation of the GPi treats Restless Legs Syndrome Gender-Based Med 10:335–41. associated with dystonia. Mov Disord 20:500. 109 Weinstock L, Fern S, Duntley S (2008) Restless legs 100 Ondo W (2006) VIM deep brain stimulation does not syndrome in patients with irritable bowel syndrome: improve pre-existing restless legs syndrome in response to small intestinal bacterial overgrowth patients with essential tremor. Parkin Rel Disord therapy. Digest Dis Sci 53:1252–6. 12:113–14. 110 Nemeth E, Tuttle M, Powelson J, et al. (2004) 101 Kedia S, Moro E, Tagliati M, et al. (2004) Energence Hepcidin regulates cellular iron efflux by binding to of Restless legs syndrome during subthalamic stimu- ferroportin and inducing its internalization. Science lation for Parkinson disease. Neurol 63:2410–12. 306:2090–3. 102 Driver-Dunckley E, Evidente V, Adler C, et al. (2006) 111 Lettieri C, Eliasson A (2009) Pneumatic compression Restless Legs Syndrome in Parkinson’s disease devices are an effective therapy for restless legs patients may improve with subthalamic stimulation. syndrome: a prospective, randomized, double- Mov Disord 21:1289. blinded, sham-controlled trial. Chest 135:74–80.

Albanese_c20.indd 330 12/24/2011 7:30:56 AM CHAPTER 21 Tardive Dyskinesias Gonzalo J. Revuelta, Leslie Cloud, Pratibha G. Aia, and Stewart A. Factor Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

Historical background 2000s, additional presumed atypical antipsychotics became available and largely replaced the typical Tardive dyskinesia (TD) is an iatrogenic movement agents for the treatment of schizophrenia and other disorder resulting from exposure to dopamine forms of psychosis. The atypical agents have also receptor blocking agents (DRBAs) for a period of at been used extensively, especially with off-label least 3 months [1] (one month in patients older prescribing, as mood stabilizers, adjunctive agents than 60 years). [2] The first typical (first genera- in the treatment of refractory depression, for tion) antipsychotic, chlorpromazine, was found to agitation in dementia, and in variety of other be effective for the treatment of psychosis in a small psychiatric conditions. Based upon preclinical data, clinical trial conducted in 1952 [3] and approved the atypical antipsychotics were expected to carry by the FDA in 1954. In 1957, the first reported a dramatically reduced risk of extrapyramidal cases of TD were described in the medical literature side effects (EPS) including tardive syndromes. when three elderly women developed lip-smacking It was expected that TD would ultimately dis- dyskinetic movements after 2–8 weeks of exposure appear. A recent review has suggested this expec- to this drug (4). TD was believed at that time to tation to be true as a drop in reports on TD be rare, with only scattered cases appearing in the (reflecting decreased interest) were seen in the medical literature [5, 6]. It was in the late 1960s literature when second generation agents became when larger studies began to reveal that it was available [11]. However, it has become apparent probably more common than initially believed. that, while they may carry lower risk for EPS and The term “tardive” dyskinesia was coined in 1964 tardive syndromes, they are not free of these side by Faurbye et al. [7] based upon the observation effects and numerous case reports and case series that dyskinetic movements usually appear late in have suggested that all atypical agents, including the course of neuroleptic exposure. TD became clozapine, carry a risk for TD [11A]. widely accepted as an iatrogenic condition in the early 1970s, and the first therapeutic trials for TD occurred shortly thereafter [8–10]. Epidemiology The first atypical (second generation) antipsychotic, clozapine, was developed in the A wide range of incidence and prevalence estimates 1950s but did not become available until 1989 after can be found in the literature for TD. Reasons for the FDA approved its use for treatment-resistant the variability across studies include differences in schizophrenia. Throughout the 1990s and early the definition of TD, ascertainment of TD diagnosis,

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inclusion of all phenotypes, and methodological incidence of TD to be 3.9% for atypical antipsychotics approaches. In addition, heterogeneity of subjects versus 5.5% for typical agents (p = 0.0001). across studies with regard to diagnosis, risk factors Prevalence rates were 13% among subjects on and exposure to neuroleptics, treatment practice atypical agents and 32% among subjects on typical variations between sites, and failure to control for agents (p = 0.0001) [18]. The conclusion from these the rate of spontaneous dyskinesias. studies is that atypical antipsychotics are not with- In a review of 56 early studies (conducted out risk of TD, but the risk appears lower than what between 1959 and 1979), Kane and Smith reported is observed with typical agents like haloperidol. an average point prevalence of 20% (range Other factors (besides drug class) related to drug 0.5%–65%) [12]. Kane and Smith also reviewed exposure such as dose and blood levels have been 19 prior studies that estimated the prevalence of difficult to correlate with risk of TD. However, it is spontaneous dyskinesias in untreated samples. generally agreed that longer exposure and high They found an average prevalence of 5% for spon- doses add to the risk of developing TD [19]. Though taneous dyskinesias. Subtracting this from their once advocated, drug holidays have been shown overall TD prevalence of 20%, they concluded that to increase risk and worsen prognosis after with- the true prevalence of TD was likely closer to 15% drawal [20, 21]. This is a practice that has been [12]. A later review of 76 studies conducted disappearing. through 1989 by Yassa and Jeste indicated an over- Advancing age is a well-established risk factor all TD prevalence of 24.2% (range 3.3–62%) [13]. for the development of TD. Several studies have In 1988, Kane et al. conducted a prospective demonstrated higher vulnerability of the geriatric study of 908 patients, estimating a 5% annual population to the development of TD following incidence of TD from their cohort [14]. Their data neuroleptic exposure [22–24]. Elderly patients are also suggest that, at least for the first 4–5 years also likely to develop more severe forms of TD. In a of neuroleptic exposure, the cumulative incidence study of 99 elderly subjects (mean age 73.5) naïve of TD increases linearly with increasing duration of to neuroleptics at study inception, Yassa et al. exposure. Both of these findings were later con- reported a TD prevalence 35.4% after 5 years of firmed by Chakos et al [15]. In 1993, Glazer et al. follow-up [22]. In a prospective longitudinal study presented long-term risk estimates for TD in a of 266 outpatients over 45 years of age, Jeste et al. prospective cohort study of 362 psychiatric outpa- found a cumulative incidence of TD of 26%, 52%, tients who were free of TD at baseline and were and 60% after 1, 2, and 3 years respectively [23]. maintained on neuroleptics [16]. They also esti- These numbers contrast sharply with those reported mated the risk of TD to be 5% per year, in keeping in a prospective study of 850 young adults (mean with prior studies. They also estimated long-term age 29), which reported a cumulative incidence of risks of 25% after 5 years, 49% after 10 years, and TD of 5%, 19%, and 26% after 1, 4, and 6 years of 68% after 25 years. treatment [25]. More recent epidemiological studies have sought Conflicting results have been published with to compare the incidence of TD in patients treated regard to gender as a risk factor. In their review of with typical versus atypical antipsychotic agents. In 75 studies, 6 of which were stratified by age groups, 2004, Correll et al. reviewed 11 studies lasting at Yassa et al. reported excess risk for women older least a year and involving samples of at least 20 than age 51 with a more evenly distributed risk in subjects. A total of 1235 patients, on different atyp- younger age groups [13]. This suggests a possible ical antipsychotics, were included. For the adult interaction between age and gender. sample, the weighted mean annual incidence of TD Studies conducted in other countries have also for atypical antipsychotics was 0.8% compared reported wide variations in TD rates [26–31]; with 5.4% for haloperidol [17]. In a subsequent however, differences in prescribing practices, review of 12 trials published between 2004 and cultural and environmental factors, and metho- 2008, Correll and Schenk found the annual dological differences make interpretation of such

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Table 21.1 Associations of candidate gene polymorphisms with TD.

Gene and Polymorphism Association Reference1

DRD3 Ser9Gly Gly allele confers susceptibility Bakker et al. [46] DRD2 Taq1A A2 variant of Taq1A SNP associated with higher risk Bakker et al. [53] DRD4 Long allele protective Lattuada et al. [176] Association 120 bp duplication marker Srivistava et al. [177] CYP2D6*10 Associated with risk/greater severity Ohmori et al. [49] Lam et al. [50] CYP1A2*1F Associated with greater severity Basile et al. [51] MnSOD Ala9Val Ala-Val and Val protective Bakker et al. [53] COMT Val-Met heterozygosity confers protection Bakker et al. [53] 5-HTR2A T102C Associated with TD Segman et al. [178] Tan et al. [179] Lerer et al. [44] GSTM1 Absence associated with TD De Leon et al. [180] NQ01 609C/T T allele associated with increased risk Pae et al. [181] T/T genotype associated with increased severity NOS3 T–4B-Glu haplotype protective Liou et al. [182] RGS9 7SNPs AGG haplotype associated Liou et al. [183] MAO A &B No associations identified Matsumoto et al. [184]

1 Where available, meta-analyses, rather than individual studies, are cited.

studies difficult. In the US, African-Americans first-degree relatives of patients [39, 40]. This was and other non-whites are more susceptible than followed by the search for the genetic determinants Caucasian Americans of European descent, even which has yielded a number of potential candidate after adjustment for neuroleptic dose and duration gene polymorphisms. Table 21.1 summarizes the of exposure [32, 33]. currently known associations. Though discussion Diabetes mellitus has been implicated as a risk of all the candidate genes is beyond the scope of factor for the development of TD [34, 35], with one this chapter, a few consensus associations warrant study reporting a risk ratio of 2.3 for diabetics com- further discussion. pared to non-diabetics exposed to neuroleptics Steen et al. reported a high frequency (22–24%) [35]. Elderly diabetics appear to be at particularly of homozygosity for the Ser9Gly variant (2–2 high risk [35]. Diabetics may also be more likely to genotype) of the dopamine D3 receptor gene manifest more severe forms of TD [34]. There are (DRD3) gene among subjects with TD in both cross- some studies that did not relate such findings [36]. sectional and longitudinal studies, as compared An increased incidence and prevalence of TD has with the relative underrepresentation (4–6%) of been noted among neuroleptic-treated patients this genotype in patients with no TD [41]. with affective disorders compared to schizophrenia Subsequent studies also demonstrated an associa- [37]. Other potential risk factors such as sub- tion between TD in schizophrenic patients and the stance abuse, smoking, exposure to other drugs like D3 receptor gene [42, 43]. Some studies reported anticholinergics and lithium, and the presence of that a serine to glycine polymorphism in the first previous structural brain damage remain contro- exon of the DRD3 gene was a risk factor for the versial [38]. development of TD [43–45]. A meta-analysis of Family studies have supported the notion that genetic studies reported an odds ratio of 1.17 for there is genetic susceptibility for TD. First, they developing TD associated with the serine to glycine have demonstrated concordance for TD among polymorphism in the D3 receptor gene [46].

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Chen et al. found a significant association between Video 21.1 Phenomenology of tardive TD and the dopamine D2 receptor gene (DRD2) dyskinesias Taq1A polymorphism [47]; several later studies and a meta-analysis later supported the association [48]. Tardive dyskinesia secondary to haloperidol. Note the presence of generalized chorea in addition to the classic Certain polymorphisms in the CYP2D6 gene, orofacial dyskinesia. which encodes a cytochrome P450 enzyme, have been reported to be positively associated with TD. Specifically, there are data supporting allele *10 [49, 50]. Other CYP genes such as the CYP1A2*1F have also been shown to be potentially associated with TD severity [51]. The notion that deranged superoxide dismutase http://bit.ly/st8X4i (SOD) activities might be a risk factor for schizophrenia and/or TD led to studies of the manganese superoxide dismutase gene (MnSOD). Hori et al. reported that the –9Ala MnSOD allele (high activ- [56]. Video 21.1 features these classical oral-buccal- ity) may play a role in protecting against suscepti- lingual movements. There are variations of TD bility to TD in schizophrenics [52], a finding later characterized by dystonia, chorea, tics and myo- supported by a subsequent meta-analysis of pooled clonus [57] in isolation or in combination with TD. genetic data [53]. It is beyond the scope of this chapter to review all of them but they are listed in Table 21.2. Classical TD tends to involve the face and the Phenomenology and other mouth region. Usually the upper face is less clinical features involved, though in some patients blepharospasm, increased blinking, arching of eyebrows and Though various phenotypes of TD exist which also oculogyric movements [57A] may be noted as well. differ with regard to pathophysiology, epidemiol- The limb and the trunk are less involved and even ogy, and pharmacology, there are commonalities, when involved, much less affected than the face including exposure to dopamine-blocking agents and the mouth. The movements are usually stereo- and their tendency to persist, in most cases after typic but can be choreic like the random and often the offending agent has been removed. The term unpredictable movements of Huntington disease. In “tardive” was originally used to denote the late TD the movements of the mouth are rhythmic, onset of the disorder (DSM criteria suggest 3 repetitive complex chewing motions and may months of exposure is needed except in the elderly involve puffing of the cheeks, protruding of the where one month is adequate). However, it is now tongue, lip smacking, puckering, pursing, and accepted that this disorder may appear relatively chewing [58]. TD movements when involving other early in the course of treatment with dopamine- distal portions of the body can be rhythmic and blocking agents (with few doses) and there is no repetitive as well. Dyskinesia in the fingers may clinical distinction between the earlier- and later- look as if the patient is playing an invisible guitar onset subtypes [54]. Some experts, however, have or piano. In the lower extremities these may suggested that young males are more likely to appear as repetitive foot tapping, crossing and exhibit tardive dystonia, particularly involving the uncrossing the legs, and when, lying down, repeated trunk and upper extremities, whereas middle-aged abduction and adduction movements of the thigh. and elderly women typically exhibit the classical, These movements in general are worsened by anxi- oral-buccal-lingual stereotypic movements. In the ety, stress, agitation, or concentration on other classical form, TD as described by Fahn [55] has voluntary movements. TD can be suppressed by oral-buccal-lingual masticatory movements; also voluntary activation of the affected muscles, relaxa- referred to as bucco-lingual-masticatory syndrome tion or sedation and, like most other hyperkinetic

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Table 21.2 Tardive dyskinesia variants.

Classical tardive dyskinesia Rapid repetitive stereotypical movements involving the oral, buccal and lingual areas. Tardive dystonia Can be indistinguishable from idiopathic torsion dystonia. Focal dystonias are the most common manifestation but segmental dystonia may be noted; generalized dystonia is rare. Tardive akathisia Characterized by feelings of inner restlessness and objectively manifested by semi purposeful movements. Tardive tics May manifest as invariant tics or may fulfill criteria for Tourette syndrome [185]. This is a common cause of adult onset tics. Tardive tremor Postural and kinetic tremor that persists despite withdrawal of dopamine blocking agents [186] Tardive myoclonus Myoclonic movements may occur in isolation or in combination with tardive dystonia or akathiasia. [187, 188] Tardive complex Three or more tardive movement disorders in same patient

Adapted from Fahn [58], pp 480–518.

movement disorders, disappears during sleep. TD Box 21.1 Differential diagnosis of orofacial needs to be distinguished from other movements that dyskinesia [58, 145, 189] involve the orofacial region. (Box 21.1). Many patients may be unaware of these movements which Orofacialcervical tremors Essential tremor – head and jaw rarely interfere with basic functions such as chewing, Parkinsonian tremor involving lips, jaw and tongue speaking, or swallowing. Occasionally, in some cases Cerebellar tremor it may cause food to be pushed out of the mouth, Palatal myoclonus – with synchronized ocular, shoulder interfering with eating, and at times patients may and head movements develop sores from the constant movement of the Orofacial myoclonus tongue over the teeth [59]. Facial myoclonus (as seen with Creuzfeld-Jacob disease) Hemifacial spasm When involving the trunk, these movements Facial myokimia may appear as rhythmic rocking or pelvic thrusting Orofacial tics motions (so-called copulatory dyskinesia [60]). Transient or chronic simple tics Video 21.2 features TD with prominent pelvic Tourette syndrome thrusting. Some patients exhibit grunting and Orofacial chorea moaning which is believed to be due to involve- Huntington disease ment of the upper air passages. Respiratory move- Sydenham chorea ments may also be affected with altered rhythmical Hepatocerebral degeneration Idiopathic basal ganglionic calcification patterns leading to hyper and hypoventilation. Neuroacanthocytosis These respiratory tardive dyskinesias may not be Encepahalitis lethargica medically significant although may look alarming Cerebellar infarction [61] however, in some cases, may be considered life Edentulous malocclusion threatening [62]. Video 21.3 features respiratory Tumors (primary or metastatic) Spontaneous oral masticatory syndrome TD. Horiguchi et al. described rare cases of esophageal dyskinesia associated with lingual dykinesias Orofacial dystonia Meige syndrome-blepharospasm and oromandibular leading to increased intraespohageal pressure and dystonia death in one patient [63]. Drug-induced chorea dyskinesia Tardive dystonia is the second most frequently Levodopa, amphetamine, cocaine, TCAs, cimetidine, observed TD variant (approximately 25% of TD cinnarizine, flunarizine, phenytoin intoxication, antihista- cases) and can often be indistinguishable from mines, anticholinergics, benzodiazepines and lithium idiopathic torsion dystonia. Tardive dystonia can Others be focal, segmental or generalized. In a study Synkinesis due to faulty regeneration of facial nerve conducted by Molho et al [64] comparing 20 Psychogenic

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receptor blocking agents that cause TD also tend Video 21.2 Phenomenology of tardive to suppress these movements. Age seems to be dyskinesias most consistently associated with the develop- Tardive dyskinesia secondary to metoclopramide. Note ment, severity and persistence of TD [14, 66, 67]. the presence of classic orofacial dyskinesia, lingual protrusion, upper face movement, pelvic thrusting, and In a study conducted by Smith and Baldessarini it dystonic posturing of the right hand. was found that both the prevalence and severity ratings for TD tend to increase with age almost linearly between 40 and 70 years [68]. Younger patients are not immune to TD; however, in children the course may be more benign and often spontaneously remits [68A]. TD, though rare in infants, has been reported; possibly the youngest

http://bit.ly/sE8rb3 being that of a 9 month old who developed TD secondary to treatment with metoclopromide [69]. The spectrum of TD varies widely from mild Video 21.3 Phenomenology of tardive dyskinesias transient dyskinesia that emerges during withdrawal to irreversible TD after the offending drug Tardive dyskinesia secondary to metoclopramide. Note the presence of lingual protrusion (so called fly catchers has been withdrawn [58]. The syndrome may tongue), jaw opening, belching, vocalizations, and take days or weeks to develop, and early cases respiratory dyskinesia. may actually remit in weeks to months after discontinuation of the offending agent. Reports have described complete remission occurring as late as 2 years or more after discontinuation of the offending agent [70]. TD may worsen transiently after discontinuation before finally disappearing. The term “withdrawal emergent syndrome” or http://bit.ly/v3GINB “dyskinesia” has been used to describe this type of TD [68A]. Many studies concerning reversibility have patients with tardive cervical dystonia to 77 patients been conducted in patients who continued to with idiopathic cervical dystonia, patients with receive DRBA, while few studies have examined tardive cervical dystonia were found to have remission of TD once the offending agent has been extracervical involvement, retrocollis and spas- discontinued [71–73]. Currently there is no defin- modic head movements more frequently than itive data that, once established, TD will continue those with idiopathic cervical dystonia. Truncal to progress in severity with continuation of the dystonia may be characterized by opisthotonic offending drug [74–76]. Gardos et al. [77] con- arching of the torso, often accompanied by prona- ducted a study in 122 neuroleptic-treated patients, tion and extension of arms at elbows [65]. and 63 patients were followed up at 5- and 10-year intervals. No progression of TD was noted in the second 5-year follow-up, as compared to the ini- Predisposing factors and clinical tial 5 years of the study; however, 11 patients had course of tardive dyskinesia remission and 12 patients who did not have TD at baseline developed TD over the 10-year period. The natural history of classical TD is difficult to In another study conducted by Fernandez et al. determine as it is affected by a variety of host and [78], 53 patients were assessed over a 14-year treatment factors. Furthermore, the dopamine period. TD improved and parkinsonism worsened

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in the patients who continued to receive neuro- this theory are reports of spontaneous dyskinesias leptic medications. In general it is suggested that in psychotic patients not exposed to DRBAs [104], 30% of cases are reversible but this depends on in elderly patients that were neither psychotic nor the age of the patient [19]. About 10% of cases of exposed to DRBAs [105], and in rodents and non- TD progress to a severe level. Given the available human primates [106]. It is important to note data, it would be prudent, especially in the elderly, that spontaneous dyskinesias are thought to be to use the smallest dose of drug for the shortest phenomenologically distinct from classic TD, and time as there appears to be a strong inverse cor- do not meet the definition of TD which requires relation between rates of spontaneous remission DRBA exposure; therefore, they are likely to repre- and age [68, 79]. sent a distinct clinical entity. Candidate causes implicated in the etiopathology of TD will be discussed in more detail in the following section. Etiology

Traditionally, TD has been defined as a clinical Pathophysiology syndrome caused specifically by chronic exposure to DRBA, particularly first generation agents The pathophysiology of TD remains under (FGAs). It has been defined as occurring after investigation. Multiple hypotheses have been 3 months of exposure but can be seen after a single proposed, but none yet has been able to reconcile exposure to DRBA. Although, the incidence has the fundamental features of this disorder. Any diminished with the advent of second generation theory proposed must explain why TD (1) agents (SGAs), TD continues to be a problem, even emerges after chronic use of DRBAs, (2) occurs in with these newer agents. Video 21.4 features TD only a fraction of exposed patients, (3) persists due to the SGA risperidone. Quetiapine and after the withdrawal of the offending agent, and clozapine are the SGAs with the lowest risk of caus- (4) responds to DRBAs and worsens with dopa- ing TD; however, they too have been reported to minergic therapy. At first glance, it is counterin- result in TD [80–91]. Dopamine-depleting agents tuitive to think of TD as a hyperkinetic movement like reserpine and tetrabenazine have not been disorder arising from dopamine blockade. reported to cause TD in humans [91A]. Non- However, clinical evidence supports TD as a rela- antipsychotic DRBAs that can cause TD include tive hyperdopaminergic state; examples include antiemetics (metoclopramide [92, 93], promethaz- the withdrawal emergent syndrome and the ame- ine [94], prochlorperazine [95, 96]), antidepressants lioration of symptoms with higher DRBA dose (amoxapine [97–102]), and calcium channel [107, 107A]. blockers are thought to have some dopamine- One of the earlier and prevailing theories blocking effects (flunarizine and cinnarizine) [103]. proposes an up-regulation of D2 receptors with a Since not all patients exposed to chronic DRBAs subsequent hypersensitivity and increased affinity develop symptoms of TD, and some appear to be to dopamine. If, in fact, there are a greater number particularly susceptible, theories emerged suggest- of D2 receptors and greater sensitivity, this model ing that other factors superimposed upon DRBA would explain why the hyperkinetic disorder exposure are necessary for the development of TD. develops, and why it responds to greater dopa- Risk factors for TD have been identified and include mine blockade and/or depletion of dopamine age, duration of DRBA exposure, and genetic pharmacologically. Furthermore, it explains the susceptibility. Furthermore there is evidence to withdrawal emergent syndrome since there would support that DRBA exposure may not be necessary be a greater number of receptors with greater at all for the development of TD, and that dopa- affinity to dopamine that would bind endogenous mine and its receptors may not play such a central dopamine once they are no longer under block- role in the pathophysiology of TD. In support of ade. However, this model does not explain why

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only a fraction of patients develop the condition, D2 affinity) [115, 116]. The duration of receptor since one would expect that hypersensitivity is binding is highly correlated with lower potency. present in all (also evidenced by animal models), However, antipsychotic effects are thought to nor does it explain why the onset is years after occur as a function of dopamine receptor occu- exposure since hypersensitivity itself is present pancy, not duration of binding, and even clozapine within days to weeks (as demonstrated in rodent has been reported to cause EPS at high enough models). Another issue is that TD is persistent, yet doses [117]. hypersensitivity diminishes over time, and dopa- Alternate theories suggest a more complicated mine receptor numbers return to baseline after process involving multiple receptors and neuro- DRBAs are withdrawn [108]. Studies in rats transmitters. Glutamic acid decarboxylase (GAD) treated with DRBAs (short term) show that the and gamma-aminobutyric acid (GABA) have been up-regulation of D2 receptors occurs universally found to be diminished in the substantia nigra after exposure and reverses once DRBAs are with- and external pallidum in animal models and in drawn [109]. When rodents are exposed for longer CSF in TD patients [118], and these levels were periods of time, symptoms can persist longer but found to correlate in rodents with increased vacu- remain reversible [110]. These models are clearly ous chewing movements (VCMs) [119]. However, not equivalent with TD in humans, but continue these findings have not been consistently repli- to be used to answer questions about its patho- cated [106, 120]. In support of this theory are physiology. To explain the delay in onset of symp- reports of suppression of TD with GABAergic toms others have postulated that interactions from agents [118, 121]. multiple peptide systems including enkephalins Opioid peptides (enkephalin and dynorphin) and neurotensin take place, and these changes and their receptors have also been implicated in take longer to occur [109]. Efforts to study dopa- the pathophysiology of TD. Increased mRNA lev- mine receptors using imaging and immunohisto- els of both peptides have been reported following chemistry in humans and animal models have exposure to neuroleptics [122–124]. Furthermore, not been able to consistently confirm either administration of selective opioid receptor antag- up-regulation or hypersensitivity of dopamine onists into specific basal ganglia structures in receptors in patients exposed to DRBAs [106, rodents not only attenuate VCMs, but do so in 111–113]. For this reason, some have suggested such a way as to suggest that increases in dynor- that an increased ratio of D1/D2 receptor function phin in the direct pathway, and enkephalin in the may be a more accurate way of representing the indirect pathway, contribute significantly to the underlying pathophysiology [114]. Structural or pathophysiology of TD [125]. In addition, recent pathological changes have not been demonstrated studies show significant changes in norepineph- consistently in humans or animal models through erine and serotonin by brain region in rats autopsy or neuroimaging. exposed to neroleptics [126]. Evidence in further To explain the difference in side effect profile support of a role for serotonin in TD include the between typical and atypical DRBAs the rapid potentiation of haloperidol-induced catalepsy dissociation hypothesis has been proposed. Here, a with co-administration of 5HT re-uptake inhibi- truly atypical agent (the prototypes being clozapine tors [127], non-selective agonists [128], and and quetiapine) are thought to bind post-synaptic lesions in the medial raphe protected against D2 receptors in the striatum loosely, then neuroleptic-induced catalepsy [129]. dissociate, while the typical DRBAs like haloperidol Another neurotransmitter that has been are thought to bind tightly and have long-lasting under investigation is glutamate. Some have effects on the receptor. In this theory, the atypical hypothesized that glutamatergic transmission is agents bind just long enough to have antip- enhanced by presynaptic dopamine blockade. sychotic action, but not long enough to cause In support of this theory are CSF studies in extrapyramidal symptoms (indicative of decreased patients with TD showing higher levels of

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N-acetylaspartate, N-acetylaspartylglutamate, and but many other enzymes have also been identified. aspartate compared with controls. These levels These enzymes have been found to be highly also correlated with severity of symptoms [130]. polymorphic. In terms of pharmacodynamics the Studies in a rat model of TD with haloperidol- dopaminergic pathway has been the primary induced VCMs support the notion that glutaatergic focus of investigation. Another potentially related transmission is affected [131]. Co-administration of category of genes is involved in the oxidative N-methyl-D-aspartate (NMDA) receptor blockers stress pathway. with haloperidol allowed rats to recover sooner To date, associated genetic polymorphisms have than those not receiving NMDA blockers, impli- been identified in all these pathways. Of these, the cating NMDA receptor overstimulation as a PM phenotype of the CYP2D6 has been reported contributing factor [132]. Other evidence suggests in several populations to be associated with sever- the involvement of oxidative stress in the ity of symptoms. In fact, these data are being used pathophysiology of TD, including (1) the finding in clinical trials and commercial testing is approved that mitochondrial complex I activity is inhibited by the FDA [138]. In the dopaminergic pathway by neuroleptics, but more so by FGAs [133], several groups have reported an association of (2) the finding that increased reactive oxygen DRD2 variants with TD. The A2 variant of Taq1A species is seen in rats exposed to haloperidol in SNP has been confirmed independently and its vitro [134], and (3) the reduction in erythrocyte association with TD has been further supported by Cu, Zn-superoxide dismutase activity in patients two meta-analyses [139]. In addition, replication exposed to neuroleptics with TD [135]. The of DRD3 Ser9Gly has been reported to be associ- neurodegenerative hypothesis of TD proposes that ated with TD by eight independent studies and damage to GABAergic neurons leads to disinhi- one meta-analyses [140]. DRD3 is an autoreceptor bition of the nigrostriatal tract, resulting in a known to control the phasic activity of dopamin- hyperdopaminergic state. Such neuronal damage ergic neurons, expressed in the limbic area pri- may result from oxidative damage generated marily. Postmortem studies have reported an from increased dopamine turnover in the face of increase in D2 receptors in the basal ganglia in neuroleptic exposure [136]. In support of this patients exposed to neuroleptics. Furthermore the hypothesis there is one early study of 28 patients glycine allele has been shown to be associated with TD and 28 psychiatric controls showing with higher dopaminergic activity [138]. In the neurodegeneration and gliosis of the basal ganglia oxidative stress pathway the Ala9Val polymor- of TD patients [137]. Studies attempting to replicate phism in the mitochondrial targeting sequence of these results have been limited by sample size, lack the MnSOD gene holds the most promise [52]. If of controls, and methodology [136]. present, this allele would lead to impaired detoxi- Another factor thought to play a significant role fication of superoxide radicals. Confirming its in the pathogenesis of TD is genetic susceptibility relevance one study found the Ala9 allele to be which, when present in patients who are exposed protective against TD while another found the Val/ to DRBAs, would result in TD. This could explain Val genotype to increase the risk of development why only selected exposed patients are afflicted. of TD tenfold. A meta-analysis contradicted these Potential candidates for susceptibility genes are findings showing a protective effect for Val carriers determined, in part, based on whether they affect [138]. Although many hypothesize that it is likely the metabolism of the drug (pharmacokinetics) or that several genes interact to result in the TD phe- the ability of the drug to interact with its target or notype, studies to understand these interactions receptor (pharmacodynamics). The major are limited [138]. Genotype-phenotype correla- enzymes involved in the metabolism of DRBAs tion studies have not been fruitful either. One have been clearly elucidated. CYP3A4 and genotype wide association analysis was performed CYP2D6 are responsible for the metabolism of up revealing eight genes from the GABAergic to 80% of the DRBAs most commonly prescribed, pathway [141].

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Treatment [144]. Nevertheless, continuing DRBAs will inevitably worsen prognosis by eliminating any TD is an iatrogenic disorder and, as such, is chance for remission. preventable. Undoubtedly, DRBAs are effective Whether the DRBA is removed or not many treatment modalities for a group of patients with patients will need therapeutic intervention. First severe and debilitating symptoms, particularly line agents for the treatment of TD are dopamine schizophrenia. The use of DRBAs is warranted in depleters both for their effectiveness, and the fact this patient population and others including that they have never been reported to cause TD. Tourette’s syndrome and Huntington disease. These agents reduce dopamine levels thereby However, using the lowest effective dose, moni- reducing TD symptoms without inducing dopamine toring for side effects routinely, reassessing the blockade. Reserpine and tetrabenazine (TBZ) are need for treatment periodically in order to limit both synthetic benzoquinolizines that inhibit the duration of exposure if possible, using alternative vesicular monoamine transporter (VMAT), keeping non-DRBAs therapies concurrently, and utilizing monoamines in the nerve terminal vesicles where the atypical antipsychotics are important strategies they are metabolized by monoamine oxidase and in terms of prevention. Of the atypical antipsy- depleted. Reserpine depletes catecholamine stores chotics it should be stressed that clozapine and in both central and peripheral (sympathetic) nerve quetiapine carry the lowest risk for TD. DRBAs terminals as it irreversibly blocks VMAT 1 and 2, should be avoided, particularly chronic use, in and for this reason has more peripheral related conditions where alternative agents are effective, side effects including orthostasis [145]. TBZ is such as depression, anxiety, sleep disorders thought to reversibly inhibit VMAT 2, primarily in and others. the CNS, and also has dopamine-blocking activity. When TD arises, the first consideration should be For these reasons, it is less likely to cause orthostasis withdrawal of the offending agent. This is a widely than reserpine and depression is more likely to be accepted practice among experts in the field with less protracted. Both drugs can cause parkinsonism, data demonstrating remission rates from 8 to 33% akathisia, and sedation at higher doses, which supporting this practice [110]. However, no ran- are reversible. Multiple studies examining efficacy domized controlled trials (RCTs) have been per- with reserpine were reported in the 1980s, inclu- formed to provide further proof of this approach ding a double-blind trial with 30 patients showing [142]. If DRBAs are absolutely necessary, con- 50% improvement in symptoms [146]. This was sideration should be given to switching to clozapine confirmed by a meta-analysis which showed or quetiapine if they are on typical or other atypical that 64–96% of patients treated showed such agents. With clozapine in particular the question improvement [67]. Some of these studies have has arisen, because of its unique pharmacology used α-methy-para-tyrosine in conjunction with whether the improvement seen is direct therapeutic reserpine to reach the reported clinical effect. This effect or just a removal of the dopamine blockade compound is a competitive inhibitor of tyrosine from the causative agent or simply masking of the hydroxylase, which can augment the dopamine- TD [143]. The answer remains unclear. If it is depleting effect of reserpine. TBZ has been studied not possible to use these agents, or they do not in one early placebo-controlled trial [8], several adequately control symptoms for which the DRBA open label, one large retrospective, and one single- was being prescribed, then treating TD with blind trial, showing safety and significant improve- another agent will need to be considered. Generally, ment in TD symptoms, even at long term [147, the use of typical DRBAs will alleviate TD symptoms 148]. A recent RCT showing safety and efficacy in by masking them; however, most experts fear it the treatment of chorea in Huntington disease led will eventually lead to worsening of symptoms, to FDA approval of this drug in the US [149] in and/or the requirement for higher doses. In fact, 2008. Video 21.4 features a patient with severe TD this hypothesis has not been supported by data before and after treatment with TBZ.

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in TD symptoms according to validated rating Video 21.4 Phenomenology of tardive scales [159]. dyskinesias and response As evidenced by the above findings, treatment to treatment for TD remains complicated, and although multiple Tardive dyskinesia secondary to risperidone Note the safe and effective modalities are available to the presence of jaw deviation, blepharospasm, facial grimacing, and respiratory dyskinesia prior to treatment, clinician, there is still much research to be done to all of which resolved entirely with tetrabenazine. determine which therapy is best. Each case of TD should be evaluated carefully and treatment should be individualized depending on multiple patient specific and treatment specific variables. In our practice we wean all non-psychotic patients off of DRBAs first. Patients with significant psychosis are switched to either quetiapine or http://bit.ly/vxUXAJ clozapine. If they are on anticholinergics these are discontinued since they can exacerbate symptoms [160, 161]. Once this transition is made, they are Multiple agents have been studied in relatively re-evaluated and if further medical therapy is small controlled trials, case series, and case reports warranted they are generally tried on propranolol as possible therapies for TD (Table 21.3). General and vitamin E concurrently. If the syndrome is very categories of therapeutic agents investigated focal and refractory to initial therapy, botulinum include: benztropine, biperiden, chorprothixene; toxin is considered early. If the syndrome is severe, cholinergics (deanol, lecithin, meclofenoxate); and depression is not of particular concern, benzodiazepines (diazepam, clonazepam); catecho- tetrabenazine is considered early. Levetiracetam laminergics (celiprolol, tiapride); GABA agonists and amantadine are generally considered next, (baclofen, valproate, prograbide, THIP); neurolep- followed by the benzodiazepine clonazepam. If tics (haloperi dol, quetiapine); dopamine agonists symptoms remain severe and refractory to multiple ( bromocriptine); and antioxidants (vitamin E). medical therapies bilateral GPi DBS is considered. Other agents that have been less well studied include Figure 21.1 outlines this treatment approach. propranolol, clonidine, buspirone, phenylalanine, estrogen, lithium, insulin, gamma-linoleic acid, leviteracetam, acetazolamide, amantadine, and Metoclopramide ceruletide. To date, no study has been able to provide high-quality convincing evidence supporting its use The drug metoclopramide deserves special attention as definitive therapy in TD [142]. in this chapter for several reasons: (1) it is a major Alternatives to medical therapy for TD include cause of TD in non-psychiatric patients; (2) it may botulinum toxin injections and deep brain be associated with unique clinical features and stimulation (DBS). Several open label reports of perhaps a more severe form of TD; (3) it recently improvement have been reported in the litera- had a label change pointing to its importance in ture, particularly for cases of severe lingual move- relation to TD and addressing the role of chronic ments where genioglossus injections of botulinum therapy, and (4) it has been the subject of substan- toxin were administered [150–154]. One small tial medical litigation. Videos 21.2 and 21.3 feature single-blind study showed benefit after correcting TD due to metoclopromide. for adjustments in neuroleptics [155]. Multiple Metoclopramide is a substituted benzamide case reports have shown significant improvement deriviative with D2 blocking effects similar to in TD with DBS [156–158]. One small, prospec- chlorpromazine [93]. Its indications include tive, phase two, multicenter study with double- post-operative or chemotherapy-induced nausea blind evaluations showed a mean decrease of 50% and vomiting, gastroesophageal reflux, and

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Table 21.3 Medical therapies for tardive dyskinesia.

Medication Type of trials Effective? Worth trying?

Dopamine depleters Tetrabenazine 1 early placebo controlled trial [8] Yes Yes 6 small early open label 1 large retrospective [190] 1 single blind [147] Reserpine Early double blind trial with alpha- Yes Yes methyldopa [146] Early meta-analysis [67] Anticholinergic Class (withdrawal) Two Small RCTs [160, 191] Yes Yes Meta-analysis [192] Benztropine Small controlled trial [161] No, worsened No! symptoms Cholinergics Class Meta-analysis [193] Insufficient evidence No Donepezil 1 small open label trial [194] Yes No GABA agonists Benzodiazepines 2 small blinded studies [195] Insufficient evidence Yes Baclofen and Valproate Cochrane review [196] No No Neuroleptics Haloperidol 1 small single blind RCT [197] Yes No Quetiapine 1 small single blind RCT [197] Yes Yes (schizophrenics) Clozapine 2 small double blind 4 open label [143] Yes Yes (schizophrenics) Dopamine agonists Bromocriptine 1 early, small double blind, controlled No No trial [198] Antioxidants Vitamin E 14 small blinded studies (4 negative) Insufficient evidence Yes Large RCT (negative) [199] Branched chain amino acids valine, isoleucine, leucine 1 small RCT [200] Yes Yes Noradrenergic antagonists Propranolol Multiple early reports, small open label Yes Yes trials [201–214] Celiprolol 1 early, small, blinded, controlled trial [215] No No Clonidine Two early, small, blinded, controlled trials No No [216, 217] Others Leviteracetam 1 recent, small, RCT [218] Yes Yes 2 open label trials Multiple case reports Amantadine Multiple case reports 9 small open label 1 Yes Yes small blinded (neg.) 1 small RCT (positive) [219]

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Clozapine Yes Quetiapine

Consider Focal dystonia Discontinue botulinum toxin anticholinergics Chronic DRBA if used use necessary? Propranolol +/– concurrenlty Vitamin E

Amantadine Mild to TD Withdraw TD moderate persists? No Clonazepam DRBA persists? Non Focal dyskinesia Levetiracetam

Severe Tetrabenazine DBS

No further No Tx

Figure 21.1 Treatment algorithm for tardive dyskinesia.

gastroparesis. It is also used for a variety of reasons psychiatric patients, particularly related to their by anesthesiology, although this is diminishing psychiatric disease. If the patient is treated with [162], and neurology for migraines. How it works metoclopramide, this is not an issue. The primary for such purposes has been reviewed elsewhere risk factors are age (elderly), sex (female), chronicity [93, 162]. Most cases of TD occur after chronic of therapy, and diabetes mellitus [169, 170]. Of therapy although short-term high-dose metoclopr- course, it could be that elderly women with diabe- amide used as an antiemetic in cancer patients has tes develop gastroparesis and are simply treated also been reported to cause it [92, 163]. The inci- more often with this drug. This data is from retro- dence and prevalence of TD secondary to this drug spective evaluations. Like TD secondary to antipsy- in non-psychiatric populations has not been for- chotics, cases caused by metoclopramide are also mally studied. Estimates for frequency range from frequently persistent (50–70% in 6 months) <1% to nearly 30%. The low estimates are based [170, 171]. Because the physicians prescribing these on prescription databases and adverse event regis- drugs do not typically see TD in their practices, it is tries, methods that notoriously underestimate the reasonable to think that it is under-recognized in frequency [164, 165]; higher figures are based on this setting [93, 169, 170]. smaller studies of less than 100 patients which There have been several suggestions that the TD certainly could result in overestimation because of caused by metoclopramide might differ from that population biases [166, 167]. Reports of TD from of antipsychotics. Most subtypes of TD have been metoclopramide dropped from 1993 to 2000 when described [62, 92, 94, 96, 172, 173], but Swell and cisapride was available for gastroparesis, but picked Jeste [170] suggested that metoclopramide may up again when this drug was removed from the more frequently affect the face and lips and less market due to cardiac adverse effects [168]. It is frequently the limbs than antipsychotics. Lang reasonable to think that the prevalence of TD is [60] indicated that pelvic thrusting and respiratory lower with metoclopramide than the first genera- dyskinesia are significantly more common with tion neuroleptics if used chronically, considering metoclopramide than antipsychotics, and that the fact that a 10- to 20-fold increase in dose is dystonia was less common. It is the respiratory required for it to have antipsychotic effects. As dyskinesia that has been considered to be life discussed elsewhere in this chapter, there are a threatening and if more common with metoclo- number of risk factors for the development of TD in pramide adds to the importance of understanding

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the phenomenology [62]. These findings have not underestimated. With the approval of second been confirmed. generation atypical antipsychotic drugs, many Metoclopramide was approved by the FDA in expected the disappearance of this disorder; however, 1979 and the first case of TD caused by it was newer DRBAs continue to result in TD at alarming reported in 1978 [174]; nevertheless, it was not rates, and the use of these agents has increased until 2009 that a label change was made and a because they are marketed as having substantially black box warning was added regarding this lower risk. DRBAs are now used for the treatment of complication. The warning focused on the chronic many psychiatric disorders – not just schizophrenia, use of the drug. The recommendation is for up to including depression, anxiety, and others – and their 12 weeks of therapy. The warning states, among use for gastrointestinal conditions and other neuro- other things, that chronic use is linked to TD, logical conditions, including migraines and sleep chronic use should be avoided, the development of disorders, has become routine. Although significant TD is directly related to length of time patient is on advances have been made, we do not yet have a it, and the number of doses taken. cohesive theory to explain the pathophysiology of We suspect that because TD generally occurs in this condition, nor do we have sufficient evidence to the psychiatric population treated chronically with support definitive therapy. Many physicians continue antipsychotics, and that chronic therapy is often to use neuroleptics to mask the symptoms, even in warranted, such cases have not aroused much non-psychiatric patients, when it makes little intui- activity in the medicolegal world with some excep- tive sense to do so. Clearly this practice can only tions. However, the occurrence of TD in non- worsen prognosis. Continued research to elucidate psychiatric cases is another story. One paper in the underlying pathophysiology of TD and deter- 1992 discussed the growing number of court cases mine the natural history of this condition definitively related to metoclopramide [170] and this was revis- (including its reversibility), in conjunction with ited in 2006 [169]. The grounds often cited for legal well-designed prospective double-blind controlled action include: (1) the physician did not obtain trials of therapeutic agents, are necessary for the appropriate consent for patients; (2) the off label development of adequate and appropriate therapy. use of the drug; (3) a lack of monitoring for TD; and Furthermore, physicians should not lose sight of the (4) a lack of the early neurology referral. However, fact that this is a preventable condition, and that the most important reason relates to uses of the even the newest DRBAs continue to have the poten- drug of more than 12 weeks since most cases occur tial of causing TD and other tardive syndromes, even with this scenario [92, 169]. This is no small target clozapine. These agents should be used with restraint, since an examination of the Caremark Dimension particularly when effective therapeutic alternatives Rx program showed that 15% of patients treated are available. with this drug received prescriptions for a period of greater than 90 days. These patients tended to be elderly females [175]. With the change in labeling References and with the advent of television commercials 1 Tardive dyskinesia: summary of a Task Force Report of seeking patients who developed TD while on the American Psychiatric Association. By the Task Force metoclopramide, there has been an increase in on Late Neurological Effects of Antipsychotic Drugs. medicolegal cases. Am J Psychiat 1980; 137(10):1163–72. 2 Jeste DV, Lacro JP, Palmer B, et al. Incidence of tardive dyskinesia in early stages of low-dose treatment with Conclusions typical neuroleptics in older patients. Am J Psychiat 1999; 156(2):309–11. TD represents a crisis in neurology and psychiatry. 3 Delay J, Deniker P. Trente-huit cas de psychoses traites Despite its being first described over 50 years par la cure prolongee et continue de 4568 R. Ann Med ago it remains underrecognized and its impact Psychol 1952; 110:364.

Albanese_c21.indd 344 12/24/2011 7:32:08 AM Tardive Dyskinesias 345

4 Schonecker M. [Paroxysmal dyskinesia as the effect 18 Correll CU, Schenk EM. Tardive dyskinesia and new of megaphen.]. Nervenarzt 1957; 28(12):550–3. antipsychotics. Curr Opin Psychiat 2008; 21(2): 5 Kruse W. Persistent muscular restlessness after phe- 151–6. nothiazine treatment: report of 3 cases. Am J 19 Hyde TM AJ, Fisher WC, Egan MF. Tardive dyskinesia. Psychiat 1960; 117:152–3. In: Factor S. A. LT, Weiner WJ, ed. Drug Induced 6 Hunter R, Earl CJ, Thronicroft S. An Apparently Movement Disorders. Second edn. Malden, Oxford, Irreversible Syndrome of Abnormal Movements Carlton: Blackwell Publishing, 2005, pp 213–256. Following Phenothiazine Medication. Proc R Soc 20 Jeste DV, Potkin SG, Sinha S, Feder S, Wyatt RJ. Med 1964; 57:758–62. Tardive dyskinesia–reversible and persistent. Arch 7 Faurbye A, Rasch PJ, Petersen PB, et al. Neurological Gen Psychiat 1979; 36(5):585–90. Symptoms in Pharmacotherapy of Psychoses. Acta 21 van Harten PN, Hoek HW, Matroos GE, et al. Psychiatr Scand 1964; 40:10–27. Intermittent neuroleptic treatment and risk for tardive 8 Kazamatsuri H, Chien C, Cole JO. Treatment of dyskinesia: Curacao Extrapyramidal Syndromes Study tardive dyskinesia. I. Clinical efficacy of a dopamine- III. Am J Psychiat 1998; 155(4):565–7. depleting agent, tetrabenazine. Arch Gen Psychiat 22 Yassa R, Nastase C, Dupont D, Thibeau M. Tardive dys- 1972; 27(1):95–9. kinesia in elderly psychiatric patients: a 5-year study. 9 Kazamatsuri H, Chien C, Cole JO. Treatment of Am J Psychiat 1992; 149(9):1206–11. tardive dyskinesia. II. Short-term efficacy of 23 Jeste DV, Caligiuri MP, Paulsen JS, et al. Risk of tardive dopamine- blocking agents haloperidol and thiopro- dyskinesia in older patients. A prospective longitudi- pazate. Arch Gen Psychiat 1972; 27(1):100–3. nal study of 266 outpatients. Arch Gen Psychiat 1995; 10 Kazamatsuri H, Cole JO. Treatment of tardive 52(9):756–65. dyskinesia. 3. Clinical efficacy of a dopamine com- 24 Mukherjee S, Rosen AM, Cardenas C, Varia V, Olarte S. peting agent, methyldopa. Arch Gen Psychiat 1972; Tardive dyskinesia in psychiatric outpatients: a study 27(6):824–7. of prevalence and association with demographic, 11 Remington G. Tardive dyskinesia: eliminated, for- clinical, and drug history variables. Arch Gen Psychiat gotten, or overshadowed? Curr Opin Psychiat 2007; 1982; 39(4):466–9. 20(2):131–7. 25 Kane J. Tardive dyskinesia: epidemiological and 11A Peña MS, Yaltho TC, Jankovic J. Tardive dyskinesia clinical presentation. In: Bloom FE K, DJ, ed. and other movement disorders secondary to ari- Psychopharmacology; The Fourth Generation of piprazole. Mov Disord 2010 (in press). Progress. New York: Raven, 1995, pp 1485–95. 12 Kane JM, Smith JM. Tardive dyskinesia: prevalence 26 Doongaji DR, Jeste DV, Jape NM, et al. Tardive and risk factors, 1959 to 1979. Arch Gen Psychiat dyskinesia in India: a prevalence study. J Clin 1982; 39(4):473–81. Psychopharmacol 1982; 2(5):341–4. 13 Yassa R, Jeste DV. Gender differences in tardive dys- 27 Inada T, Ohnishi K, Kamisada M, et al. A prospective kinesia: a critical review of the literature. Schizophr study of tardive dyskinesia in Japan. Eur Arch Psychiat Bull 1992; 18(4):701–5. Clin Neurosci 1991; 240(4–5):250–4. 14 Kane JM, Woerner M, Lieberman J. Tardive 28 Miller CH, Simioni I, Oberbauer H, et al. Tardive dyskinesia: prevalence, incidence, and risk factors. J dyskinesia prevalence rates during a ten-year follow- Clin Psychopharmacol 1988; 8(4 Suppl):52S–6S. up. J Nerv Ment Dis 1995; 183(6):404–7. 15 Chakos MH, Alvir JM, Woerner MG, et al. Incidence 29 Hayashi T, Nishikawa T, Koga I, et al. Prevalence of and correlates of tardive dyskinesia in first episode and risk factors for respiratory dyskinesia. Clin of schizophrenia. Arch Gen Psychiat 1996; Neuropharmacol 1996; 19(5):390–8. 53(4):313–19. 30 Go CL, Rosales RL, Caraos RJ, Fernandez HH. The 16 Glazer WM, Morgenstern H, Doucette JT. Predicting current prevalence and factors associated with tardive the long-term risk of tardive dyskinesia in outpa- dyskinesia among Filipino schizophrenic patients. tients maintained on neuroleptic medications. J Clin Parkinsonism Relat Disord 2009; 15(9):655–9. Psychiat 1993; 54(4):133–9. 31 Swartz JR, Burgoyne K, Smith M, et al. Tardive dyski- 17 Correll CU, Leucht S, Kane JM. Lower risk for tar- nesia and ethnicity: review of the literature. Ann Clin dive dyskinesia associated with second-generation Psychiat 1997; 9(1):53–9. antipsychotics: a systematic review of 1-year studies. 32 Tenback DE, van Harten PN, van Os J. Non-therapeutic Am J Psychiat 2004; 161(3):414–25. risk factors for onset of tardive dyskinesia in

Albanese_c21.indd 345 12/24/2011 7:32:08 AM 346 Chapter 21

schizophrenia: a meta-analysis. Mov Disord 2009; 46 Bakker PR, van Harten PN, van Os J. Antipsychotic- 24(16):2309–15. induced tardive dyskinesia and the Ser9Gly poly- 33 Wonodi I, Adami HM, Cassady SL, et al. Ethnicity and morphism in the DRD3 gene: a meta analysis. the course of tardive dyskinesia in outpatients pre- Schizophr Res 2006; 83(2–3):185–2. senting to the motor disorders clinic at the Maryland 47 Chen CH, Wei FC, Koong FJ, Hsiao KJ. Association psychiatric research center. J Clin Psychopharmacol of TaqI A polymorphism of dopamine D2 receptor 2004; 24(6):592–8. gene and tardive dyskinesia in schizophrenia. Biol 34 Ganzini L, Heintz RT, Hoffman WF, Casey DE. The Psychiat 1997; 41(7):827–9. prevalence of tardive dyskinesia in neuroleptic-treated 48 Zai CC, De Luca V, Hwang RW, et al. Meta-analysis of diabetics. A controlled study. Arch Gen Psychiat 1991; two dopamine D2 receptor gene polymorphisms 48(3):259–63. with tardive dyskinesia in schizophrenia patients. 35 Woerner MG, Saltz BL, Kane JM, et al. Diabetes and Mol Psychiat 2007; 12(9):794–5. development of tardive dyskinesia. Am J Psychiat 49 Ohmori O, Suzuki T, Kojima H, et al. Tardive dyski- 1993; 150(6):966–8. nesia and debrisoquine 4-hydroxylase (CYP2D6) 36 Raja M, Azzoni A. Diabetes is not a risk factor for tar- genotype in Japanese schizophrenics. Schizophr Res dive dyskinesia: a retrospective observational study. 1998; 32(2):107–13. Hum Psychopharmacol 2002; 17(1):61–3. 50 Lam LC, Garcia-Barcelo MM, Ungvari GS, et al. 37 Kane JM, Woerner M, Weinhold P, et al. Incidence of Cytochrome P450 2D6 genotyping and association tardive dyskinesia: five-year data from a prospective with tardive dyskinesia in Chinese schizophrenic study. Psychopharmacol Bull 1984; 20(3):387–9. patients. Pharmacopsychiat 2001; 34(6):238–41. 38 Chong SA, Sachdev PS, eds. The epidemiology of 51 Basile VS, Ozdemir V, Masellis M, et al. A functional tardive dyskinesia. NY, NY Marcel Dekker 2004. polymorphism of the cytochrome P450 1A2 39 Yassa R, Ananth J. Familial tardive dyskinesia. Am (CYP1A2) gene: association with tardive dyskinesia J Psychiat 1981; 138(12):1618–19. in schizophrenia. Mol Psychiat 2000; 5(4):410–17. 40 Muller DJ, Schulze TG, Knapp M, et al. Familial 52 Hori H, Ohmori O, Shinkai T, et al. Manganese occurrence of tardive dyskinesia. Acta Psychiatr Scand superoxide dismutase gene polymorphism and 2001; 104(5):375–9. schizophrenia: relation to tardive dyskinesia. 41 Steen VM, Lovlie R, MacEwan T, McCreadie RG. Neuropsychopharmacol 2000; 23(2):170–7. Dopamine D3-receptor gene variant and susceptibility 53 Bakker PR, van Harten PN, van Os J. Antipsychotic- to tardive dyskinesia in schizophrenic patients. Mol induced tardive dyskinesia and polymorphic varia- Psychiat 1997; 2(2):139–45. tions in COMT, DRD2, CYP1A2 and MnSOD genes: a 42 Segman RH, Lerer B. Age and the relationship of meta-analysis of pharmacogenetic interactions. Mol dopamine D3, serotonin 2C and serotonin 2A Psychiat 2008; 13(5):544–56. receptor genes to abnormal involuntary movements 54 Frank Skidmore WJW, Robert Burke, ed. Neuroleptic in chronic schizophrenia. Mol Psychiat 2002; induced tardive dyskinesia variants Blackwell, 2008. 7(2):137–9. 55 Fahn S, ed. The Tardive dyskinesias. Edinburgh: 43 Liao DL, Yeh YC, Chen HM, et al. Association between Churchill Livingstone, 1984. the Ser9Gly polymorphism of the dopamine D3 56 DeLeon ML JJ. Clinical features and management receptor gene and tardive dyskinesia in Chinese of tardive dyskinesias, tardive myoclonus, tardive schizophrenic patients. Neuropsychobiol 2001; tremor, and tardive tourettism. In: Sethi K, ed. Drug 44(2):95–8. Induced Movement Disorders, New York, NY: Marcel 44 Lerer B, Segman RH, Fangerau H, et al. Dekker, Inc, 2004. Pharmacogenetics of tardive dyskinesia: combined 57 Frank Skidmore WW, Robert Bruke. Neuroleptic analysis of 780 patients supports association with induced tardive dyskinesia variants. In: Factor SA, dopamine D3 receptor gene Ser9Gly polymorphism. Lang AE, Weiner WJ, eds. Drug induced movement Neuropsychopharmacol 2002; 27(1):105–19. disorders. Massachusetts: Blackwell, 2005, pp 257–84. 45 Ozdemir V, Basile VS, Masellis M, Kennedy JL. 57A FitzGerald P, Jankovic J. Tardive oculogyric crises. Pharmacogenetic assessment of antipsychotic-induced Neurol 1989; 39:1434–7. movement disorders: contribution of the dopamine 58 Fahn S JJ, ed. Principles and Practice of Movement D3 receptor and cytochrome P450 1A2 genes. Disorders. Philadelphia Churchill Livingstone J Biochem Biophys Methods 2001; 47(1–2):151–7. Elsevier, 2007.

Albanese_c21.indd 346 12/24/2011 7:32:08 AM Tardive Dyskinesias 347

59 Stacy M CF, Jankovic J. Tardive stereotypy and other 75 Rittmannsberger H. Ten year outcome of tardive movement disorders in tardive dyskinesias. Neurol dyskinesia during continuous treatment with first 1993; 43:937–40. generation antipsychotics. Psychiatr Danub 2008; 60 Lang AE. Clinical differences between metoclopra- 20(4):461–5. mide- and antipsychotic-induced tardive dyskine- 76 Casey DE. Tardive dyskinesia: reversible and irre- sias. Can J Neurol Sci 1990; 17(2):137–9. versible. Psychopharmacol Suppl 1985; 2:88–97. 61 Weiner WJ, Goetz CG, Nausieda PA, Klawans HL. 77 Gardos G, Casey DE, Cole JO, et al. Ten-year outcome Respiratory dyskinesias: extrapyramidal dysfunction of tardive dyskinesia. Am J Psychiat 1994; and dyspnea. Ann Intern Med 1978; 88(3): 151(6):836–41. 327–31. 78 Fernandez HH, Krupp B, Friedman JH. The course of 62 Samie MR, Dannenhoffer MA, Rozek S. Life- tardive dyskinesia and parkinsonism in psychiatric threatening tardive dyskinesia caused by metoclo- inpatients: 14-year follow-up. Neurology 2001; pramide. Mov Disord 1987; 2(2):125–9. 56(6):805–7. 63 Horiguchi J, Shingu T, Hayashi T, et al. Antipsychotic- 79 Burke RE. Tardive dyskinesia: current clinical issues. induced life-threatening ‘esophageal dyskinesia’. Int Neurology 1984; 34(10):1348–53. Clin Psychopharmacol 1999; 14(2):123–7. 80 Ghaemi SN, Ko JY. Quetiapine-related tardive dyski- 64 Molho ES, Feustel PJ, Factor SA. Clinical Comparison nesia. Am J Psychiat 2001; 158(10):1737. of Tardive and Idiopathic Cervical Dystonia. Mov 81 Rizos E, Douzenis A, Gournellis R, et al. Tardive dys- Disord 1998; 13(3):486–9. kinesia in a patient treated with quetiapine. World J 65 Burke RE, Fahn S, Jankovic J, et al. Tardive dystonia: Biol Psychiat 2009; 10(1):54–7. late-onset and persistent dystonia caused by 82 Bruscas MJ, Gonzalez F, Santos JL, Sanchez E. antipsychotic drugs. Neurol 1982; 32(12): 1335–46. Tardive dyskinesia associated with clozapine treat- 66 Marsden C.D MRHS, Baldessarini R.J., eds. ment. Prog Neuropsychopharmacol Biol Psychiat Extrapyrimidal movement disorders produced by 2007; 31(4):963–4. antipsychotic drugs. Oxford University Press. 83 Dave M. Clozapine-related tardive dyskinesia. Biol 67 Jeste DV, Wyatt RJ. Therapeutic strategies against Psychiat 1994; 35(11):886–7. tardive dyskinesia. Two decades of experience. Arch 84 Duggal HS, Mendhekar DN. Clozapine-induced Gen Psychiat 1982; 39(7):803–16. tardive dystonia (blepharospasm). J Neuropsychiat 68 Smith JM BR. Changes in prevalence, severity, and Clin Neurosci 2007; 19(1):86–7. recovery in tardive dyskinesia with age Arch Gen 85 Ertugrul A, Demir B. Clozapine-induced tardive dys- Psychiat 1980; 37:1368–73. kinesia: a case report. Prog Neuropsychopharmacol 68A Mejia NI, Jankovic J. Tardive dyskinesia and with- Biol Psychiat 2005; 29(4):633–5. drawal emergent syndrome in children. Expert Rev 86 Iqbal MM, Rahman A, Husain Z, et al. Clozapine: a Neurother. 2010; 10:893–901. clinical review of adverse effects and management. 69 Mejia NI JJ. Metoclopramide-induced tardive dyski- Ann Clin Psychiat 2003; 15(1):33–48. nesia in an infant. Mov Dis 2005; 20(1):86–9. 87 Kane JM, Woerner MG, Pollack S, et al. Does clozap- 70 Klawans HL, Tanner CM, Barr A. The reversibility of ine cause tardive dyskinesia? J Clin Psychiat 1993; “permanent” tardive dyskinesia. Clin 54(9):327–30. Neuropharmacol 1984; 7(2):153–9. 88 Kumet R, Freeman MP. Clozapine and tardive dyski- 71 Wegner JT KJ. Follow-up study on the reversibility nesia. J Clin Psychiat 2002; 63(2):167–8. of tardive dyskinesia. Am J Psychiat 1982; 139(3): 89 Li CR, Chung YC, Park TW, et al. Clozapine-induced 368–9. tardive dyskinesia in schizophrenic patients taking 72 Bergen JA, Eyland EA, Campbell JA, et al. The clozapine as a first-line antipsychotic drug. World J course of tardive dyskinesia in patients on long-term Biol Psychiat 2009; 10(4 Pt 3):919–24. neuroleptics. Br J Psychiat 1989; 154:523–8. 90 Mendhekar DN, Duggal HS. Clozapine-induced tar- 73 Glazer WM, Morgenstern H, Schooler N, et al. dive dyskinesia and hypothyroidism. J Neuropsychiat Predictors of improvement in tardive dyskinesia fol- Clin Neurosci 2006; 18(2):245–6. lowing discontinuation of neuroleptic medication. 91 Miller DD. Clozapine and tardive dyskinesia. Am J Br J Psychiat 1990; 157:585–92. Psychiat 2003; 160(3):588. 74 Tarsy D. Tardive Dyskinesia. Curr Treat Options 91A Jankovic J. Treatment of hyperkinetic movement Neurol 2000; 2(3):205–14. disorders. Lancet Neurol 2009; 8:844–56.

Albanese_c21.indd 347 12/24/2011 7:32:08 AM 348 Chapter 21

92 Kenney C, Hunter C, Davidson A, Jankovic J. 107A Seeman P. Dopamine D2 Receptors as treatment Metoclopramide, an increasingly recognized cause targets in schizophrenia. Clin Schizoph Related of tardive dyskinesia. J Clin Pharmacol 2008; Psychos, 2010; 56–73. 48(3):379–84. 108 Lohr JB, Kuczenski R, Niculescu AB. Oxidative 93 Rao AS, Camilleri M. Review article: metoclopra- mechanisms and tardive dyskinesia. CNS Drugs mide and tardive dyskinesia. Aliment Pharmacol 2003; 17(1):47–62. Ther 2010; 31(1):11–19. 109 Watts RL KW. Movement Disorders: Neurologic 94 Skidmore F, Reich SG. Tardive Dystonia. Curr Treat Principles and Practice, Second edn. McGraw-Hill Options Neurol 2005; 7(3):231–6. Professional, 2004. 95 Alberts VA, Catalano G, Poole MA. Tardive dyskine- 110 Fahn S JJ. Principles and Practice of Movement sia as a result of long-term prochlorperazine use. Disorders. First edn. Philadelphia: Churchill South Med J 1996; 89(10):989–91. Livingstone, 2007. 96 Factor SA, Matthews MK. Persistent extrapyramidal 111 Ashby CR, Jr, Hitzemann R, Rubinstein JE, Wang syndrome with dystonia and rigidity caused by RY. One year treatment with haloperidol or clozap- combined metoclopramide and prochlorperazine ine fails to alter neostriatal D1- and D2-dopamine therapy. South Med J 1991; 84(5):626–8. receptor sensitivity in the rat. Brain Res 1989; 97 Hayashi Y, Ohyagi Y, Inoue I, et al. [A case of 493(1):194–7. amoxapine-induced tardive dystonia successfully 112 Blin J, Baron JC, Cambon H, et al. Striatal dopa- treated with a low dose anti-cholinergic agent]. mine D2 receptors in tardive dyskinesia: PET Rinsho Shinkeigaku 2000; 40(4):367–71. study. J Neurol Neurosurg Psychiat 1989; 98 Huang CC. Persistent tardive dyskinesia associated 52(11):1248–52. with amoxapine therapy. Am J Psychiat 1986; 113 Farde L, Wiesel FA, Stone-Elander S, et al. D2 143(8):1069–70. dopamine receptors in neuroleptic-naive schizo- 99 Huang CC. Persistent tardive dyskinesia associated phrenic patients. A positron emission tomography with amoxapine therapy–two case reports. Hillside J study with [11C]raclopride. Arch Gen Psychiat Clin Psychiat 1986; 8(2):209–13. 1990; 47(3):213–19. 100 Singh GP. Amoxapine-induced tardive dyskinesia. 114 Gerlach J. Current views on tardive dyskinesia. Indian J Psychiat 2009; 51(4):327. Pharmacopsychiat 1991; 24(2):47–8. 101 Tao GK, Harada DT, Kootsikas ME, et al. Amoxapine- 115 Stahl SM. “Hit-and-Run” actions at dopamine induced tardive dyskinesia. Drug Intell Clin receptors, part 2: Illustrating fast dissociation from Pharmacol 1985; 19(7–8):548–9. dopamine receptors that typifies atypical antipsy- 102 Thornton JE, Stahl SM. Case report of tardive dyski- chotics. J Clin Psychiat 2001; 62(10):747–8. nesia and parkinsonism associated with amoxapine 116 Stahl SM. “Hit-and-run” actions at dopamine therapy. Am J Psychiat 1984; 141(5):704–5. receptors, part 1: Mechanism of action of atypical 103 Chouza C, Scaramelli A, Caamano JL, et al. antipsychotics. J Clin Psychiat 2001; 62(9):670–1. Parkinsonism, tardive dyskinesia, akathisia, and 117 Casey DE. Pathophysiology of antipsychotic drug- depression induced by flunarizine. Lancet 1986; induced movement disorders. J Clin Psychiat 2004; 1(8493):1303–4. 65(Suppl 9):25–8. 104 xFenn DS, Moussaoui D, Hoffman WF, et al. 118 Thaker GK, Tamminga CA, Alphs LD, et al. Brain Movements in never-medicated schizophrenics: a gamma-aminobutyric acid abnormality in tardive preliminary study. Psychopharmacol (Berl) 1996; dyskinesia. Reduction in cerebrospinal fluid GABA 123(2):206–10. levels and therapeutic response to GABA agonist 105 Casey DE. Spontaneous and tardive dyskinesias: clin- treatment. Arch Gen Psychiat 1987; 44(6):522–9. ical and laboratory studies. J Clin Psychiat 1985; 46 119 Gunne LM, Haggstrom JE. Reduction of nigral (4 Pt 2):42–7. glutamic acid decarboxylase in rats with neurolep- 106 Casey DE. Tardive dyskinesia: pathophysiology and tic-induced oral dyskinesia. Psychopharmacol animal models. J Clin Psychiat 2000; 61(Suppl 4):5–9. (Berl) 1983; 81(3):191–4. 107 Jankovic J, Tolosa E. Parkinson’s Disease and 120 Perry TL, Hansen S, Jones K. Schizophrenia, tardive Movement Disorders. Fifth edn: Lippincott Williams & dyskinesia, and brain GABA. Biol Psychiat 1989; Wilkins, 2006. 25(2):200–6.

Albanese_c21.indd 348 12/24/2011 7:32:08 AM Tardive Dyskinesias 349

121 Seiler N, Grauffel C, Elands J, et al. Suppression of persistent oral dyskinesias induced by long-term haloperidol-induced oral dyskinesias in rats by haloperidol treatment of rats. Br J Pharmacol 1996; vigabatrin. Pharmacol Biochem Behav 1995; 50(2): 119(4):751–7. 181–9. 133 Maurer I, Moller HJ. Inhibition of complex I by 122 Auchus AP, Pickel VM. Quantitative light micro- neuroleptics in normal human brain cortex parallels scopic demonstration of increased pallidal and striatal the extrapyramidal toxicity of neuroleptics. Mol Cell met5-enkephalin-like immunoreactivity in rats Biochem 1997; 174(1–2):255–9. following chronic treatment with haloperidol but not 134 Sagara Y. Induction of reactive oxygen species with clozapine: implications for the pathogenesis of in neurons by haloperidol. J Neurochem 1998; neuroleptic-induced movement disorders. Exp 71(3):1002–12. Neurol 1992; 117(1):17–27. 135 Yamada K, Kanba S, Anamizu S, et al. Low superoxide 123 Hong JS, Yang HY, Fratta W, Costa E. Rat striatal dismutase activity in schizophrenic patients with tar- methionine-enkephalin content after chronic treat- dive dyskinesia. Psychol Med 1997; 27(5):1223–5. ment with cataleptogenic and noncataleptogenic 136 Elkashef AM, Wyatt RJ. Tardive dyskinesia: possible antischizophrenic drugs. J Pharmacol Exp Ther 1978; involvement of free radicals and treatment with 205(1):141–7. vitamin E. Schizophr Bull 1999; 25(4):731–40. 124 Tang F, Costa E, Schwartz JP. Increase of proenkepha- 137 Christensen E, Moller JE, Faurbye A. Neuropatho- lin mRNA and enkephalin content of rat striatum logical investigation of 28 brains from patients with after daily injection of haloperidol for 2 to 3 weeks. dyskinesia. Acta Psychiatr Scand 1970; 46(1):14–23. Proc Natl Acad Sci U S A 1983; 80(12):3841–4. 138 Thelma B, Srivastava V, Tiwari AK. Genetic 125 McCormick SE, Stoessl AJ. Blockade of nigral and underpinnings of tardive dyskinesia: passing the pallidal opioid receptors suppresses vacuous chewing baton to pharmacogenetics. Pharmacogenomics movements in a rodent model of tardive dyskinesia. 2008; 9(9):1285–1306. Neurosci 2002; 112(4):851–9. 139 Hori H, Ohmori O, Shinkai T, t al. Association between 126 Bishnoi M, Chopra K, Kulkarni SK. Neurochemical three functional polymorphisms of dopamine D2 changes associated with chronic administration of receptor gene and tardive dyskinesia in schizophre- typical antipsychotics and its relationship with nia. Am J Med Genet 2001; 105(8):774–8. tardive dyskinesia. Methods Find Exp Clin Pharmacol 140 Segman RH, Heresco-Levy U, Yakir A, et al. Interactive 2007; 29(3):211–16. effect of cytochrome P450 17alpha-hydroxylase and 127 Waldmeier PC, Delini-Stula AA. Serotonin– dopamine D3 receptor gene polymorphisms on dopamine interactions in the nigrostriatal system. abnormal involuntary movements in chronic schizo- Eur J Pharmacol 1979; 55(4):363–73. phrenia. Biol Psychiat 2002; 51(3):261–3. 128 Balsara JJ, Jadhav JH, Muley MP, Chandorkar AG. 141 Inada T, Koga M, Ishiguro H, et al. Pathway-based Effect of drugs influencing central serotonergic association analysis of genome-wide screening data mechanisms on methamphetamine-induced stereo- suggest that genes associated with the gamma- typed behavior in the rat. Psychopharmacol (Berl) aminobutyric acid receptor signaling pathway are 1979; 64(3):303–7. involved in neuroleptic-induced, treatment-resistant 129 Kinon BJ, Lieberman JA. Mechanisms of action of tardive dyskinesia. Pharmacogenet Genom 2008; atypical antipsychotic drugs: a critical analysis. 18(4):317–23. Psychopharmacol (Berl) 1996; 124(1–2):2–34. 142 Soares-Weiser K, Fernandez HH. Tardive dyskinesia. 130 Tsai G, Goff DC, Chang RW, Flood J, Baer L, Coyle JT. Semin Neurol 2007; 27(2):159–69. Markers of glutamatergic neurotransmission and 143 Lieberman JA, Saltz BL, Johns CA, et al. The effects oxidative stress associated with tardive dyskinesia. of clozapine on tardive dyskinesia. Br J Psychiat Am J Psychiat 1998; 155(9):1207–13. 1991; 158:503–10. 131 Andreassen OA, Meshul CK, Moore C, Jorgensen HA. 144 Labbate LA, Lande RG, Jones F, Oleshansky MA. Oral dyskinesias and morphological changes in rat Tardive dyskinesia in older out-patients: a follow-up striatum during long-term haloperidol administration. study. Acta Psychiatr Scand 1997; 96(3):195–8. Psychopharmacol (Berl) 2001; 157(1):11–19. 145 Fernandez HH, Friedman JH. Classification and treat- 132 Andreassen OA, Aamo TO, Joorgensen HA. ment of tardive syndromes. Neurologist 2003; Inhibition by memantine of the development of 9(1):16–27.

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146 Huang CC, Wang RI, Hasegawa A, Alverno L. tardive dyskinesia. Arch Gen Psychiat 2007; 64(2): Reserpine and alpha-methyldopa in the treatment of 170–6. tardive dyskinesia. Psychopharmacol (Berl) 1981; 160 Greil W, Haag H, Rossnagl G, Ruther E. Effect of 73(4):359–62. anticholinergics on tardive dyskinesia. A controlled 147 Ondo WG, Hanna PA, Jankovic J. Tetrabenazine discontinuation study. Br J Psychiat 1984; 145: treatment for tardive dyskinesia: assessment by ran- 304–10. domized videotape protocol. Am J Psychiat 1999; 161 Gardos G, Cole JO, Rapkin RM, et al. Anticholinergic 156(8):1279–81. challenge and neuroleptic withdrawal. Changes in 148 Jankovic J, Beach J. Long-term effects of tetrabena- dyskinesia and symptom measures. Arch Gen zine in hyperkinetic movement disorders. Neurology Psychiat 1984; 41(11):1030–5. 1997; 48(2):358–62. 162 Moos DD, Hansen DJ. Metoclopramide and extrapy- 149 Tetrabenazine as antichorea therapy in Huntington ramidal symptoms: a case report. J Perianesth Nurs disease: a randomized controlled trial. Neurol 2006; 2008; 23(5):292–9. 66(3):366–72. 163 Breitbart W. Tardive dyskinesia associated with 150 Esper C.D. FA, Factor S.A. Lingual protrusion dysto- high-dose intravenous metoclopramide. N Engl J nia: Frequency, etiology and botulinum toxin ther- Med 1986; 315(8):518–19. apy. Parkinsonism Relat Disord 2010; in press. 164 Bateman DN, Rawlins MD, Simpson JM. Extra- 151 Krause E, Gurkov R. [Local botulinum neurotoxin pyramidal reactions with metoclopramide. Br Med A therapy in tardive lingual dyskinesia]. J (Clin Res Ed) 1985; 291(6500):930–2. Laryngorhinootol 2009; 88(8):508–10. 165 Wiholm BE, Mortimer O, Boethius G, Haggstrom JE. 152 Tschopp L, Salazar Z, Micheli F. Botulinum toxin in Tardive dyskinesia associated with metoclopramide. painful tardive dyskinesia. Clin Neuropharmacol Br Med J (Clin Res Ed) 1984; 288(6416):545–7. 2009; 32(3):165–6. 166 Sewell DD, Kodsi AB, Caligiuri MP, Jeste DV. 153 Hennings JM, Krause E, Botzel K, Wetter TC. Metoclopramide and tardive dyskinesia. Biol Psychiat Successful treatment of tardive lingual dystonia with 1994; 36(9):630–2. botulinum toxin: case report and review of the 167 Ganzini L, Casey DE, Hoffman WF, McCall AL. literature. Prog Neuropsychopharmacol Biol Psychiat The prevalence of metoclopramide-induced tardive 2008; 32(5):1167–71. dyskinesia and acute extrapyramidal movement dis- 154 van Harten PN, Hovestadt A. Botulinum toxin as a orders. Arch Intern Med 1993; 153(12):1469–75. treatment for tardive dyskinesia. Mov Disord 2006; 168 Shaffer D, Butterfield M, Pamer C, Mackey AC. 21(8):1276–7. Tardive dyskinesia risks and metoclopramide use 155 Slotema CW, van Harten PN, Bruggeman R, Hoek HW. before and after US market withdrawal of cisapride. J Botulinum toxin in the treatment of orofacial tar- Am Pharm Assoc (2003) 2004; 44(6):661–5. dive dyskinesia: a single blind study. Prog 169 Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic Neuropsychopharmacol Biol Psychiat 2008; 32(2): J. Drug Insight: from disturbed motility to disordered 507–9. movement–a review of the clinical benefits and 156 Eltahawy HA, Feinstein A, Khan F, et al. Bilateral medicolegal risks of metoclopramide. Nat Clin Pract globus pallidus internus deep brain stimulation in Gastroenterol Hepatol 2006; 3(3):138–48. tardive dyskinesia: a case report. Mov Disord 2004; 170 Sewell DD, Jeste DV. Metoclopramide-associated 19(8):969–72. tardive dyskinesia. An analysis of 67 cases. Arch Fam 157 Kefalopoulou Z, Paschali A, Markaki E, et al. A dou- Med 1992; 1(2):271–8. ble-blind study on a patient with tardive dyskinesia 171 Grimes JD, Hassan MN, Preston DN. Adverse neuro- treated with pallidal deep brain stimulation. Acta logic effects of metoclopramide. Can Med Assoc Neurol Scand 2009; 119(4):269–73. J 1982; 126(1):23–5. 158 Schrader C, Peschel T, Petermeyer M, et al. Unilateral 172 Shearer RM, Bownes IT, Curran P. Tardive akathisia deep brain stimulation of the internal globus pallidus and agitated depression during metoclopra- alleviates tardive dyskinesia. Mov Disord 2004; mide therapy. Acta Psychiatr Scand 1984; 70(5): 19(5):583–5. 428–31. 159 Damier P, Thobois S, Witjas T, et al. Bilateral deep 173 Tarsy D, Indorf G. Tardive tremor due to metoclopra- brain stimulation of the globus pallidus to treat mide. Mov Disord 2002; 17(3):620–1.

Albanese_c21.indd 350 12/24/2011 7:32:08 AM Tardive Dyskinesias 351

174 Lavy S, Melamed E, Penchas S. Tardive dyskinesia 186 Stacy M JJ. Tardive tremor. Mov Disord 1992; 7:53–7. associated with metoclopramide. Br Med J 1978; 187 Little JT, Jankovic J. Tardive myoclonus. Mov Disord 1(6105):77–8. 1987; 2(4):307–11. 175 Kaplan S, Staffa JA, Dal Pan GJ. Duration of therapy 188 Tominaga H, Fukuzako H, Izumi K, et al. Tardive with metoclopramide: a prescription claims data study. myoclonus. Lancet 1987; 1(8528):322. Pharmacoepidemiol Drug Saf 2007; 16(8):878–81. 189 Jankovic J. Drug-Induced and Other Orofacial- 176 Lattuada E, Cavallaro R, Serretti A, et al. Tardive dys- Cervical Dyskinesias. Annals of Internal Medicine kinesia and DRD2, DRD3, DRD4, 5-HT2A variants in 1981; 94(6):788. schizophrenia: an association study with repeated 190 Jankovic J HC, Mejia N, Vuong K. Tetrabenazine: assessment. Int J Neuropsychopharmacol 2004; effective treatment for tardive dyskinesia. Mov 7(4):489–93. Disord 2004; 19(Suppl 9):S73. 177 Srivastava V, Varma PG, Prasad S, et al. Genetic sus- 191 Double DB, Warren GC, Evans M, Rowlands RP. ceptibility to tardive dyskinesia among schizophrenia Efficacy of maintenance use of anticholinergic subjects: IV. Role of dopaminergic pathway gene pol- agents. Acta Psychiatr Scand 1993; 88(5):381–4. ymorphisms. Pharmacogenet Genom 2006; 192 Soares KV, McGrath JJ. Anticholinergic medication 16(2):111–17. for neuroleptic-induced tardive dyskinesia. Cochrane 178 Segman RH, Heresco-Levy U, Finkel B, et al. Database Syst Rev 2000(2):CD000204. Association between the serotonin 2A receptor gene 193 Tammenmaa IA, Sailas E, McGrath JJ, et al. and tardive dyskinesia in chronic schizophrenia. Mol Systematic review of cholinergic drugs for Psychiat 2001; 6(2):225–9. neuroleptic-induced tardive dyskinesia: a meta- 179 Tan EC, Chong SA, Mahendran R, et al. Susceptibility analysis of randomized controlled trials. Prog to neuroleptic-induced tardive dyskinesia and the Neuropsychopharmacol Biol Psychiat 2004; T102C polymorphism in the serotonin type 2A 28(7):1099–1107. receptor. Biol Psychiat 2001; 50(2):144–7. 194 Caroff SN, Campbell EC, Havey J, et al. Treatment of 180 de Leon J, Susce MT, Pan RM, et al. Polymorphic tardive dyskinesia with donepezil: a pilot study. variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, J Clin Psychiat 2001; 62(10):772–5. and dopamine D2 and D3 receptors and their associ- 195 Thaker GK, Nguyen JA, Strauss ME, et al. ation with tardive dyskinesia in severe mental illness. Clonazepam treatment of tardive dyskinesia: a prac- J Clin Psychopharmacol 2005; 25(5):448–56. tical GABAmimetic strategy. Am J Psychiat 1990; 181 Pae CU, Yu HS, Kim JJ, et al. Quinone oxidoreduc- 147(4):445–51. tase (NQO1) gene polymorphism (609C/T) may 196 Soares K, Rathbone J, Deeks J. Gamma-aminobutyric be associated with tardive dyskinesia, but not acid agonists for neuroleptic-induced tardive with the development of schizophrenia. Int J dyskinesia. Cochrane Database Syst Rev 2004(4): Neuropsychopharmacol 2004; 7(4):495–500. CD000203. 182 Liou YJ, Lai IC, Lin MW, et al. Haplotype analysis of 197 Emsley R, Turner HJ, Schronen J, et al. A single- endothelial nitric oxide synthase (NOS3) genetic blind, randomized trial comparing quetiapine and variants and tardive dyskinesia in patients with schizo- haloperidol in the treatment of tardive dyskinesia. phrenia. Pharmacogenet Genom 2006; 16(3):151–7. J Clin Psychiat 2004; 65(5):696–701. 183 Liou YJ, Chen ML, Wang YC, et al. Analysis of genetic 198 Lieberman JA, Alvir J, Mukherjee S, Kane JM. variations in the RGS9 gene and antipsychotic- Treatment of tardive dyskinesia with bromocriptine. induced tardive dyskinesia in schizophrenia. Am J A test of the receptor modification strategy. Arch Gen Med Genet B Neuropsychiatr Genet 2009; Psychiat 1989; 46(10):908–13. 150B(2):239–42. 199 Adler LA, Rotrosen J, Edson R, et al. Vitamin E 184 Matsumoto C, Shinkai T, Hori H, et al. Polymorphisms treatment for tardive dyskinesia. Veterans Affairs of dopamine degradation enzyme (COMT and MAO) Cooperative Study #394 Study Group. Arch Gen genes and tardive dyskinesia in patients with schizo- Psychiat 1999; 56(9):836–41. phrenia. Psychiat Res 2004; 127(1–2):1–7. 200 Richardson MA, Bevans ML, Read LL, et al. Efficacy 185 Bharucha KJ, Sethi KD. Tardive tourettism after of the branched-chain amino acids in the treatment exposure to neuroleptic therapy. Mov Disord 1995; of tardive dyskinesia in men. Am J Psychiat 2003; 10(6):791–3. 160(6):1117–24.

Albanese_c21.indd 351 12/24/2011 7:32:08 AM 352 Chapter 21

201 Bacher NA, Lewis HA. Propranolol, anxiety, and 212 Roberts PW. The use of propranolol in treating tardive dyskinesia. J Clin Psychiat 1983; 44(5):196. tardive dyskinesia. Can Med Assoc J 1980; 123(11): 202 Bacher NM, Lewis HA. Low-dose propranolol in tar- 1106–7. dive dyskinesia. Am J Psychiat 1980; 137(4):495–7. 213 Schrodt GR, Jr, Wright JH, Simpson R, et al. 203 Chaudhry R, Radonjic D, Waters B. Efficacy of Treatment of tardive dyskinesia with propranolol. propranolol in a patient with tardive dyskinesia and J Clin Psychiat 1982; 43(8):328–31. extrapyramidal syndrome. Am J Psychiat 1982; 214 Wilbur R, Kulik FA. Propranolol (Inderal) for tardive 139(5):674–6. dyskinesia and extrapyramidal side effects from 204 Einarson TR. Use of propranolol in treating neuroleptics: possible involvement of beta-adrenergic tardive dyskinesia. Can Med Assoc J 1981; mechanisms. Prog Neuropsychopharmacol 1980; 124(10):1260–2. 4(6):627–32. 205 Kulik FA, Wilbur R. Propranolol for tardive dyskine- 215 Hebenstreit GF, Hoffmann H, Hoffmann W, Pittner H. sia and extrapyramidal side effects (pseudoparkin- [Beta blockade with celiprolol in tardive dyskinesia sonism) from neuroleptics. Psychopharmacol Bull patients treated with neuroleptics]. Wien Klin 1980; 16(3):18–19. Wochenschr 1986; 98(12):388–92. 206 Moreira MJ, Karniol IG. [Improvement of tardive 216 Browne J, Silver H, Martin R, et al. The use of dyskinesia with high doses of propranolol]. Rev Paul clonidine in the treatment of neuroleptic-induced Med 1979; 93(3–4):76–8. tardive dyskinesia. J Clin Psychopharmacol 1986; 207 Novac A. Improvement in tardive dyskinesia and 6(2):88–92. MMPI scores with propranolol. J Clin Psychiat 1986; 217 Tripodianakis J, Markianos M. Clonidine trial in 47(4):218–19. tardive dyskinesia. Therapeutic response, MHPG, 208 Olivera AA, Kiefer MW. Propranolol therapy in a and plasma DBH. Pharmacopsychiat 1986; 19(5): patient with panic disorder, tardive dyskinesia, and 365–7. essential tremor. J Clin Psychiat 1984; 45(11):484–5. 218 Woods SW, Saksa JR, Baker CB, et al. Effects of 209 Perenyi A, Farkas A. Propranolol in the treatment of levetiracetam on tardive dyskinesia: a randomized, tardive dyskinesia. Biol Psychiat 1983; 18(3):391–4. double-blind, placebo-controlled study. J Clin 210 Pitts FN, Jr. Treatment of tardive dyskinesia with pro- Psychiat 2008; 69(4):546–54. pranolol. J Clin Psychiat 1982; 43(8):304. 219 Angus S, Sugars J, Boltezar R, et al. A controlled trial 211 Risch SC, Cohen RM, Kalin NH. Propranolol, chlor- of amantadine hydrochloride and neuroleptics promazine, and tardive dyskinesia. Am J Psychiat in the treatment of tardive dyskinesia. J Clin 1980; 137(9):1125. Psychopharmacol 1997; 17(2):88–91.

Albanese_c21.indd 352 12/24/2011 7:32:08 AM CHAPTER 22 Stereotypies and Other Developmental Hyperkinesias Jayasri Srinivasan and Jonathan W. Mink Department of Neurology, Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, USA

Introduction Stereotypies

Children exhibit a variety of hyperkinesias that Phenomenology and other clinical consist of stereotyped, repetitive movement features patterns. Many of these share features that allow Definition them to be grouped together under the category of Stereotypies are broadly defined as involuntary, stereotypies. Others have features in common with patterned, coordinated, repetitive, non-reflexive stereotypies, but occur at specific developmental movements that are typically rhythmic and occur stages and are usually transient. Indeed, the devel- in the same fashion with each repetition. [1–3]. oping nervous system produces a variety of motor These movements can vary considerable across patterns that would be considered pathologic in individual patients, but within each patient are older children and adults, but are simply a manifes- characterized by a fixed and repetitive pattern that tation of CNS immaturity. Like many of the so- does not change over time. Stereotypies are not called “primitive reflexes” (e.g. grasping, rooting, preceded by a premonitory urge and in many cases sucking, placing, tonic neck reflexes), these motor the child is unaware he or she is making the move- patterns disappear as neuronal connectivity pro- ment until it is pointed out. Stereotypies typically gresses and myelination matures. Some transient arise from a background of normal movement and hyperkinetic movement disorders in childhood have sudden onset and offset. They are most often may be manifestations of abnormal neural function, seen when the child is excited, anticipating some- but do not correlate with serious underlying thing, or engrossed. Common stereotypies include pathology. These are typically associated with hand waving, arm flapping, finger wiggling, head complete resolution of the abnormal movements nodding, and body rocking. Stereotypies can be and ultimately normal development and neurolog- divided into simple or complex types. Simple ste- ical function. Others are symptomatic of more reotypies include body rocking, head nodding, serious underlying disorders. This chapter is focused walking in circles, hand flapping or clapping, and on stereotypies, but other transient hyperkinesias facial grimacing. Complex stereotypies are more of childhood will also be described. complicated in nature, such as sitting and rising

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Table 22.1 Factors distinguishing stereotypies from tics.

Tics Stereotypies

Age at onset: 6–7 years <2 years Pattern: Variable, changing in type and complexity Fixed, identical, patterned, predictable over time Movements: Blink, grimace, twist, shrug Arms/hands (flap, wave), body rocking, pacing Vocalizations: Sniffing, throat clearing Moaning, humming Rhythm: Rapid, sudden, random Rhythmic Duration: Intermittent, brief, abrupt Intermittent, continuous, prolonged Premonitory urge: Yes No Precipitant: Excitement, stress Excitement, stress, also when engrossed Suppression: Brief, voluntary (but have increased “inner With distraction, rare conscious effort tension”) Distraction: Reduction of tics Stops Family history: Frequently positive May be positive Treatment: Alpha-2 agonists, antidopaminergic drugs, Poorly responsive, may respond to behavioral behavioral therapy therapy

Source: Mahone et al. [3]

from a chair (2). In children, hand flapping is the Mannerisms are habits unique to an individual that most common primary stereotypy (48%), followed are attached to normal activity, such as an athlete’s by clenching stiffening (38%), shaking (28%), and routine before a game. They are typically unique to ritualistic behaviors (13%) [3]. The most common the individual, are brief, rarely repetitive, and are body part involved is the arms in 70% of children, less complex than stereotypies [4]. Akathisia is a followed by face-hand-mouth (53%) and hands- syndrome of motor restlessness that typically fingers (48%). Two-thirds of children used more includes both a subjective sense of inner restless- than one body part in their stereotypy, and 57% ness and outwardly observed repetitive movements made multiple movements each time [3]. such as rocking or repeatedly crossing and Differentiating stereotypies from tics is central to uncrossing the legs while sitting. Although the making a definitive diagnosis of stereotypies [3–4]. movements may appear similar to stereotypies, the The major distinguishing features are presented in associated sensations and common association with Table 22.1. Tics are non-rhythmic, discrete, brief neuroleptic medications help distinguish akathisia movements that fluctuate in location and type over from stereotypies [6]. Compulsions are repetitive time. Their frequency and severity also waxes and purposeful behaviors (such as hand washing) that wanes, and they can be either simple or complex. the person feels driven to perform in response to an Compared to tics, stereotypies tend to be longer obsession, or according to rules that must be applied and more rhythmic in nature. Tics are more likely rigidly [7]. Compulsions are often acknowledged as to involve head, shoulder, and eye movements, being excessive or unreasonable, but this may not such as eye blinking or shoulder jerking, are typi- be the case in children. Paroxysmal dyskinesias are cally non-rhythmic, and are often preceded by a a group of movement disorders that are episodic, premonitory sensation [5]. In contrast, stereotypies usually arising out of a background of normal involve more limb movements, such as hand movement and behavior [8]. They usually consist flapping, and are typically rhythmic. of chorea, dystonia, athetosis, or a combination Other considerations in the differential diagnosis and may be associated with specific triggers. of stereotypies are mannerisms, akathisia (Chapter 1), Masturbation, also known as self-stimulation or compulsions, paroxysmal dyskinesias (Chapter 23), gratification behavior, is a normal sexual behavior and self-gratification behavior (masturbation). that can begin at any age [9]. Manifestations can

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include repetitive movements such as dystonic Box 22.1 Etiologies of stereotypies posturing of the lower extremities, rocking, and grunting. I. Primary Common type In children under the age of 2 years, other Head nodding developmentally specific conditions should also be Complex motor considered. These are discussed at the end of this II. Secondary (in the presence of other pathology) chapter. Autism: Infantile autism, Asperger’s syndrome, pervasive developmental disability, Rett syndrome Etiology Mental retardation (in the absence of autism) Sensory deprivation: Congenital blindness/deafness, Stereotypies can be classified into two etiological caging, constraints categories: primary (or physiological), and second- Inborn errors of metabolism: Lesch–Nyhan syndrome, ary (see Box 22.1). neuroacanthocytosis Drug induced: Psychostimulants, tardive dyskinesia Primary stereotypies Infection: Encephalitis Tumor: Bobble-headed doll syndrome Primary stereotypies are those that are not due to Trauma: an identifiable underlying cause and typically occur Psychiatric: OCD, schizophrenia, catatonia, functional without other neurologic signs or symptoms. Source: Singer et al. [4] Primary stereotypies can be further subdivided into (a) common stereotypies (such as body rocking, head banging, and hair twirling), (b) head nodding, torso [15–16]. These developmental patterns may and (c) complex hand and arm stereotypies [2, 10]. include head rolling, head banging, and body Head nodding may represent a specific develop- rocking [17]. In typically developing pre-school mental case, as discussed at the end of this chapter. children, other stereotypies identified by parents In general, primary stereotypies have a typical included thumb sucking (25%), and nail biting onset before 3 years of age in 90% of patients. They (23%), both correlating with negative mood are more common in males, with a M:F ratio of 3:2. states [18]. Symptoms occur at least once daily in 90%, are triggered by excitement in 70%, and stopped when cued in 98%. The movements cease when cued or Secondary stereotypies distracted [11]. A family history of stereotypies is Secondary stereotypies are those associated with common; 25% of children with motor stereotypies neurological or sensory impairment. They have have an identified family history of motor classically been associated with autism, which is stereotypies in one study [12]. defined as impaired social interaction and commu- Primary stereotypies typically occur in normally nication associated with restricted repetitive and developing children. The type of stereotypy can stereotyped patterns of behavior, interests, and vary with developmental stage, such as thumb activities [7]. Thus, stereotyped and repetitive motor sucking in the younger child versus college students mannerisms can be central diagnostic features of who may exhibit more body rocking or playing autism. Young children with autism, particularly with pens [13]. Some children may have a past his- those aged between 3 and 4 years, tend to display tory of delayed milestones despite currently normal more stereotypic behaviors than age-matched peers development [2, 11–14]. Cognitive and behavioral [19]. One observational study reported stereotypies comorbidities have been identified, including in 25% of children with autism, and more prevalent attention deficit hyperactivity disorder (ADHD) in in the lower functioning autism subtype [20], but 25% and a learning disability in 20% [3]. others have reported that as many as 100% of autis- It has been argued that normal motor develop- tic subjects had stereotypies [21–22]. Autistic stere- ment in infants is characterized by a number of otypies include body movements involving the stereotypies, primarily involving legs, arms and hands (such as clapping) or whole body (such as

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swaying or rocking). There may also be a fascination Video 22.1 Stereotypies in Rett syndrome with the movement of other objects which may be incorporated into the stereotypy, such as the spin- Young girl with typical hand and other stereotypies associated with Rett syndrome. [Video courtesy of ning wheels of toys or other rapidly revolving Joseph Jankovic, MD, Houston, Texas] object. However, one observational study demonstrated the lack of predictive value in stereotypies with autism, as both autistic and non-autistic children were found to have a similar degree of stereotypies [23]. A high degree of abnormal repetitive behaviors have been identified in individuals with autism and in those with cognitive impairment in http://bit.ly/vPDuim the absence of autism. Autistic individuals were associated with more frequent and more severe stereotypies than those with mental retardation without autism [24]. However, compared to individuals children who were blind included body rocking, without mental retardation, a greater proportion of repetitive handling of objects, hand and finger individuals with mental retardation engaged in ste- movements, eye pressing, eye poking, lying face reotypies, such as body rocking [25]. downwards, and jumping. Rett syndrome is a regressive disorder of psycho- A study of non-handicapped children in residen- motor development following a normal early his- tial care identified a prevalence of stereotypies in tory till 5 months of age. It is characterized by 58.5 % of the children studied [28]. However, the developmental arrest or regression associated with types of stereotypies seen were not different to that loss of communication skills. The loss of previously identified in the normal and autistic populations. acquired purposeful hand skills between ages 5 and Various metabolic disorders associated with ste- 30 months are often seen, with the subsequent reotypic movements have been reported. These development of stereotyped hand movements [7]. include Lesch–Nyhan disease [31], neuroacantho- Hand stereotypies are a hallmark of Rett syndrome cytosis [32], Wilson disease [33], and ornithine (RS), particularly hand washing stereotypies, transcarbamylase deficiency [34]. In Lesch–Nyhan although a variety of motor stereotypies have been disease and neuroacanthocytosis, the stereotypic described in RS [26] (Video 22.1). These include movements are often self-injurious in nature due most frequently bruxism, mouthing, pill rolling, to orofaciolingual movements, such as self-biting. and twisting of the trunk. Although initial reports Typically, metabolic disorders do not present with suggested that children with RS who are MeCP2 stereotypies in isolation, and are usually accompa- positive are more likely to have diverse stereotypies nied by other clinical features of the underlying that diminish with age [26], more recent reports condition. suggest that hand stereotypies in adults can persist, Stereotypies can accompany psychiatric disorders and may help in making a diagnosis of RS [27]. such as anxiety or other affective disorders, Sensory deprivation, particularly visual impair- obsessive compulsive disorder, Tourette syndrome, ment, has been associated with stereotypies. tardive dyskinesia, schizophrenia, and akathisia Specific impairments may be associated with dis- [14] (Video 22.2). tinctive stereotypies. For example, eye-poking and pressure on the eyeball appears to be relatively spe- Pathophysiology cific to children with a vision impairment, and The underlying origins of stereotypies are still being especially to those with an intact optical nerve but investigated, but many explanations have been put a damaged cornea [28], and rocking is strongly forward. Basal ganglia circuit dysfunction has associated with retinopathy of prematurity [29–30]. been implicated in the underlying pathogenesis of Stereotyped behaviors most frequently observed in stereotypies. Rhythmic stereotypies are manifesta-

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ylphenidate intraperitoneally [40]; pretreatment Video 22.2 Tardive stereotypies with selective serotonin reuptake inhibitors in the This is a 72 year old man previously treated with latter trial significantly reduced stimulant-induced haloperidol for 5 years for anxiety gradually developed stereotypies. Clinically, punding, a stereotypical “nervous rubbing” of the right thumb and index finger, which progressed to more generalized stereotypies as motor behavior involving repetitive handling of part of tardive akathisia. Both the motor and sensory objects, is seen in patients with Parkinson disease as components improved markedly with tetrabenazine. a complication of dopaminergic drugs [41]. [Video courtesy of Joseph Jankovic, MD, Houston, Texas] A positive family history of stereotypies has been identified in 25% of children with complex stereotypies, suggesting a possible genetic predisposition [3]. It has been suggested that stereotypic movements in normal infants allow them to experience kinesthetic sensations [17]. Deficient sensory processing http://bit.ly/rsFZOJ has been implicated in various studies as a cause of stereotypies in autism [42]. Wing and Gould described a triad of features in tions of the immature brain, reflecting incomplete autism, and suggested that impaired imagination is cortical control of the motor system [15]. Immature linked with restricted repetitive behaviors [43], the circuitry is also suggested by onset of stereotypies latter acting to compensate for the deficits in the in 90% of a population of children aged before former. More recent studies have identified a 3 years [3], with improvements reported over time. negative correlation between the amount of Studies involving administration of a dopamine repetitive behavior, including motor stereotypies, receptor agonist to rats induced motor stereotypies, in children with autism and the amount of time and correlated with an activation of striatal neurons engaged in play activities, suggesting a possible [35–36]. Deep brain stimulation (DBS) in two association between repetitive behaviors and primates of the anterior, or limbic, subthalamic imagination [44]. nucleus resulted in a dramatic reduction in stereo- Whether this is a behavioral “function” of typies [37]. stereotypies has been debated. Troster studied Volumetric magnetic resonance imaging studies 142 non-handicapped children in residential in children with complex stereotypies have care, and classified four types of situations which demonstrated a reduction in volumes of frontal correla ted with an increase in certain stereotyp- white matter disproportionate to the total cerebral ies: concentration and nail or lip biting; boredom white matter, and in the caudate nuclei compared and thumb sucking and hair twisting; frustration/ to age-matched controls [38]. This supports the concentration and face pulling or scratching view that dysfunction in the cortico-striatal- oneself, and stimulation, in which no specific thalamo-cortical circuitry may underlie stereotyp- stereotypy was identified [28]. However, we ies. Indeed, stereotypic behaviors are often seen in favor the view that stereotypies are akin to other patients who have evidence of frontal-subcortical hyperkinetic movement disorders in which the dysfunction such as seen in fronto-temporal movements are involuntary and arise from degenerations and other tauopathies [39] abnormal neuronal discharge patterns [45]. (Video 22.3). These patterns reflect underlying pathophysiol- Neurotransmitter dysfunction may also be ogy and not underlying psychopathology. In involved. Stereotypies characterized by sniffing non-autistic, non-retarded children, it is quite have been reproduced following injection of common for children to be unaware that they are dopamine agonists into the anterior ventral doing the stereotypies unless that is pointed out striatum of rats [36] or d-amphetamine and meth- to them [3]. Stereotypies typically cease when

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the child is distracted or redirected. This apparent Video 22.3 Stereotypies in suspected unawareness of stereotypies is similar to what taupathy has been observed for chorea in Huntington disease and dopa-induced dyskinesia in Parkinson This is a 58 year old right-handed man with a 12 year history of a progressive disorder which began with disease [46]. A careful investigation in patients low-volume speech difficulty, vertical with Huntington disease was able to reject any ophthalmoparesis, gait and balance disorder and a psy chodynamic contribution to the reduced self- change in his personality becoming increasingly awareness of involuntary movements [46]. apathetic and anxious with emergence of stereotypic Similarly, many patients with tic disorders are behavior, foot and finger tapping, repetitive button pushing on a TV remote control. In addition he unaware of some or all of their tics, if they are manifests problems with chewing and jaw opening, mild [47]. These findings suggest that low aware- hyypomimia, micrographia. His symptoms failed to ness of certain kinds of involuntary movements improve with levodopa but the stereotypies improved is common and supports the idea that involun- markedly with tetrabenazine. MRI showed non-specific tary movements are not done for functional frontal-mesencephalic atrophy. The suspected diagnosis is tauopathy. [Video courtesy of Joseph reasons. Jankovic, MD, Houston, Texas]

Treatment

For primary stereotypies, usually education and reassurance is sufficient. For secondary stereotypies,

treatment should be targeted at the underlying http://bit.ly/tAQkCK condition when possible. The efficacy of behavioral techniques for stereotypies has been studied, particularly for stereotypies considered less socially acceptable such as head weaving [48]. The achieved by stimulating appropriate adaptive various behavioral techniques are divided into behavior [50]. aversive procedures or positive procedures. There have been no controlled therapeutic trials Aversive procedures include electric shock, physi- examining the efficacy of benzodiazepines, alpha- cal restraint, aversive physical consequences, aver- adrenergic agonists, opiate antagonists, beta- sive music, overcorrection, timeout from positive blockers, antiepileptic medications, antipsychotics, reinforcement, and verbal punishment. In addition monoamine depletors, such as tetrabenazine, and to the unethical nature of some of these techniques, selective serotonin reuptake inhibitors (see [4] for there have been no long-term studies demonstrat- review). Isolated reports have reported some ing sustained efficacy outside of isolated case improvement with selective serotonin reuptake reports. Positive procedures to reduce stereotypies inhibitors [51], clonazepam [52], clonidine [53], includes habit reversal and awareness training, self- and dopamine depleting agents [54]. stimulation tokens, and differential reinforcement of other or incompatible behaviors. There are reports that combined use of habit reversal and Prognosis differential reinforcement of other behavior is beneficial in reducing motor stereotypies in non- Few long-term follow up studies characterizing the autistic children who were followed for a mean outcome of children with stereotypies have been period of 12 months [49]. Besides this however, no performed, and many of these have suggested that long-term efficacy studies in these areas have been stereotypies are less likely to resolve than once conducted. In children with sensory deprivation, a suspected. Harris et al. followed a clinical cohort of reduction in stereotyped behavioral traits was children with motor stereotypies for a mean period

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of 6.8 years [12], and 94% of children continued to [56, 58]. Parallels to stereotypies include age at have stereotypies at their most recent follow-up, onset in infancy and early childhood, rhythmicity suggesting stereotypies had a more chronic course, of movements, and common association of facial particularly if arm or hand movements were grimacing. However, the movement frequency is involved. Mahone et al. [10] found that only 5% of usually slower in stereotypies, the duration of the children in their study had resolution of their stereotypies tends to be longer (up to minutes), and stereotypy after a mean interval of 6.5 years after stereotypies tend to persist into late childhood, or age of onset, despite studying a population of longer. Shuddering episodes typically resolve as the children without mental retardation. 50% of these child grows older. The prognosis for development children continued to have stereotypies that were and neurological function is uniformly good. Some unchanged in frequency and severity. Several investigators (e.g. Vanasse et al. [69]; Kanazawa comorbidities associated with stereotypies were [56]) have suggested that “shuddering attacks” of also identified from these studies, including infancy might be the initial manifestation of attention deficit hyperactivity disorder (30%), tics essential tremor, but a true link has not been (18%), and obsessive compulsive traits (10%) [3]. proven. A similar study of stereotypies in 10 children by Tan et al. found that stereotypies resolved in only 2 Head nodding children [55]. Both parents and teachers reported Head nodding without accompanying nystagmus a decrease in stereotyped behaviors associated can occur as paroxysmal events in older infants and with nervousness (thumb sucking, nail biting) with toddlers [59]. These head movements can be lateral age [18]. Conversely, certain stereotypies such as (“no–no”), vertical (“yes–yes”), or oblique. The thumb sucking and rocking were found to persist frequency (1–2 Hz) is slower than that of shudder- into adulthood more than other stereotypies, ing. They typically occur many times a day. The particularly if there were comorbid anxiety or movements do not occur when the child is lying, affective disorders [14]. Many of these studies were but can occur in the sitting or standing position. performed at referral centers and may be associated The movements typically resolve within months, with substantial ascertainment bias. but can persist longer. Some children with head nodding have a prior history of shuddering spells; others may have a family history of essential tremor Other developmental [60]. However, it is unclear whether there is any hyperkinesias etiological relationship with these other conditions. An unusual head nodding epileptic syndrome has A variety of largely benign hyperkinesias have been been described in sub-Saharan Africa. This head- described in infants and toddlers. Many of these nodding epilepsy syndrome appears to be associated disorders may belong more properly to the with hippocampal sclerosis and may be related to spectrum of stereotypies, but they have been infection with O. volvulus [61]. Developmental defined based on the nature of the movements. and neurological outcome are benign in idiopathic head nodding. Although the literature has referred Shuddering to “head nodding” as a specific entity, we prefer Shuddering episodes are characterized by periods to regard it as a simple primary stereotypy (see of rapid tremor of the head, shoulders, and arms Box 22.1). that resemble shivering [56–57]. Age at onset is typically during infancy or early childhood. The Spasmus nutans episodes last several seconds and can occur up to Spasmus nutans is a condition beginning in late 100 times each day. During a spell, there is no infancy (3–8 months) that is characterized by a change in consciousness. Similarity to benign slow head tremor (approximately 2 Hz) that can be myoclonic epilepsy in infancy has been suggested horizontal (“no–no”) or vertical (“yes–yes”). The

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head movements are indistinguishable from head References nodding stereotypies. However, in spasmus nutans, the head movements are accompanied by a small- 1 Jankovic J. Stereotypies. In: Marsden CD, Fahn S, eds. amplitude nystagmus that can be dysconjugate, Movement Disorders 3. Oxford: Butterworth- conjugate, or uniocular [62]. The nystagmus is Heinemann, 1994: pp 501–17. typically pendular with high frequencies (up to 2 Tan A, Salgado M, Fahn S. The characterization and 15 Hz) and low amplitudes (0.5–3 degrees) and is outcome of stereotypical movements in nonautistic children. Mov Disord 1997; 12:47–52. most commonly dysconjugate [63]. When the child 3 Mahone EM, Bridges D, Prahme C, Singer HS. fixates on an object, the nodding may increase. If Repetitive arm and hand movements (complex motor the head is held still, the amplitude of the nystagmus stereotypies) in children. J Pediat 2004; 145:391–5. typically increases. Spasmus nutans generally 4 Singer HS, Mink JW, Gilbert DL, Jankovic J. Movement resolves within several months, but the majority of Disorders in Childhood. Philadelphia: Saunders, 2010. patients continue to have a fine, subclinical, 5 Crosland KA, Zarcone JR, Schroeder S, et al. Use of an nystagmus until at least 5–12 years of age [64]. antecedent analysis and a force sensitive platform to Long-term outcome is good. compare stereotyped movements and motor tics. Am Thus, ophthalmologic evaluation is recommended J Ment Retard 2005; 110:181–92. for children with spasmus nutans. Neuroimaging 6 Kumar R, Sachdev PS. Akathisia and second- abnormalities, including tumor and aplasia of the generation antipsychotic drugs. Curr Opin Psychiat 2009; 22:293–9. cerebellar vermis, have been described in patients 7 American Psychiatric Association. Diagnostic and with spasmus nutans, but this is an uncommon Statistical Manual of Mental Disorders, 4th-TR ed. association [65–67]. Routine neuroimaging in the Washington, D.C.: American Psychiatric Association, absence of other evidence for intracranial pathol- 2000. ogy has limited yield [68]. 8 Mink JW. Paroxysmal dyskinesias. Curr Opin Pediat 2007; 19:652–6. 9 Yang ML, Fullwood E, Goldstein J, Mink JW. Conclusions Masturbation in infancy and early childhood presenting as a movement disorder: 12 cases and a review of Stereotyped repetitive behaviors are one of the the literature. Pediat 2005; 116:1427–32. more common forms of hyperkinetic movement 10 Mahone EM, Bridges D, Prahme C, Singer HS. Repetitive arm and hand movements (complex motor disorder in childhood. Although commonly stereotypies) in children. J Pediat 2004; 145:391–5. associated with autism and other developmental 11 Muthugovindan D, Singer H. Motor stereotypy disorders, they occur in many children with no disorders. Curr Opin Neurol 2009; 22:131–6. other neurologic disorders. The primary stereotyp- 12 Harris KM, Mahone EM, Singer HS. Nonautistic motor ies are likely to have a generally good outcome. The stereotypies: clinical features and longitudinal follow- neural basis of stereotypies is not known, but is up. Pediat Neurol 2008; 38:267–72. likely to involve basal ganglia and frontal cortical 13 Rafaeli-Mor N, Foster L, Berkson G. Self-reported circuits. Whether stereotypies are purposeless or body-rocking and other habits in college students. Am “self-stimulating” is controversial, but it seems in J Ment Retard 1999; 104:1–10. non-autistic individuals with stereotypies that the 14 Castellanos FX, Ritchie GF, Marsh WL, Rapoport JL. movements are not done for any specific “purpose.” DSM-IV stereotypic movement disorder: persistence of stereotypies of infancy in intellectually normal ado- Behavioral and pharmacologic therapies have been lescents and adults. J Clin Psychiat 1996; 57:116–22. reported in small studies, but there is no consensus 15 Thelen E. Rhythmical stereotypies in normal human regarding efficacy. Disorders that substantially infants. Animal Behav 1979; 27:699–715. resemble stereotypies have been defined as specific 16 Thelen E. Rhythmical behavior in infancy: an etho- age-related syndromes. However, it is likely that logical perspective. Dev Psychol 1981; 17:237–57. many of these represent a developmentally specific 17 Mitchell R, Etches P. Rhythmic habit patterns (stereo- part of the stereotypy spectrum. typies). Dev Med Child Neurol 1977; 19:545–50.

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18 Foster LG. Nervous habits and stereotyped behaviors 34 Hyman SL, Batshaw ML. A case of ornithine in preschool children. J Am Acad Child Adolesc transcarbamylase deficiency with Rett syndrome man- Psychiat 1998; 37:711–17. ifestations. Am J Med Genet Suppl 1986; 1:339–43. 19 MacDonald R, Green G, Mansfield R, et al. Stereotypy 35 Canales JJ, Graybiel AM. A measure of striatal in young children with autism and typically developing function predicts motor stereotypy. Nat Neurosci children. Res Dev Disabil 2007; 28:266–77. 2000; 3:377–83. 20 Rapin I, ed. Preschool children with inadequate 36 Bordi F, Carr KD, Meller E. Stereotypies elicited by communication. Developmental language disorder, injection of N-propylnorapomorphine into striatal autism, low IQ. Bromley, Kent: Mac Keith Press, 1996. subregions and nucleus accumbens. Brain Res 1989; 21 Shay J, Sanchez L, Cueva J, et al. Neuroleptic-related 489:205–15. dyskinesia and stereotypies in autistic children. 37 Baup N, Grabli D, Karachi C, et al. High-frequency Psychopharm Bull 1993; 29:359–63. stimulation of the anterior subthalamic nucleus 22 Campbell M, Locasio J, Choroco MC, et al. Sterotypies reduces stereotyped behaviors in primates. J Neurosci and tardive dyskinesia: Abnormal movements in 2008; 28:8785–8. autistic children. Psychopharm Bull 1990; 26:260–6. 38 Kates WR, Lanham DC, Singer HS. Frontal white 23 Mandelbaum DE, Stevens M, Rosenberg E, et al. matter reductions in healthy males with complex Sensorimotor performance in school-age children stereotypies. Pediat Neurol 2005; 32:109–12. with autism, developmental language disorder, or low 39 Shigenobu K, Ikeda M, Fukuhara R, et al. The IQ. Dev Med Child Neurol 2006; 48:33–9. Stereotypy Rating Inventory for frontotemporal lobar 24 Bodfish JW, Symons FJ, Parker DE, Lewis MH. Varieties degeneration. Psychiat Res 2002; 110:175–87. of repetitive behavior in autism: Comparisons to men- 40 Roffman JL, Raskin LA. Stereotyped behavior: effects tal retardation. J Aut Dev Disord 2000; 30:237–43. of d-amphetamine and methylphenidate in the 25 Berkson G, Rafaeli-Mor N, Tarnovsky S. Body-rocking young rat. Pharmacol Biochem Behav 1997; and other habits of college students and persons with 58:1095–1102. mental retardation. Am J Ment Retard 1999; 41 Fernandez HH, Friedman JH. Punding on L-dopa. 104:107–16. Mov Disord 1999; 14:836–38. 26 Temudo T, Freitas P, Sequeiros J, et al. Atypical 42 Gabriels RL, Cuccaro ML, Hill DE, et al. Repetitive stereotypies and vocal tics in Rett syndrome: An behaviors in autism: relationships with associated illustrative case. Mov Disord 2008; 23:622–4. clinical features. Res Dev Disabil 2005; 26:169–81. 27 Vignoli A, La Briola F, Canevini MP. Evolution of 43 Wing L, Gould J. Severe impairments of social stereotypies in adolescents and women with Rett interaction and associated abnormalities in children: syndrome. Mov Disord 2009; 24:1379–83. epidemiology and classification. J Aut Dev Disord 28 Troster H. Prevalence and functions of stereotyped 1979; 9:11–29. behaviors in nonhandicapped children in residential 44 Honey E, Leekam S, Turner M, McConachie H. care. J Abnorm Child Psychol 1994; 22:79–97. Repetitive behaviour and play in typically developing 29 Gal E, Dyck MJ, Passmore A. The relationship between children and children with autism spectrum disorders. stereotyped movements and self-injurious behavior in J Aut Dev Disord 2007; 37:1107–15. children with developmental or sensory disabilities. 45 Mink J. The basal ganglia and involuntary movements: Res Dev Disabil 2009; 30:342–52. Impaired inhibition of competing motor patterns. 30 Troster H, Brambring M, Beelmann A. The age depend- Arch Neurol 2003; 60:1365–8. ence of stereotyped behaviours in blind infants and 46 Snowden JS, Craufurd D, Griffiths HL, Neary D. preschoolers. Child Care Health Dev 1991; 17:137–57. Awareness of involuntary movements in Huntington 31 Cauwels RG, Martens LC. Self-mutilation behaviour disease. Arch Neurol 1998; 55:801–5. in Lesch-Nyhan syndrome. J Oral Pathol Med 2005; 47 Pappert EJ, Goetz CG, Louis ED, et al. Objective 34:573–5. assessments of longitudinal outcome in Gilles de la 32 Hardie RJ, Pullon HW, Harding AE, et al. Tourette’s syndrome. Neurol 2003; 61:936–40. Neuroacanthocytosis. A clinical, haematological and 48 LaGrow SJ, Repp AC. Stereotypic responding: a pathological study of 19 cases. Brain 1991; 114 review of intervention research. Am J Ment Defic (Pt 1A):13–49. 1984; 88:595–609. 33 Yorio AA, Mesri JC, Pagano MA, Lera G. Stereotypies 49 Miller JM, Singer HS, Bridges DD, Waranch HR. in Wilson’s disease. Mov Disord 1997; 12:614–16. Behavioral therapy for treatment of stereotypic

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movements in nonautistic children. J Child Neurol 61 Winkler AS, Friedrich K, Konig R, et al. The head 2006; 21:119–25. nodding syndrome – clinical classification and possible 50 Fazzi E, Lanners J, Danova S, et al. Stereotyped behav- causes. Epilepsia 2008; 49:2008–15. iours in blind children. Brain Dev 1999; 21:522–8. 62 Anthony J, Ouvrier R, Wise G. Spasmus nutans, a 51 Kalapatapu RK. Escitalopram treatment of stereotypic mistaken entity. Arch Neurol 1980; 37:373–5. movement disorder in an adolescent with mitochon- 63 Weissman BM, Dell’Osso LF, Abel LA, Leigh RJ. drial disorder and mental retardation. J Child Adolesc Spasmus nutans. A quantitative propsective study. Psychopharmacol 2009; 19:313–16. Arch Ophthalmol 1987; 105:525–8. 52 Ferrara J, Jankovic J. Psychogenic movement 64 Gottlob I, Wizov S, Reinecke R. Spasmus nutans. disorders in children. Mov Disord 2008; 23:1875–81. A long-term follow-up. Invest Ophthalmol Vis Sci 53 Tan A, Salgado M, Fahn S. The characterization and 1995; 36:2768–71. outcome of stereotypical movements in nonautistic 65 Unsold R, Ostertag C. Nystagmus in suprasellar children. Mov Disord 1997; 12:47–52. tumors: recent advances in diagnosis and therapy. 54 Jankovic J. Treatment of hyperkinetic movement Strabismus 2002; 10:173–7. disorders. Lancet Neurol 2009; 8:844–56. 66 Kim JS, Park SH, Lee KW. Spasmus nutans and 55 Bejjani B, Damier P, Arnulf I, et al. Pallidal stimulation congenital ocular motor apraxia with cerebellar for Parkinson’s disease. Two targets? Neurol 1997; vermian hypoplasia. Arch Neurol 2003; 60:1621–4. 49:1564–9. 67 Kiblinger GD, Wallace BS, Hines M, Siatkowski RM. 56 Kanazawa O. Shuddering attacks-report of four Spasmus nutans-like nystagmus is often associated children. Pediat Neurol 2000; 23:421–4. with underlying ocular, intracranial, or systemic 57 Holmes G, Russman B. Shuddering attacks. Evaluation abnormalities. J Neuroophthalmol 2007; 27:118–22. using electroencephalographic frequency modulation 68 Arnoldi K, Tychsen L. Prevalence of intracranial radiotelemetry and videotape monitoring. Amer J Dis lesions in children initially diagnosed with disconjugate Child 1986; 140:72–3. nystagmus (spasmus nutans). J Pediatric Ophthalmol 58 Pachatz C, Fusco L, Vigevano F. Benign myoclonus of Strabismus 1995; 32:296–301. early infancy. Epilep Disord 1999; 1:57–62. 69 Vanasse M, Bedard P, Andermann F. Shuddering attacks 59 Nellhaus G. Abnormal head movements of young in children: an early clinical manifestation of essential children. Dev Med Child Neurol 1983; 25:384–9. tremor. Neurol 1976; 26:1027–30. 60 DiMario FJ. Childhood head tremor. J Child Neurol 2000; 15:22–5.

Albanese_c22.indd 362 12/24/2011 8:52:51 PM CHAPTER 23 Paroxysmal Dyskinesias Miryam Carecchio,1,2 João Massano,1,3 and Kailash P. Bhatia1 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK 2 Department of Neurology, Amedeo Avogadro University, Novara, Italy 3 Department of Neurology, Hospital de S. João, and Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, Porto, Portugal

Paroxysmal kinesigenic dyskinesia Video 23.1 Infantile paroxysmal kinesigenic dyskinesia Historical background This is a 7-month-old child with early onset paroxysmal In 1901 Gowers described choreoathetotic attacks kinesigenic dyskinesias. He is taken while playing with triggered by sudden movement without loss of a toy. Paroxysmal dystonia is induced by the voluntary consciousness [1], but considered them to be an movement of pushing the toy button. [Video courtesy epileptic phenomenon. An even earlier description of Nardo Nardocci, MD, Milan, Italy] exists, by Shuzo Kure (1892), who reported a 23-year-old man with brief episodes of involuntary movements triggered by sudden movement. Given the absence of previous reports at that time, the Japanese physician made a diagnosis of “atypical” myotonia congenita [2]. The term “paroxysmal kinesigenic dyskinesia” http://bit.ly/tETZw4 (PKD) was first coined in 1967 [3] when Kertesz reported 10 new cases and reviewed 31 cases from The typical trigger of the attacks is a sudden the literature. movement, such as standing up from a sitting or lying position, but also the simple intention to Phenomenology and other clinical move or focal movements of the limbs can trigger an features attack. Other rare precipitants include menstruation, The current diagnostic criteria for PKD include an cold weather, humidity, hunger, external motion, identified kinesigenic trigger, short duration of and startle. attacks (<1 minute), and no loss of consciousness A premonitory sensation preceding the attacks or pain during the attacks. Interictal neurologic (aura) is reported in up to 82% of cases [4]. examination is normal and attacks are well Typically, it is a general feeling of malaise, but also controlled with phenytoin or carbamazepine [4]. focal numbness and tingling of the extremities can The age of onset is between 1 and 20 years and a be felt before the attacks; some patients can abort higher prevalence in males has been reported an attack, avoiding the movement when they feel (up to 8:1) [5–7]. the premonitory sensation.

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Video 23.2 Paroxysmal kinesigenic Video 23.3 Autosomal dominant dyskinesia while standing paroxysmal kinesigenic This patient presents paroxysmak kinesigenic dyskinesia dyskinesias of the trunk, neck and upper limbs while This young patient with paroxysmal kinesigenic standing. EEG is recorded during videotaping. [Video dyskinesias has a positive family history with autosomal courtesy of Nardo Nardocci, MD, Milan, Italy] dominant transmission. The video shows an episode of paroxysmal dyskinesias that the young boy manages by playing with his hands against the wall. As soon as the episode is over, he starts walking normally. [Video courtesy of Nardo Nardocci, MD, Milan, Italy]

http://bit.ly/tGgY2i

Clinically, attacks are characterized by dystonia http://bit.ly/s92SZK (the most common manifestation), chorea, ballismus, or a combination of these. Attacks are mostly unilateral, but can also be bilateral or alternating in distribution. Frequency ranges from a Video 23.4 Ballic paroxysmal kinesigenic few attacks per year to more than 40 per day. More dyskinesia than 50% of patients report a spontaneous remis- This patient presents ballic movements on the right sion or significant reduction in the frequency after hand side induced by voluntary movements and by the age of 20 years [4]. Attacks last less than 1 walking. [Video courtesy of Nardo Nardocci, MD, Milan, Italy] minute in most cases but a duration of up to 5 minutes has been reported. Unlike epileptic seizures, consciousness is always preserved during the episodes and there is no postictal confusion or drowsiness. However, speech disturbances (dysarthria or anarthria), probably related to facial involvement, can occur. http://bit.ly/rZUCJB Epidemiology PKD is a rare neurological disorder and the precise prevalence is unknown, although it is estimated found that 17/76 (22%) patients with paroxysmal at 1:150.000. dyskinesias had a secondary underlying cause [8]. Of these, only 2 had PKD and 5 had intermediate Etiology symptoms between PKD and PNKD. Secondary PKD can be primary or secondary. Most cases are causes of PKD include multiple sclerosis, vascular primary – either sporadic or familial. In a recent lesions, central or peripheral trauma and metabolic series, 67% of patients had a family history with decompensation [2] (see Box 23.1). Psychogenic an autosomal dominant pattern of inheritance, PKD have been reported as well [9]. sometimes with reduced penetrance [4]. Several patients with PKD also present infantile Secondary PKD, due to structural cerebral lesions convulsions (Infantile Convulsions and Choreo- or other identifiable causes, have been described athethosis, ICCA syndrome) and in 1997 a locus in in 7.6% of patients [6]. Blakeley and Jankovic the pericentromeric region of chromosome 16 was

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reported for the first time [10]. This linkage for the in the caudate nuclei has been reported [28]. In PKD and ICCA syndrome has subsequently been this regard, diffusion tensor imaging (DTI) showed confirmed by several groups to chromosome 16 ultrastructural abnormalities in the thalamus of 7 (DYT10) [11–13], although no genes have been PKD patients [29]. The exact neurophysiological identified so far [14]. ICCA and PKD are now mechanisms of PKD are still unknown but various believed to be different manifestations of the defects in cortical and spinal inhibitory mechanisms same disorder, given the overlap of the genetic have been described, including extended surround loci. Moreover, a Sardinian family with Rolandic inhibition (see [30] for review). epilepsy, paroxysmal exercise-induced dystonia, and writer’s cramp (RE-PED-WC) was also found Therapy to share the same locus on chromosome 16. Patients with PKD have a particularly good response A different locus (EKD2) on chromosome 16 has to low doses of carbamazepine (100–200 mg daily) been identified in an Indian family with PKD [15] or phenytoin. Other anticonvulsants (oxcarbazepine, and a British family not linked to either of these hydantoin, lamotrigine, topiramate) can also be loci has been described, providing evidence for a effective in reducing the number of attacks, which third locus (EKD3) [16]. Interestingly, some often completely cease after initiation of therapy. patients with episodic ataxia-1, caused by mutations in the KCNA1 gene on chromosome 12 encoding a potassium channel [17], can also present PKD Paroxysmal non-kinesigenic and the two conditions share several features, dyskinesia including age of onset, triggering factors, and duration of the attacks. Historical background In 1940 Mount and Reback reported the first Pathophysiology family with paroxysmal non-kinesigenic dyskinesia The paroxysmal nature of PKD attacks, along with (PNKD), calling it familial paroxysmal choreoathetosis. the frequent presence of an aura and the dramatic The patient described had attacks of involuntary response to anticonvulsants, led some to consider flexion of the arms and posturing of the legs lasting PKD as a form of reflex epilepsy arising from a up to 2 hours without loss of consciousness. Richards subcortical focus [18, 19], but surface EEG is and Barnet [31] introduced the term “paroxysmal usually normal during attacks and EEG changes dystonic choreoathetosis” for long-lasting attacks (rarely reported) are of a questionable significance not triggered by sudden movement; this definition [19–21]. An involvement of basal ganglia (BG) is was also used by Lance in 1977 [32]. The term supported by the observation that secondary PKD “ paroxysmal-non kinesigenic dyskinesia” was first occurs in conditions affecting the basal ganglia and used by Demirkiran and Jankovic [33] in the cur- response to levodopa has been described [22]. rently used classification of paroxysmal movement During attacks, accordingly, discharges from the disorders. caudate nucleus [23] as well as an increased metabolism in the BG with photon emission Phenomenology and other tomography (PET) [24] have been demonstrated. clinical features Furthermore, Single-photon emission computed PNKD is characterized by intermittent attacks tomography (SPECT) studies have shown an of dystonia, chorea, or ballismus involving the increased perfusion in the contralateral basal extremities, trunk, and face. A combination of ganglia [25] that normalizes between attacks and dystonia and chorea is the most frequent presenta- an ictal hyperperfusion has been detected in the tion [34]. Attacks mostly start in infancy and early thalamus [26]. On the other hand, a bilateral hypo- childhood with mean age at onset reported to be 12 metabolism in the ventral striatum has been shown years in a large review of cases [35] and 4 years in in late-onset PKD [27] and ictal hypoperfusion MR-1 gene mutation carriers (see “Etiology” below).

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Up to 41% of patients report an aura-like sensation Box 23.1 Secondary causes of paroxysmal (stiffening or numbness, internal feeling of anxi- dyskinesia ety) before the attacks [34] that typically last from 10 minutes to few hours. Frequency ranges from a • Multiple sclerosis few per year to several per day and tends to decrease • Stroke and TIAs (thalamus, putamen, medulla), moyamoya with aging and during pregnancy. Typically, attacks are triggered by coffee, alcohol, and emotional • Infections (CMV encephalitis, syphilis, HIV) stress; other precipitants include exercise, fatigue, • Central and peripheral trauma heat, hunger, and menstruation [34, 36, 37]. Sleep • Metabolic disorders (hypoglicemia, hyperglicemia, benefit (attack resolved if the patient goes to hypocalcemia) sleep) is reported by several patients (34, 38). • Migraine Consciousness is always preserved during the • Neurodegenerative diseases, such as Parkinson disease episodes and transient dysarthria and dysphagia and Fahr disease can be present during severe attacks. • Others: kernicterus, coeliac disease

Epidemiology Idiopathic (primary) PNKD is a rare disorder and its Pathophysiology exact prevalence is unknown. However, familial The pathophysiology of PNKD remains controver- cases are more frequent than the sporadic ones. sial. The gene MR-1 encodes MR-1, a protein PNKD was described in 52% of patients with expressed in three different isoforms (MR1-1L, secondary paroxysmal dyskinesias reported by MR-1M, MR-1S) by alternative splicing. MR-1L is Blakeley and Jankovic [8]. specifically expressed in the brain and is homologous to hydroxyacylglutathione hydrolase, an enzyme Etiology involved in the detoxification of methylglyoxal, a by- Primary PNKD is transmitted as an autosomal product of oxidative stress also found in coffee and dominant trait with a 98% penetrance [34]. In 2004, tea, thus a mechanism whereby alcohol, caffeine, or two disease-causing missense mutations in the stress may precipitate attacks has been suggested myofibrillogenesis regulator-1 gene (MR-1, also [40]. According to recent findings, MR-1L and MR-1S referred to as PNKD or DYT8) on chromosome 2 are proteins imported into mitochondria through a were found in patients with familial PNKD [39, 40]. mitochondrial targeting sequence that contains the These have been confirmed in other families [34] mutations discovered so far [41]. However, the exact and recently another mutation in the same gene function of the protein and its role in neuronal excit- has been reported [41]. A second locus (PNKD2) ability as well as the mechanisms by which MR-1 has been described on chromosome 2q31 in a mutations cause PNKD remain unknown. Canadian family but no gene has been identified. Alterations of the basal ganglia, such as striatal Affected subjects of this family differ from those dopaminergic dysfunction, have been postulated as with MR-1 mutations in that coffee and alcohol an underlying mechanism but 11C-dihydro- do not trigger attacks [42]. MR-1 mutation carriers tetrabenazine PET imaging failed to reveal an abnor- show a homogeneous clinical phenotype and mal binding, thus ruling out an altered density of specific diagnostic criteria to individuate these nigrostriatal innervation [46]. On the other hand, a subjects have been proposed [34]. marked reduction in the density of postsynaptic Secondary causes of PNKD include stroke, central dopamine D2 receptors has been shown by 18F-dopa and peripheral trauma, kernicterus, multiple sclerosis, PET and 11C-raclopride PET [47]. Moreover, ictal hypoglycemia, encephalitis [8], Fahr disease [43], SPECT showed hyperperfusion on the right caudate and coeliac disease [44]. Psychogenic PNKD must and thalamus of a patient with PNKD, supporting the also be taken into account [32, 45] (see Box 23.1). notion that the basal ganglia are the anatomical

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substrate of this disorder [48]. Finally, a mutation in and sleep deprivation, as reported for GLUT1 KCNMA1 on chromosome 10q22 encoding a calcium- gene-mutated patients (see “Etiology” below) [54]. activated potassium channel has been identified in a Alleviating factors encompass eating (especially family with various combinations of epileptic seizures sugar) and rest. Mean age of onset is 8 years (range and PNKD [49]. 3 to 30 years). The attacks last minutes to hours with a median duration of 15 minutes. Dystonia of Treatment the exercised limb with distal involvement (feet Although PNKD has been traditionally considered and hands) is the most common presentation, difficult to treat, in contrast to the dramatic sometimes spreading to the adjacent muscles. response of PKD to anticonvulsants, Bruno, et al. Chorea affecting axial and orobuccal muscles has [34] reported that 97% of MR-1 mutated patients also been reported [55]. Episodes are mostly sym- responded to benzodiazepines (clonazepam, metrical but can be unilateral, with a frequent diazepam), while antiepileptic drugs (valproate, hemidystonic presentation [7]. Frequency of the carbamazepine, phenytoin) were less effective. attacks varies from daily to monthly. Autonomic MR-1 negative patients tend to have a partial symptoms (sweating, pallor, hyper ventilation), an response either to benzodiapzepine or to anticon- uncomfortable epigastric sensation, anxiety, and vulsants. Lorazepam has been reported to abort paresthesias are reported by some patients prior to the attacks within 5 minutes from onset if the onset of the attacks. Neurological examination administered sublingually [50]. Deep brain stimula- is normal between attacks, although interictal tion (DBS) of the ventrointermediate thalamus and myoclonus and dystonia have been described [56]. of the internal globus pallidus has been successful in PED can be isolated or part of more complex phe- 2 cases of secondary PNKD [51, 52]. Bilateral inter- notypes, including various combination of epilepsy, nal globus pallidus DBS was successful in a case of hemolytic anemia, ataxia, spasticity, cognitive primary PNKD who, however, also had other problems, migraine, and other interictal movement neurological and psychiatric features [53]. disorders (dystonia, tremor, myoclonus) with different degrees of severity (see [55] and [57] for Paroxysmal exercise-induced reviews). diskynesia

Historical background Video 23.5 GLUT1 deficiency In his classification of paroxysmal movement This patient has a GLUT1 deficiency syndrome. Segment disorders, Lance defined an intermediate form 1 shows the patient at age 19 years presenting with including attacks lasting 5 to 30 minutes that dysarthria, ataxia, hyperreflexia in lower limbs, and mild choreoathetoid movements of arms. Segment 2 shows were triggered by continuous exertion rather than the patient during an exercise-induced paroxysmal sudden movement [32]. The term “paroxysmal dyskinesia, characterized by dystonic posturing of legs exertion-induced dyskinesia” (now named paroxysmal and trunk and choreoathetoid movements of arms. The exercise-induced dyskinesia, PED) was first used case has been previously reported [58]. [Video courtesy in Demirkiran and Jankovic’s classification in of Nardo Nardocci, MD, Milan, Italy] 1995 [33].

Phenomenology and other clinical features PED is characterized by dyskinesias induced by prolonged exercise of 15- to 60-minute duration. http://bit.ly/sMAGop Other precipitating factors include stress, starvation,

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ganglia dysfunction. This hypothesis is supported Epidemiology by PET studies showing thalamocortical and PED is a rare disorder with unknown prevalence cerebellar hypometabolism and increased metabo- and incidence, and cases reported worldwide are lism in the putamen [54, 61]. Ictal SPECT has biased by the awareness of the disorder. Incidence/ shown hyperperfusion of the putamen and leg prevalence of GLUT1 deficiency in Queensland, cortical areas [54]. EEG is generally normal during Australia, has been estimated at approximately attacks. 1:90.000 by Coman, et al. [58].

Treatment Etiology Beneficial effect of a ketogenic diet (high fat, low Most cases of PED are primary, familial or sporadic. carbohydrate) has been noted. Ketones produced PED can also be secondary to different underlying through fatty acid oxidation, in fact, can cross the conditions, including peripheral trauma, Dopa- BBB providing an alternative energy substrate responsive dystonia, Parkinson’s disease [59, 60]. for brain metabolism. Ketogenic diet markedly In Parkin mutations carriers PED can be the improves seizures and complex motor disorders in presenting symptom (see Box 23.1). the classical GLUT1 deficiency syndrome [57]. Its Recently, mutations in SCLA1 (DYT18) have been effect on PED is variable, ranging from complete identified in patients with PED alone or in combi- remission of symptoms [54, 61] to no improve- nation with epilepsy and hemolytic anemia ment, although a general improvement of gait has [54, 61], with some patients exhibiting a mild men- been observed in a recent series [55]. tal retardation. SCLA1 encodes the glucose transporter type 1 (GLUT1), expressed in red blood cells and in the blood–brain barrier (BBB). Mutations in this gene are now thought to be responsible for Other paroxysmal movement a spectrum of disorders with different degrees disorders of severity, ranging from the so-called GLUT1 deficiency syndrome (epilepsy, deceleration of head Episodic ataxias The first cases of familial periodic ataxia were growth, developmental delay, spasticity, dystonia probably reported in 1946 by Parker; in the 1990s and ataxia) described by De Vivo in 1991 [62] to the first gene locus of an episodic ataxia (EA) was pure PED [57]. SCLA1 mutations are inherited as an mapped to chromosome 12p. EAs are characterized autosomal dominant trait; penetrance is generally by intermittent attacks of ataxia and vertigo [63] complete but 3 unaffected carriers have been and are infrequent autosomal dominant disorders reported [54]. with unknown prevalence. EA2 is the most The absence of SCLA1 mutations in some familial frequent form, followed by EA1. Ictal and interictal cases suggests the involvement of other genes in myokymia is a hallmark of EA1. Interictal nystag- the pathogenesis of PED. mus and slowly progressive ataxia are common in EA2, that is allelic with Familial Hemiplegic Pathophysiology Migraine type 1 and Spinocerebellar Ataxia type 6, Reduced transport of glucose across the BBB when explaining the frequent clinical overlap [63, 64]. the energy demand of the brain overcomes its A comparative summary of EAs is shown in supply after prolonged exertion is thought to be Table 23.1. the pathophysiological mechanism responsible for Other causes of paroxysmal ataxia: intermittent the attacks in SCLA1 mutation carriers; accordingly, attacks of ataxia have been reported in multiple patients display hypoglycorrhachia and a reduced sclerosis [66–68], Behçet disease [69], Hartnup CSF/serum glucose ratio. A decreased availability disease [70], maple syrup urine disease [71], and of glucose could thus result in a transient basal pyruvate decarboxylase deficiency [72, 73].

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Table 23.1 Primary episodic ataxias: summary of characteristics.

Locus, gene Age of Typical Triggers Ictal features Interictal features Effective onset duration of treatment (years) attacks

EA1 12p13, 2–15 Seconds to Stress, startle, Ataxia, vertigo, dizziness, Myokymia, sometimes Acetazolamide, KCN1A minutes fatigue, hunger, dysarthria, head titubation, seizures carbamazepine, exertion, sudden tremor, oscillopsia, diplopia, valproic acid movement nausea, headache, myokymia EA2 19p13, 2–20 Hours Anxiety, exercise, Ataxia, vertigo, nausea, Nystagmus, progressive Acetazolamide, CACNA1A heat, fever migraine cerebellar ataxia 4-aminopiridine EA3 1q42 1–42 1 minute to Stress, exertion, Ataxia, vertigo, tinnitus, Congenital nystagmus, Acetazolamide 6 hours fatigue, head nausea, visual blurring, coloboma, seizures movements, headache, diplopia, bending, arousal myokymia from sleep EA4 Unknown 23–60 Minutes Sudden change in Ataxia, vertigo, diplopia Defective smooth pursuit, Acetazolamide is head position, gaze-evoked nystagmus unhelpful fatigue EA5 2q22–23, 20–30 Hours None reported Ataxia, vertigo Downbeat and gaze- Acetazolamide CACNB4 evoked nystagmus, mild (transient dysarthria, ataxia benefit) EA6 5p, SLC1A3 Months to Hours to Fever, stress, Hypotonia (infancy), ataxia, Ataxia, hyperreflexia Acetazolamide 14 years days fatigue, exercise, slurred speech, diplopia, alcohol, caffeine blurred vision, alternating hemiplegia, aphasia, seizures, migraine, nausea, phonophobia, photophobia, fluctuating alertness EA7 19q13 <20 Hours Exercise, Ataxia, vertigo, dysarthria, None None reported excitement weakness LOHEA Unknown 48–56 1 minute to Coffee, alcohol, Ataxia, vertigo, diplopia, Progressive ataxia, Poor response 2 hours emotion, overwork, slurred speech nystagmus, cerebellar to acetazolamide head movements atrophy in MRI 22/0173:6AM 7:34:16 12/24/2011 7:34:16AM 370 Chapter 23

Psychogenic paroxysmal movement Video 23.6 Paroxysmal dyskinesia in disorders (P-PMDs) patient with cerebral palsy Classical clues pointing to a diagnosis of a psychogenic This patient has generalized paroxysmal kinesigenic movement disorder (abrupt onset, intermittent dyskinesias secondary to cerebral palsy. The video shows symptoms, variability) can all occur in organic PMDs, that movements prevalently affect the lower limbs and making the diagnosis challenging. Other information the right upper limb and are activated by voluntary may be particularly useful for a positive diagnosis of movement and standing. [Video courtesy of Nardo a P-PMD, for instance secondary gain (e.g. litigation), Nardocci, MD, Milan, Italy] distractibility, other physical findings (e.g. give-way weakness), and improvement or remission with suggestion, placebo or psychotherapy [74, 75].

Other episodic disorders that can be confused with paroxysmal http://bit.ly/vq3MnA movement disorders

Epileptic disorders Tonic spasms Epileptic disorders with motor manifestation should They consist of intermittent uni- or bilateral be considered in the differential diagnosis of PxD, dystonic posturing usually lasting less than 2 especially when consciousness is preserved during the minutes, occurring in a stereotyped fashion in each motor events. Juvenile myoclonic epilepsy is charac- patient, sometimes several times per hour; pain terized by myoclonic jerks especially in the upper often coexists (painful tonic spasms). Preceding limbs appearing upon awakening. These patients auras are common, and triggers include movement, occasionally drop objects, thus being labeled as clumsy hyperventilation and emotions. Tonic spasms have [76]. Focal motor seizures are also a possible differen- been mainly reported in multiple sclerosis. tial diagnosis of paroxysmal dyskinesias [77]. Symptoms are thought to result from ephaptic The so called hypnogenic paroxysmal dyskinesias are spreading of spontaneous discharges originating now recognized as part of the nocturnal frontal from demyelinated axons in various locations along lobe epilepsy (NFLE) spectrum. Attacks occur at the motor pathway. Corticosteroids and carbamaz- night and are characterized by tonic and dystonic epine have been used for the treatment [81, 82]. postures of the limbs, trunk, pelvis, sometimes accompanied by vocalizations and automatisms. An Superior oblique muscle (SOM) myokymia autosomal dominant family history is frequently They consist in sudden, intermittent, involuntary, observed and mutations in CHRNA3, CHRNA5, and unilateral SOM contractions and corresponding eye CHRNB4, encoding α3, α5, and β4 subunits of the movements, usually lasting seconds, resulting in nicotinic acetylcholine receptor have been reported oscillopsia or vertical diplopia. Patients complain of in familial and sporadic cases [78]. “jumpy”, “shaky” or “vibrating” vision. Many cases are idiopathic, but vessels contacting the trochlear Limb-shaking transient ischemic attacks nerve have also been found [83]. Carbamazepine Shaking movements of an arm or leg resembling and propranolol are usually effective [84]; success focal motor seizures can occur in contralateral with memantine has also been reported. Surgery transient brain ischemia (carotid stenosis or occlu- has been beneficial in severe refractory cases [85]. sion [79], Moyamoya disease [80]), without EEG abnormalities. Accurate diagnosis is mandatory, Disorders of infancy and childhood since adequate investigation, treatment, and Benign paroxysmal torticollis of infancy (BPTI) is char- preventive measures are warranted. acterized by torticollis, head tilting, and occasional

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retrocollis with ipsilateral trunk bending. Age at and unproductive diagnostic efforts. The episodes onset is before 9 months, and spontaneous are fairly stereotyped, with the child exerting remission occurs around 3 years in most children. pressure on the perineum or suprapubic area, BPTI is infrequent (1% of all cases of primary accompanied by typical lower limb posturing torticollis), but it is probably underdiagnosed. Some and rhythmic pelvic movements; facial flushing, patients have motor delay; a family history of diaphoresis and grunting are common, but genital migraine is frequent. There is no known effective manipulation is rare. Age of onset ranges from 3 therapy, but the condition is self limited [86, 87]. months to 3 years. No impairment of consciousness is observed, interruption of behavior occurs with Sandifer syndrome (SS), named after the neurologist distraction, and the examination is normal [94, 95]. Paul Sandifer, was first reported by Kinsbourne in the 1960s. It is an uncommon and probably under-recognized disorder encompassing gastroe- Conclusion sophageal reflux (GER) and paroxysmal abnormal movements of the head, eyes, neck, and trunk. Paroxysmal dyskinesias are uncommon hereditary These movements include ocular and cephalic disorders. Three major syndromes are now recog- version, head tilting, torticollis, retrocollis, and nized: PKD, PNKD, and PED. A causative gene has trunk dystonia. Irritability and crying usually been found for two of these. A number of other accompany the episodes, which may occur several disorders that manifest intermittently with motor times a day. Sandifer syndrome is more common in disturbance are important to be considered in the young males (2 months to 5 years); motor growth differential diagnosis. Management and prognosis retardation was found in some patients, but normal of each disorder specified in this text is quite differ- neurological examination is the rule. Treatment of ent, rendering diagnostic accuracy imperative. GER generally leads to improvement of abnormal movements [88, 89].

Paroxysmal tonic upgaze (PTU) of childhood is an References uncommon condition usually emerging before 1 year of age and remitting by 5 years, character- 1 Gowers WR (1901) Epilepsy and Other Chronic ized by involuntary tonic upward ocular deviations, Convulsive Diseases; Their Causes, Symptoms and Treatment. JAMA; XXXVII (13):848. associated with compensatory neck flexion and 2 Kure S (1892) An atypical case of Thomsen’s disease. downbeating saccades when attempting downgaze. Tokyo Igakukai Zasshi 6:505–14. Fever triggers the episodes and sleep provides 3 Kertesz A (1967) Paroxysmal kinesigenic choreoatheto- relief. Ataxia and mild developmental cognitive sis. An entity within the paroxysmal choreoathetosis difficulties can be present. Differential diagnosis syndrome. Description of 10 cases, including 1 includes iatrogenic oculogyric crisis, brainstem autopsied. Neurol 17:680–90. lesions, epileptic events [90], but consciousness is 4 Bruno MK, Hallett M, Gwinn-Hardy K, et al. (2004) unimpaired; cases associated with absence epilepsy Clinical evaluation of idiopathic paroxysmal kinesigenic have been reported [91, 92]. A two-generation dyskinesia: new diagnostic criteria. Neurol 28: family has been described with individuals affected 2280–87. by either PTU, EA or BPTI, and one patient with 5 Houser MK, Soland VL, Bhatia KP, et al. (1999) Paroxysmal kinesigenic choreoathetosis: a report of 26 both PTU and EA; a point mutation in CACNA1A patients. J Neurol 246:120–6. gene was found [93]. Levodopa is helpful in some 6 Nagamitsu S, Matsuishi T, Hashimoto K, et al. (1999) cases [90]. Multicenter study of paroxysmal dyskinesias in Japan- clinical and pedigree analysis. Mov Disord 14:658–63. Childhood masturbation is a normal behavior that 7 Bhatia KP (1999) The paroxysmal dyskinesias. J Neurol may resemble a PMD, sometimes prompting long 246:149–55.

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8 Blakeley J, Jankovic J (2002) Secondary paroxysmal 22 Marsden CD, Obeso Ja, Zarranz JJ, et al. (1985) The dyskinesias. Mov Disord 17, 726–34. anatomical basis of symptomatic dystonia. Brain 9 Baik JS, Han SW, Park JH, et al. (2009) Psychogenic 198:463–483. paroxysmal dyskinesia: the role of placebo in the diag- 23 Lombroso CT (1996) Paroxysmal choreoathetosis: an nosis and management. Mov Disord. 15, 1244–5. epileptic or nonepileptic disorder? Ital J Neuro Sci 10 Szepetowski P, Rochette J, Berquin P, et al. (1997) 16:271–7. Familial infantile convulsions and paroxysmal choreo- 24 Perlmutter JS, Raichle ME (1984) Pure hemidystonia athetosis: a new neurological syndrome linked to the with basal ganglion abnormalities on positron emis- pericentromeric region of human chromosome 16. sion tomography. Ann Neurol 15:228–33. Am J Hum Genet 61, 889–98. 25 Ko CH, Kong CK, Ngai WT, et al. (2001) Ictal (99m)Tc 11 Swoboda KJ, Soong BW, McKenna C, et al. (2000) ECD SPECT in paroxysmal kinesigenic choreoathetosis. Paroxysmal kinesigenic dyskinesia and infantile con- Pediatr Neurol 24: 225–7. vulsions. Clinical and linkage studies. Neurology 55, 26 Shirane S, Sasaki M, Kogure D, et al. (2001) Increased 224–30. ictal perfusion of the thalamus in paroxysmal kinesigenic 12 Lee WL, Tay A, Ong HT, et al. (1998) Association of dyskinesia. J Neurol Neurosurg Psychiat 71:408–10. infantile convulsions with paroxysmal dyskinesias 27 Iwasaki Y, Nakamura T, Hamada K (2004) Late-onset (ICCA syndrome): confirmation of linkage to human of idiopathic paroxysmal kinesigenic choreoathetosis: chromosome 16p12-q12 in a Chinese family. Hum a case report. Rinsho Shinkeigaku 44:365–8. Genet 103:608–12. 28 Joo EY, Hong SB, Tae WS, et al. (2005) Perfusion 13 Bennett LB, Roach ES, Bowcock AM (2000) A locus abnormality of the caudate nucleus in patients with for paroxysmal kinesigenic dyskinesia maps to human paroxysmal kinesigenic choreoathetosis. Eur J Nucl chromosome 16. Neurology 54, 125–30. Med Mol Imag 32:1205–9. 14 Kikuchi T, Nomura M, Tomita H, et al. (2007) Paroxysmal 29 Zhou B, Chen Q, Gong Q, et al. (2010) The thalamic kinesigenic choreoathetosis (PKC): confirmation of ultrastructural abnormalities in paroxysmal kinesigenic linkage to 16p11–q21, but unsuccessful detection of choreoathetosis: a diffusion tensor imaging study. mutations among 157 genes at the PKC-critical region in J Neurol 257:405–9. seven PKC families. J Hum Genet 52, 334–41. 30 Shin HW, Kang SY, Hallett M, et al. (2010) Extended 15 Valente EM, Spacey SD, Wali GM, et al. (2000) A second surround inhibition in idiopathic paroxysmal kinesi- paroxysmal kinesiogenic choreoathetosis locus (EKD2) genic dyskinesia. Clin Neurophysiol Mar 2. [Epub mapping on chromosome 16q13-q22.1 indicates a ahead of print] family of genes which give rise to paroxysmal disorders 31 Richards RN, Barnett HJ (1968) Paroxysmal dystonic in human chromosome 16. Brain 123:2040–45. choreoathetosis. A family study and review of the 16 Spacey SD, Valente EM, Wali GM, et al. (2002) Genetic literature. Neurol 18:461–9. and clinical heterogeneity in paroxysmal kinesigenic 32 Lance JW (1977) Familial paroxysmal dystonic chore- dyskinesia: evidence for a third EKD gene. Mov Disord oathetosis and its differentiation from related 17, 717–25. syndromes. Ann Neurol 2:285–93. 17 Browne DL, Gancher ST, Nutt JG, et al. (1994) 33 Demirkiran M, Jankovic J (1995) Paroxysmal Episodic ataxia/myokymia syndrome is associated dyskinesias: clinical features and classification. Ann with point mutations in the human potassium channel Neurol 38:571–9. gene, KCNA1. Nat Genet 8:136–40. 34 Bruno MK, Lee HY, Auburger GW, et al. (2007) 18 Fukuyama S, Okada R (1967) Hereditary kinesigenic Genotype–phenotype correlation of paroxysmal non- reflex epilepsy. Report of five families of peculiar kinesigenic dyskinesia. Neurol 68:1782–9. seizures induced by sudden movements. Adv Neurol 35 Fahn S (1994) The paroxysmal dyskinesias. In: Sci 11:168–97. Marsden, CD, Fahn S, eds. Movement Disorders 3. 19 Lishman WA, Symonds CD, Whitty CW, et al. (1987) Oxford: Butterworth-Heinemann, pp 310–45. Seizures induced by movement. Brain 85:93–108. 36 Fouad, GT, Servidei S, Durcan S, et al. (1996) A gene 20 Hirata K, Katayama S, Saito T, et al. (1991) Paroxysmal for familial paroxysmal dyskinesia (FPD1) maps to kinesigenic choreoathetosis with abnormal electroen- chromosome 2q.m. J Hum Genet 59:135–9. cephalogram during attacks. Epilepsia 32:492–4. 37 Matsuo, H., Kamakura, K., Saito, et al. (1999) Familial 21 Perez-Borja C, Tassinari AC, Swanson AG (1967) paroxysmal dystonic choreoathetosis: clinical findings Paroxysmal choreoathetosis and seizure induced by in a large Japanese family and genetic linkage to 2q. movement (reflex epilepsy). Epilepsia 8:260–70. Arch Neurol 56:721–6.

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38 Byrne E, White O, Cook M (1991) Familial dystonia 53 Kaufman CB, Mink JW, Schwalb JM (2010) Bilateral choreoathetosis with myokymia: a sleep responsive deep brain stimulation for treatment of medically disorder. J Neurol Neurosurg Psych 54,1090–2. refractory paroxysmal nonkinesigenic dyskinesia. 39 Rainier S, Thomas D, Tokarz D, et al. (2004) J Neurosurg 112:847–50. Myofibrillogenesis regulator 1 gene mutations cause 54 Suls A, Dedeken P, Goffin K, et al. (2008) Paroxysmal paroxysmal dystonic choreoathetosis. Arch Neurol exercise-induced dyskinesia and epilepsy is due to 61:1025–9. mutations in SLC2A1, encoding the glucose 40 Lee HY, Xu Y, Huang Y, Ahn AH, et al. (2004) The gene transporter GLUT1. Brain 131:1831–44. for paroxysmal non-kinesigenic dyskinesia encodes an 55 Pons R, Collins A, Rotstein M, et al. (2010) The spec- enzyme in a stress response pathway. Hum Mol Genet trum of movement disorders in GLUT1 deficiency. 13:3161–70. Mov Disord 15:275–81. 41 Ghezzi D, Viscomi C, Ferlini A, et al. (2009) Paroxysmal 56 De Grandis E, Mir P, Edwards MJ, et al. (2008) non-kinesigenic dyskinesia is caused by mutations of Paroxysmal dyskinesia with interictal myoclonus and the MR-1 mitochondrial targeting sequence. Hum dystonia: a report of two cases. Parkinsonism Relat Mol Genet 18:1058–64. Disord 14:250–2. 42 Spacey SD, Adam s PJ, Lam PC, et al. (2006) Genetic 57 Brockmann K (2009) The expanding phenotype of heterogeneity in paroxysmal nonkinesigenic GLUT1-deficiency syndrome. Brain Dev 31:545–52. dyskinesia. Neurology 66:1588–90. 58 Coman DJ, Sinclair KG, Burke CJ, et al. (2006) 43 Alemdar M, Selek A, Is¸eri P, et al. (2008) Fahr’s disease Seizures, ataxia, developmental delay and the presenting with paroxysmal non-kinesigenic dyskine- general paediatrician: glucose transporter 1 deficiency sia: a case report. Parkinsonism Relat Disord 14:69–71. syndrome. J Paediat Child Health 42:263–7. 44 Hall DA, Parsons J, Benke T (2007) Paroxysmal non- 59 Bozi M, Bhatia KP (2003) Paroxysmal exercise- kinesigenic dystonia and celiac disease. Mov Disord induced dystonia as a presenting feature of young- 15:708–10. onset Parkinson’s disease. Mov Disord 18:1545–7. 45 Bressman SB, Fahn S, Burke RE (1988) Paroxysmal 60 Bruno MK, Ravina B, Garraux G, et al. (2004) non-kinesigenic dystonia. Adv Neurol 50:403–13. Exercise-induced dystonia as a preceding symptom of 46 Bohnen NI, Albin RL, Frey KA, et al. (1999).(+)-alpha- familial Parkinson’s disease. Mov Disord 19:228–30. [11C]Dihydrotetrabenazine PET imaging in familial 61 Weber YG, Storch A, Wuttke TV, et al. (2008) GLUT1 paroxysmal dystonic choreoathetosis. Neurol mutations are a cause of paroxysmal exercise-induced 23:1067–9. dyskinesias and induce hemolytic anemia by a cation 47 Lombroso CT, Fischman A (1999). Paroxysmal non- leak. J Clin Invest 118:2157–68. kinesigenic dyskinesia: pathophysiological investiga- 62 De Vivo DC, Trifiletti RR, Jacobson RI, et al. (1991) tions. Epileptic Disord 1:187–93. Defective glucose transport across the blood–brain 48 del Carmen García M, Intruvini S, Vazquez S, et al. barrier as a cause of persistent hypoglycorrhachia, sei- (2000) Ictal SPECT in paroxysmal non-kinesigenic zures, and developmental delay. N Engl J Med 325: dyskinesia. Case report and review of the literature. 703–9. Parkinsonism Relat Disord 1:119–21. 63 Jen JC, Graves TD, Hess EJ, et al. (2007) Primary epi- 49 Du W, Bautista JF, Yang H, et al. (2005) Calcium- sodic ataxias: diagnosis, pathogenesis and treatment. sensitive potassium channelopathy in human epilepsy Brain 130:2484–93. and paroxysmal movement disorder. Nat Genet 64 Subramony SH, Schott K, Raike RS, et al. (2003) 37:733–8. Novel CACNA1A mutation causes febrile episodic 50 Dooley JM, Brna PM (2003) Sublingual Lorazepam in ataxia with interictal cerebellar deficits. Ann Neurol the treatment of familial paroxysmal non kinesigenic 54:725–31. dyskinesia. Pediatr Neurol 30:365–6. 65 Steckley JL, Ebers GC, Cader MZ, et al. (2001) An 51 Loher TJ, Krauss JK, Burgunder JM, et al. (2001) autosomal dominant disorder with episodic ataxia, Chronic thalamic stimulation for treatment of dystonic vertigo, and tinnitus. Neurol 57:1499–1502. paroxysmal nonkinesigenic dyskinesia. Neurol 66 Andermann F, Cosgrove JB, Lloyd-Smith D, et al. 56:268–70. (1959) Paroxysmal dysarthria and ataxia in multiple 52 Yamada K, Goto S, Soyama N, et al. (2006) Complete sclerosis; a report of 2 unusual cases. Neurol suppression of paroxysmal nonkinesigenic dyskinesia 9:211–15. by globus pallidus internus pallidal stimulation. Mov 67 Ostermann PO, Westerberg CE (1975) Paroxysmal Disord 21:576–9. attacks in multiple sclerosis. Brain 98:189–202.

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68 Twomey JA, Espir ML (1980) Paroxysmal symptoms 82 O’Connor AB, Schwid SR, Herrmann DN, et al. (2008) as the first manifestations of multiple sclerosis. Pain associated with multiple sclerosis: systematic J Neurol Neurosurg Psychiat 43:296–304. review and proposed classification. Pain 137:96–111. 69 Akman-Demir FG, Eraksoy M, Gurvit IH, et al. (1995) 83 Mikami T, Minamida Y, Ohtsuka K, et al. (2005) Paroxysmal dysarthria and ataxia in a patient with Resolution of superior oblique myokymia following Behçet’s disease. J Neurol 242:344–7. microvascular decompression of trochlear nerve. Acta 70 Baron DN, Dent CE, Harris H, et al. (1956) Neurochirurg (Wien) 147:1005–6. Hereditary pellagra-like skin rash with temporary 84 Williams PE, Purvin VA, Kawasaki A (2007) Superior cerebellar ataxia, constant renal amino-aciduria, oblique myokymia: efficacy of medical treatment. J and other bizarre biochemical features. Lancet 271: of AAPOS 11:254–7. 421–8. 85 Agarwal S, Kushner BJ (2009) Results of extraocular 71 Dancis J, Hutzler J, Rokkones T (1967) Intermittent muscle surgery for superior oblique myokymia. J of branched-chain ketonuria. Variant of maple-syrup- AAPOS 13:472–6. urine disease. New Engl J Med 276:84–9. 86 Drigo P, Carli G, Laverda AM (2000) Benign paroxys- 72 Lonsdale D, Faulkner WR, Price JW, et al. (1969) mal torticollis of infancy. Brain Devel 22:169–72. Intermittent cerebellar ataxia associated with 87 Rosman NP, Douglass LM, Sharif UM, et al. (2009) The hyperpyruvic acidemia, hyperalaninemia, and neurology of benign paroxysmal torticollis of infancy: hyperalaninuria. Pediat 43:1025–34. report of 10 new cases and review of the literature. J 73 Blass JP, Avigan J, Uhlendorf BW (1970) A defect in Child Neurol 24:155–60. pyruvate decarboxylase in a child with an intermittent 88 Kabakus N, Kurt A (2006) Sandifer Syndrome: a con- movement disorder. J Clin Invest 49:423–32. tinuing problem of misdiagnosis. Pediat Internat 74 Bhatia KP, Schneider SA (2007) Psychogenic tremor 48:622–5. and related disorders. J Neurol 254:569–74. 89 Lehwald N, Krausch M, Franke C, et al. (2007) Sandifer 75 Baik JS, Han SW, Park JH, et al. (2009) Psychogenic syndrome – a multidisciplinary diagnostic and thera- paroxysmal dyskinesia: the role of placebo in the diag- peutic challenge. Eur J Pediat Surg 17:203–6. nosis and management. Mov Disord 24:1244–5. 90 Ouvrier R, Billson F (2005) Paroxysmal tonic upgaze 76 Nordli DR, Jr (2005) Idiopathic generalized epilepsies of childhood – a review. Brain Devel 27:185–8. recognized by the International League Against 91 Luat AF, Asano E, Chugani HT (2007) Paroxysmal Epilepsy. Epilepsia 46(Suppl 9):48–56. tonic upgaze of childhood with co-existent absence 77 Crompton DE, Berkovic SF (2009) The borderland epilepsy. Epilept Disord 9:332–6. of epilepsy: clinical and molecular features of 92 Verrotti A, Di Marco G, la Torre R, et al. (2010) phenomena that mimic epileptic seizures. The Lancet Paroxysmal tonic upgaze of childhood and childhood Neurology 8:370–81. absence epilepsy. Eur J Paediat Neurol 14:93–6. 78 Derry CP, Duncan JS, Berkovic SF (2006) Paroxysmal 93 Roubertie A, Echenne B, Leydet J, et al. (2008) Benign motor disorders of sleep: the clinical spectrum and dif- paroxysmal tonic upgaze, benign paroxysmal torticol- ferentiation from epilepsy. Epilepsia 47:1775–91. lis, episodic ataxia and CACNA1A mutation in a fam- 79 Baquis GD, Pessin MS, Scott RM (1985) Limb ily. J Neurol 255:1600–2. shaking – a carotid TIA. Stroke 16:444–8. 94 Yang ML, Fullwood E, Goldstein J, et al. (2005) 80 Kim HY, Chung CS, Lee J, et al. (2003) Masturbation in infancy and early childhood Hyperventilation-induced limb shaking TIA in presenting as a movement disorder: 12 Cases and a Moyamoya disease. Neurol 60:137–9. review of the literature. Pediat 116:1427–32. 81 Tranchant C, Bhatia KP, Marsden CD (1995) 95 Mallants C, Casteels K (2008) Practical approach to Movement disorders in multiple sclerosis. Mov Disord childhood masturbation – a review. Eur J Pediat 10:418–23. 167:1111–17.

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Introduction young women are often thought to be particularly vulnerable to PMDs, the disorder certainly affects Psychogenic movement disorders (PMDs) are both genders and may be manifested even in caused by psychologic factors rather than by an children [6, 7]. Typically, patients are diagnosed by organic etiology. Other terms such as “functional,” the predominant movement feature, e.g. psycho- “non-organic,” and “medically unexplained genic tremor, psychogenic dystonia, psychogenic symptoms” have been used. Although the term myoclonus, etc. When categorized this way, tremor “functional” might be more convenient to convey is the most common psychogenic phenomenology, to patients and their families – because of old followed by dystonia (Table 24.1). stigmas regarding having a psychologic disorder – the term “psychogenic” describes the condition best because it places the emphasis on etiology and Diagnosis thereby guides the physician toward appropriate treatment. The term “functional” is ambiguous The diagnosis of a PMD is a two-stage process [8]. because it has been used in the past to denote First, the clinician makes a positive diagnosis that organic diseases in which a specific cause could not the movements are psychogenic and not due to an be determined, and to organic illnesses considered organic illness. The second step is to identify the physiologic rather than anatomic, such as chorea, nature of the psychiatric disorder that could explain epilepsy, and neuralgias [see historical reviews by the etiology of the abnormal movements and Fahn [1] and Munts and Koehler [2]. The terms prepare the way to deciding the best course for “organic” means “not due to a psychogenic or therapy of the individual patient. Deciding between voluntary mechanism.” Thus, non-organic refers to abnormal movements due to a psychogenic cause a psychogenic or voluntary etiology. A non- and an organic one can be extremely difficult. epileptic seizure is also being designated as psycho- Never having seen strange movements before and genic rather than the less satisfying term of pronouncing them to be psychogenic is insufficient pseudoseizure [3, 4]. and prone to error. Not even a senior movement PMDs are not uncommon. In one large movement disorder specialist who has seen a whole gamut of disorder clinic, such patients account for 10% of all organic abnormal movements has seen all there is. non-parkinsonian new patient visits [5]. Although An organic cause of the movements needs to be

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last item applies principally to the analysis of Table 24.1 Predominant movement feature in psychogenic movement disorders. myoclonus and tremor, since other movements can be easily duplicated by voluntary movements. Predominant movement feature N Percent Probable PMD. The movements are inconsistent

Tremor 467 37.5 over time or are incongruent but the other features Dystonia 365 29.3 listed above are lacking. Myoclonus 146 11.7 Possible PMD. Suspicion that the movements are Gait disorder 114 9.2 psychogenic and the presence of a definite psychi- Parkinsonism 60 4.8 atric disturbance. Tics 29 2.3 Other 64 5.1 Total 1,245 100 Psychiatric classification Data from Lang [13]. A tabulation of psychogenic movement disorders seen at eight centers; most centers In addition to the neurologist making the diagnosis report their patients by a single primary motor feature, of a PMD, the psychiatrist needs to evaluate the but some report multiple features if more than one is patient to explore psychodynamics and relevant present. environmental contingencies [8]. PMDs can be due excluded, but this alone is insufficient. Rather, the to one of the following three categories. diagnosis of a psychogenic disorder depends on Somatoform disorder. The physical symptoms are finding positive criteria and not simply the failure linked to psychological factors, yet the symptom to find an organic cause. production is not under voluntary control, i.e. not The degree of certainty that the abnormal consciously produced. The two main types of soma- movements are psychogenic in origin was first pro- toform disorders producing psychogenic neurologic posed by Fahn and Williams [9] and categorized problems are conversion disorder and somatization into four sections. disorder, the latter also being known as hysteria or Documented PMD. The movements are relieved Briquet syndrome. A somatization disorder involves by psychotherapy, by the clinician utilizing psy- recurrent and multiple complaints of several years chological suggestion including physiotherapy, or duration for which medical care has been sought, by administration of placebos, or the patient must but which are apparently not due to any physical be witnessed as being free of symptoms when left disorder. The dynamics are presumably the same as alone, supposedly unobserved. Surveillance those of conversion disorder and the symptoms monitoring has been utilized by insurance may emerge from chronic, recurrent, untreated companies to guard against fraudulent malinger- conversion disorder. It should be noted that ing [10], but this approach is rarely used by depression commonly accompanies somatoform clinicians. disorders. Clinically established PMD. The movements are Factitious disorder. The physical symptoms are inconsistent over time (i.e. the features are differ- intentionally produced (hence under voluntary ent when the patient is observed at subsequent control) due to psychological need. This group examinations) or are incongruent with a classical includes Munchausen syndrome. Factitious movement disorder. If only one of these is wit- disorders are due to a mental disorder. They are nessed, then one or more additional features are generally associated with severe dependent, maso- needed: fake weakness (i.e. give-way weakness), chistic, or antisocial personality disorders. false sensory findings, self-inflicted injuries, multi- Malingering. The physical symptoms are ple somatizations, deliberate slowness, excessive voluntarily produced in pursuit of a goal such as fatigue, movements disappear with distraction, or financial compensation, avoidance of school or electrophysiologic evidence that the movements do work, evasion of criminal prosecution, or acquisi- not fit with an organic pattern of movement. The tion of drugs. Malingering is not considered to be a

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Table 24.2 Movement disorders that are part of the Clues suggesting the presence of symptom complex of specific psychiatric disorders. a psychogenic movement disorder

Abnormal movements that Psychiatric disorder Often there are clues from the history and occur in specific psychiatric neurologic examination that lead the clinician to disorders suspect a diagnosis of a PMD. If present, these clues Psychomotor slowness Depression should alert the observant clinician to consider the Obsessional slowness Obsessive compulsive possibility that the abnormal movement could have disorder a psychogenic etiology. Compulsive movements Obsessive compulsive disorder Catatonia Schizophrenia, Historical depression 1 Abrupt onset Stereotypies Obsessive compulsive 2 Spontaneous remissions disorder, autism, 3 schizophrenia Onset after minor trauma 4 Fear of falling Anxiety, agoraphobia Multiple somatizations of undiagnosed conditions 5 Obvious psychiatric disturbances 6 Employed in the health profession or in health insurance claims mental disorder. It is listed as a PMD, not because of 7 Presence of secondary gain, including continuing a psychologic cause, but because it is voluntary and care by a “devoted” spouse not due to an organic cause. 8 Litigation or compensation pending Somatoform disorders are the most easily treated, while factitious disorders persist until the patient is psychologically ready to give up the Clinical examination abnormal movements. Malingering may be 1 Inconsistent movements (changing characteris- impossible to treat until the patient’s gain is tics over time; pattern, body distribution, rapidly obtained or the patient voluntarily gives up the varying severity) symptoms. 2 Incongruous movements and postures (move- In some psychiatric conditions, abnormal ments don’t fit with recognized patterns or with involuntary movements are part of the clinical normal physiological patterns spectrum. These abnormal movements should not 3 Presence of rhythmic shaking be considered as PMDs. Some of the movements 4 Bizarre gait including knee-buckling seen are not equivalent to abnormal movements 5 Deliberate slowness carrying out requested vol- that can be seen as part of some psychiatric untary movement condition. Table 24.2 lists some of these movement 6 Bursts of verbal gibberish difficulties seen as part of the psychiatric condition, 7 Delayed or excessive startle (bizarre movements such as stereotypies in schizophrenia or autism. in response to sudden, unexpected noise or threat- The condition of “fear of falling” has been ening movement). considered psychogenic [11]. But, patients with 8 Presence of additional types of abnormal move- this condition have usually fallen in the past and ments that are not known to be part of the primary now have a genuine fear of falling. It’s possible that or principal movement pattern that the patient the fear is excessive and is due to unrealistic manifests. anxiety. But in that situation, the condition is a 9 Manifesting exhaustion, excessive fatigue. psychiatric one and the gait disorder is not a 10 Movements decrease or disappear with conversion reaction. Thus, it seems reasonable to distraction consider the gait abnormality of “fear of falling” to 11 Disappearance of tremors when handling treas- be classified as a psychiatric disorder. ured objects

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12 Entrainment of the tremor to the rate of the Video 24.1 Psychogenic tremor requested rapid successive movement the patient is asked to perform. This 53 year old woman fell and hit her head 5 years earlier and one year later she was involved in motor 13 Response to placebo, suggestion or vehicle accident. Immediately after the accident, she psychotherapy developed involuntary spasms of her body. Patient says 14 Dystonia beginning as a fixed posture that she can suppress these movements sometimes. The 15 Manifestation as a paroxysmal disorder dramatic tremor is instantly relieved by pressure in a 16 Dystonia beginning as a rest dystonia or as a certain spot in left scapular area. [Video courtesy of Joseph Jankovic, MD, Houston, Texas] fixed posture 17 Twisting facial movements that move the mouth to one side or the other (Note: Organic dystonia of the facial muscles usually does not move the mouth sidewise, whereas organic jaw dystonia can move the jaw sidewise) 18 Fake weakness 19 False sensory complaints http://bit.ly/s40TmK 20 Self-inflicted injuries

This was the most common PMD diagnosis General clinical features reported by Lang [13] and by Jankovic and Thomas [14]. The tremor tends to be present equally at Besides the specificities of the abnormal movements rest, with posture holding and with action. there are some demographic features that have Distracting the patient with a disappearance of the been observed in patients with PMDs. In their tremor is a helpful sign that the tremor is psycho- review of 131 cases of documented or medically genic [15], but it is not specific enough. Many established PMDs, Williams and colleagues [12] patients with organic tremor can temporarily observed that: the mean age at onset was 36.9 years suppress the tremor, such as with parkinsonian (range: 4–73 years); the female gender predomi- tremor; furthermore, distractibility is often diffi- nates (87%); an organic component occurred in cult to observe. Many patients are sophisticated, 13%; 75% of cases had previously received an and it is difficult to eliminate their tremor with organic diagnosis; 79% had more than a single type distraction. Entrainment of the tremor to a new of abnormal movement; the movements were frequency may sometimes be seen by having the paroxysmal in 55%; onset was abrupt in 60%; and patient touch thumb to the different fingers in a symptoms spread from the original site to other dictated pattern either in the involved hand or in sites in 43%. They also reported that the psychiatric the opposite hand. Of 12 patients with psycho- diagnosis was conversion disorder in 75%, genic tremor compared to 33 with organic essen- somatization disorder in 12.5%, factitious disorder tial tremor studied by Kenney and colleagues [16], in 8.3%, and malingering in 4.2%. Depression was psychogenic tremor was significantly more likely seen in 71% and anxiety in 17%. to start suddenly and was more likely associated with spontaneous remissions compared to essential tremor. McKeon and colleagues [17] followed Psychogenic tremor up their 62 patients with psychogenic tremor; 33 responded over time. The outcome was good Rhythmical shaking occurs in the majority of (mild or no tremor) in 36%, moderate in 24%, patients with PMDs. When tremor is the only and severe in 40%. Five patients with the good abnormal movement or the predominant one, the outcome had spontaneous improvement without patient is classified as having psychogenic tremor. psychotherapy.

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duplicated voluntarily. Both organic and psycho- Video 24.2 Psychogenic tremor genic dystonia patients show a reduced cortical and 59 year old woman with history of congestive heart spinal inhibition [21–23]. However, cortical plas- failure, 200 lb weight loss and progressive fatigue, ticity has been found in organic dystonia, but not attributed to anemia and cervical and ovarian cancer. She developed episodes of full body jerking, excessive in psychogenic dystonia [23], and if this is repli- rapid flexion of her arms, legs, and neck. In addition she cated, testing for plasticity might turn out to be a has nearly constant shaking involving synchronously useful test. both legs. The tremor, however, has a variable For many years after dystonia was first described, frequency, is distractable, and markedly suppressible many cases had been considered psychogenic, 52% and stops completely after an application of a tuning fork She also exhibits bouncing gait and astasia-abasia. in the series by Eldridge et al. [24], 43% seen by All symptoms resolved with carbidopa, used as a Marsden and Harrison [25], 25% reported by placebo, but this was later fully disclosed to the patient, Cooper and his colleagues [26], and 44% in the and she has continued to benefit from it. [Video series by Lesser and Fahn [27]. With the wider courtesy of Joseph Jankovic, MD, Houston, Texas] recognition of dystonia by neurologists, and with the knowledge that most cases are primary, not secondary dystonia, it seems that psychogenic dystonia is currently underdiagnosed. The clinical clues listed above and reported by Fahn and Williams [9] should help the clinician to suspect psychogenic dystonia when it is encountered. http://bit.ly/vjOKyS Idiopathic torsion dystonia usually begins with action dystonia [28], but psychogenic dystonia often begins with a fixed posture. Fixed postures are Deuschl et al. [18] observed that finger tremor is sustained postures that resist passive movement, usually absent in psychogenic tremors. They also and the presence of such fixed postures are reported the “coactivation sign” in which psycho- highly likely to be due to a psychogenic dystonia genic tremors often show an increase of tremor [9, 29–31]. Fixed posture dystonia is rare and when amplitude, when a weight is applied to the involved encountered it is often psychogenic in origin; the limb. This contrasts to a reduction in tremor ampli- evaluation of fixed postures requires the aid of tude with applied weights in organic tremors. anesthesia to see if contractures are present [32]. Accelerometers applied to the affected body part The posture can manifest so much rigidity that it is can be helpful. Psychogenic tremors show larger extremely difficult to move the limb about a joint. tremor frequency changes and higher intraindivid- Often, such psychogenic fixed dystonia resembles ual variability while tapping [19]. Motor control reflex sympathetic dystrophy (complex regional physiology can be useful to distinguish psychogenic pain syndrome, CRPS) because there is accompany- from organic tremor [20]. ing pain, tenderness (allodynia) and skin changes [29–31, 33–36]. Nerve injury leading to pain, shiny red skin and fixed postures was called causalgia by Psychogenic dystonia Mitchell et al. [37]. Charcot [38] considered the disorder hysterical (see Munts and Koehler [2]). The Psychogenic dystonia is the second most common term “reflex sympathetic dystrophy” was coined by type of PMD. Psychogenic dystonia is difficult to Evans [39] because the phenotype could occur in diagnose since there are no laboratory tests, such the absence of trauma to a major nerve and might as EMG, to establish the diagnosis of organic be due to sympathetic nerves. “Complex regional primary idiopathic dystonia. Simultaneous con- pain syndrome “ was the recommended term in tractions of agonist and antagonist muscles, the 1994, with Type 1 being reflex sympathetic dystro- EMG hallmark for organic dystonia, can be easily phy and Type 2 being causalgia [40]. Some cases of

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Video 24.3 Psychogenic dystonia Video 24.4 Psychogenic myoclonus This patients is 58 years old. At age 50 she presented This is a 35-year-old woman, who acutely had onset of a sudden onset of headache, dysarthria, blurred vision left lower limb hyperkinetic disorder suddenly after a and deviation of the mouth. No laboratory surgical procedure to the left knee, which required investigations abnormalities were found and brain MRI epidural anesthesia. The hyperkinetic disorder had the was unremarkable. The symptoms persisted but were appearance of a pseudo-rhythmic jerky proximal inconsistent over time and periods of spontaneous movement, with bilateral spread and exacerbation remission were observed. One year later she developed during either passive or active mobilization. A clinical fixed dystonia of both lower limbs, started wearing diagnosis of possible psychogenic movement disorder orthopedic aids and using a wheelchair. She received a was made based on Fahn and Williams criteria [9]. The clinical diagnosis of probable psychogenic movement videotape shows irregular and jerky movements at rest, disorder. The videotape shows that the patient can walk with prevalence in the left limb. The involuntary without aid. When pulled, the patient walks forward. movement is accentuated when holding a posture. With She is able to stand up from the chair without using arm the patient sitting in her wheelchair there is a support and to sit back again without aid. [Video tremor-like appearance. The upper limbs are courtesy of Alberto Albanese, MD, Milan, Italy] unaffected. The patient stands easily from her wheelchair, but does not walk autonomously. [Video courtesy of Alberto Albanese, MD, Milan, Italy]

http://bit.ly/vmdLYD

http://bit.ly/trdIWV CRPS have been proven to be psychogenic; it’s possible that some cases are organic. This is a highly controversial topic. A recent proposal that small [50, 51]. The short duration of a myoclonic jerk fiber neuropathy might be responsible for CRPS (usually less than 100 ms) is almost impossible to [41] has been countered that the patient had the duplicate voluntarily. The EMG pattern of voluntary phenomenology of a psychogenic dystonia [42]. jerks exhibits a triphasic pattern of activity between To make matters confusing, sometimes organic antagonistic muscles, whereas cortical myoclonus dystonia of a body part can be preceded by an injury consists of short-duration 25–50 ms bursts of cocon- to that body part [43–47], so it can be difficult to tracting antagonist muscles [52]. Furthermore, the distinguish between organic and psychogenic dys- latency of reflex myoclonus is physiologically short tonia. Fixed painful postural torticollis following (40 to 100 ms) whereas abnormal reactive voluntary trauma is not uncommon, and determining whether jerks are much longer [52]. it is organic or psychogenic may be difficult [48]. In the 18 patients with psychogenic myoclonus The prognosis of fixed dystonia is often poor reported by Monday and Jankovic [50], the jerks [49], but it depends on recognizing this disorder as were segmental in 10, generalized in 7 and focal in likely to be a psychogenic one and then applying 1. Inconsistency with continuously changing pat- treatment according the principles described below. tern anatomically and temporally were common. The movements often increased with stress, anxiety, and exposure to noise or light. A Bereitschaftspotential Psychogenic myoclonus preceding muscle jerks was found in 5 of 6 patients with a diagnosis of psychogenic myoclonus [53]. Psychogenic myoclonus should be relatively easy to A case of propriopsinal myoclonus was presumed distinguish from organic myoclonus if access to a be of psychogenic etiology when it disappeared motor control physiology laboratory is available after some minor procedure [54].

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reported 14 patients with this disorder. Eleven had Video 24.5 Psychogenic gait disorder tremor at rest, but the tremor did not disappear 45 year old man with acute onset of right side with movement of the limb, and the frequency and weakness, extreme fatigue, and “confusion”. He exhibits psychogenic dysarthria, gait, athetosis, tremor, rhythmicity varied. Rigidity was present in 6 and dystonia, with marked distractibility. He responds to patients, but without cogwheeling. All 14 patients a self-induced sensory trick, tuning fork accompanied by had slowness of movement (bradykinesia) without a powerful suggestion. [Video courtesy of Joseph the typical decrementing feature of organic Jankovic, MD, Houston, Texas] bradykinesia. Dopaminergic SPECT imaging has helped to distinguish this diagnosis from pure psychogenic parkinsonism [59–61]. Besides tremor, dystonia, myoclonus, gait disorders. and parkinsonism, many other phenom- enologies, including tics and chorea [62] can present as PMD. http://bit.ly/uiRGKB

Psychogenic gait disorder Physiologic brain changes in psychogenic disorders An abnormal gait is a common feature in patients with a psychogenic movement disorder. Of 279 Mentioned above in the discussion of psychogenic patients with a PMD, 118 (42%) had an abnormal dystonia was the observation of abnormal cortical gait [55]. Of these, 102 (86%) had other psycho- and spinal inhibition in both psychogenic and genic movements. Slowing of gait (18.6%), organic dystonia. Abnormal neuroimaging has also dystonic gait (17.8%), bizarre gait (11.9%), asta- been found in psychogenic disorders, indicating sia–abasia (11.9%), and buckling of the knee that the brain may physiologically respond to the (7.6%) are the most common gait abnormalities abnormal disarray of motor function. Reduced when other abnormal psychogenic movements are regional cerebral blood flow and fMRI has been present. Among the pure psychogenic gait disorders, reported in psychogenic blindness [63] and sensory buckling of the knee was the most common feature loss [64, 65]. In one study utilizing fMRI, the right (31.3%), followed by astasia–abasia (18.8%). temporoparietal junction (TPJ) hypoactivity and In Keane’s report of 60 cases [56] with psycho- lower functional connectivity between the right genic gaits, the most common was “ataxia.” Others TPJ, sensorimotor regions, and limbic regions was had trembling, knee buckling, “dystonia,” truncal hypothesized to relate to the perception that the “myoclonus,” and camptocormia (markedly conversion movement is not self-generated [66]. stooped posture). In a video review of psychogenic gaits, Hayes and colleagues [57] emphasized certain features of the gait: exaggerated effort, extreme Treatment of psychogenic slowness, variability throughout the day, unusual movement disorders or uneconomic postures, collapses, convulsive tremors, and distractibility. On the other hand, it Treatment depends on a team approach between is possible to misdiagnose as psychogenic an neurologist, psychiatrist, and physiotherapist. abnormal gait that is organic. Having the patient accept the diagnosis is a major hurdle. Most patients are reluctant to accept the Psychogenic parkinsonism diagnosis of PMD, and it takes tact to explain this diagnosis, which should be told in a positive and Psychogenic parkinsonism is a rare cause of gentle manner. The neurologist should do all nec- parkinsonism, but it does occur. Lang et al, [58] essary and reasonable tests to feel comfortable and

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the neurologist who makes the diagnosis and rein- Video 24.6 Psychogenic tic disorder forces the benefits of the above treatments. After 22 year old woman with sudden-onset tic-like making the diagnosis the neurologist explains to movements about 8 months ago, precipitated by life the patient that s/he can get better only if he or she stressors such as a recent abortion. There are many features of a psychogenic movement disorder, including is willing to work hard with physiotherapy. The inducement of the movements (tics, shaking and neurologist plays the role of a “bad cop,” emphasiz- dystonia) with a tuning fork and a suggestion. [Video ing to the patient that improvement must be seen courtesy of Joseph Jankovic, MD, Houston, Texas] each day of treatment. This adds the onus to the patient to work with the therapies to show such improvement. The psychiatrist takes the “good cop” role and reinforces the need for improvement to please the neurologist and keep the neurologist involved. Such an approach between the neurologist and the psychiatrist can hasten improvement. http://bit.ly/sXGgGL Admitting the patient to the hospital is the best way to provide intensive physiotherapy and psychotherapy, with the patient seen each day by secure that an organic basis for the symptoms has the neurologist to keep emphasizing the treatment not been overlooked. and provide encouragement. Such encouragement When explaining the diagnosis to the patient, it is is important to keep the patient motivated. usually helpful to state firmly that he/she has a After the patient has improved, maintaining the movement disorder (specifically identify the disorder improvement is not always easy because the patient - e.g. dystonia, tremor, etc.). Then state that “such returns to the same environment that led to disorders are caused by many different etiologies. causation of the movement disorder. Continual Structural damage to the brain can be one cause, but psychotherapy will be necessary. that is not seen in your situation.” It is very helpful to use the analogy of a computer problem and explain that “instead of a hardware problem, you References have a software problem. The brain can react physiologically to stress to produce this type of 1 Fahn S. The history of psychogenic movement disorders. In Hallett M, et al. (eds). Psychogenic movement, which is the cause in your case.” Also Movement Disorders – Neurology and Neuropsychiatry, emphasize the positive news that “because the symp- Philadelphia, Lippincott Williams & Wilkins, 2006; toms are not due to a structural lesion, the chance pp 24–31. for reversing the abnormal physiology is great.” 2 Munts AG, Koehler PJ. How psychogenic is dystonia? Treatment is a three-pronged approach, with the Views from past to present. Brain 2010 May; 133 psychiatrist playing the major role with psycho- (Pt 5):1552–64. therapy and exploring the psychodynamics [67]. 3 Benbadis SR. Psychogenic nonepileptic “seizures” or A coexisting depression or anxiety should be “attacks”?: It’s not just semantics: Attacks. Neurol 2010 treated with appropriate pharmacotherapy. A Jul 6; 75(1):84–6. second prong is intensive physiotherapy, such 4 LaFrance WC Jr. Psychogenic nonepileptic “seizures” or as retraining an abnormal posture to restore it to “attacks”?: It’s not just semantics: Seizures. Neurol 2010 Jul 6; 75(1):87–8. its proper alignment, overcoming any weakness. If 5 Portera-Cailliau C, Victor D, Frucht SJ, Fahn S. there is excess startle, “desensitization” techniques Movement disorders fellowship training program at should be used. Use a gentle stimulus that doesn’t University Medical Center in 2001–2002. Mov Disord trigger the abnormal jerk, and then gradually 2006 Apr; 21(4):479–85. increase the strength of the stimulus until the jerks 6 Ferrara J, Jankovic J. Psychogenic movement disorders are no longer present. The third prong is the part of in children. Mov Disord 2008; 23(13):1875–81.

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7 Schwingenschuh P, Pont-Sunyer C, Surtees R, et al. 21 Espay AJ, Morgante F, Purzner J, et al. Cortical and Psychogenic movement disorders in children: a report spinal abnormalities in psychogenic dystonia. Ann of 15 cases and a review of the literature. Mov Disord Neurol 2006 May; 59(5):825–34. 2008; 23:1882–8. 22 Avanzino L, Martino D, van de Warrenburg BP, et al. 8 Williams DT, Ford B, Fahn S. Treatment issues in Cortical excitability is abnormal in patients with the psychogenic-neuropsychiatric movement disorders. “fixed dystonia” syndrome. Mov Disord 2008 Apr 15; Adv Neurol 2005; 96:350–63. 23(5):646–52. 9 Fahn S, Williams DT. Psychogenic dystonia. Adv 23 Quartarone A, Rizzo V, Terranova C, et al. Abnormal Neurol 1988; 50:431–55. sensorimotor plasticity in organic but not in psycho- 10 Kurlan R, Brin MF, Fahn S. Movement disorder in genic dystonia. Brain 2009 Oct; 132(Pt 10):2871–7. reflex sympathetic dystrophy: a case proven to be 24 Eldridge R, Riklan M, Cooper IS. The limited role of psychogenic by surveillance video monitoring. Mov psychotherapy in torsion dystonia. Experience with Disord 1997; 12:243–5. 44 cases. JAMA 1969; 210:705–8. 11 Kurlan R. “Fear of falling” gait: a potentially reversible 25 Marsden CD, Harrison MJG. Idiopathic torsion psychogenic gait disorder. Cogn Behav Neurol 2005 dystonia. Brain 1974; 97:793–810. Sep; 18(3):171–2. 26 Cooper IS, Cullinan T, Riklan M. The natural history 12 Williams DT, Ford B, Fahn S. Phenomenology and of dystonia. Adv Neurol 1976; 14:157–69. psychopathology related to psychogenic movement 27 Lesser RP, Fahn S. Dystonia: a disorder often disorders. Adv Neurol 1995; 65:231–57. misdiagnosed as a conversion reaction. Am J Psychiat 13 Lang AE. General overview of psychogenic movement 1978; 153:349–452. disorders: epidemiology, diagnosis, and prognosis. 28 Fahn S, Marsden CD, Calne DB. Classification and In Hallett M, et al. (eds). Psychogenic Movement investigation of dystonia. In Marsden CD, Fahn S Disorders – Neurology and Neuropsychiatry, (eds). Movement Disorders 2. London: Butterworths, Philadelphia, Lippincott Williams & Wilkins, 2006; 1987; pp 332–58. pp 35–41. 29 Lang A, Fahn S. Movement disorder of RSD. Neurol 14 Jankovic J, Thomas M. Psychogenic tremor and 1990; 40:1476–7. shaking. In Hallett M, et al. (eds). Psychogenic 30 Schrag A, Trimble M, Quinn N, Bhatia K. The Movement Disorders – Neurology and syndrome of fixed dystonia: an evaluation of 103 Neuropsychiatry. Philadelphia, Lippincott Williams & patients. Brain 2004; 127:2360–72. Wilkins, 2006; pp 42–7. 31 Schrag A. Psychogenic dystonia and reflex sympathetic 15 Campbell J. The shortest paper. Neurol 1979; dystrophy. In Hallett M, et al. (eds). Psychogenic 29:1633. Movement Disorders – Neurology and 16 Kenney C, Diamond A, Mejia N, et al. Distinguishing Neuropsychiatry. Philadelphia, Lippincott Williams & psychogenic and essential tremor. J Neurol Sci. 2007 Wilkins, 2006; pp 53–61. Dec 15; 263(1–2):94–9. 32 Fahn S. The role of anesthesia in the diagnosis and 17 McKeon A, Ahlskog JE, Bower JH, et al. Psychogenic treatment of psychogenic movement disorders. tremor: long-term prognosis in patients with In Hallett M, et al. (eds). Psychogenic Movement electrophysiologically confirmed disease. Mov Disord Disorders – Neurology and Neuropsychiatry, 2009 Jan 15; 24(1):72–6. Philadelphia, Lippincott Williams & Wilkins, 2006; 18 Deuschl G, Koster B, Lucking CH, Scheidt C. Diagnostic pp 256–61. and pathophysiological aspects of psychogenic trem- 33 Schwartzman RJ, Kerrigan J. The movement disorder ors. Mov Disord 1998; 13:294–302. of reflex sympathetic dystrophy. Neurol 1990; 19 Zeuner KE, Shoge RO, Goldstein SR, et al. Accelerometry 40:57–61. to distinguish psychogenic from essential or parkinso- 34 Bhatia KP, Bhatt MH, Marsden CD. The causalgia- nian tremor. Neurol 2003; 61(4):548–50. dystonia syndrome. Brain 1993; 116:843–51. 20 Deuschl G, Raethjen J, Kopper F, Govindan RB. The 35 Jankovic J. Peripherally induced movement disorders. diagnosis and physiology of psychogenic tremor. Neurol Clin 2009; 27:821–32. In Hallett M, et al. (eds). Psychogenic Movement 36 van Rooijen DE, Geraedts EJ, Marinus J, et al. Peri- Disorders – Neurology and Neuropsychiatry, pheral trauma and movement disorders: a systematic Philadelphia, Lippincott Williams & Wilkins, 2006; review of reported cases. J Neurol Neurosurg Psychiat pp 265–73. 2011 (in press).

Albanese_c24.indd 383 12/24/2011 7:35:41 AM 384 Chapter 24

37 Mitchell SW, Morehouse GR, Keen WW. Gunshot 53 Terada K, Ikeda A, Van Ness PC, et al. Presence of wounds and other injuries of nerves. Philadelphia: Bereitschaftspotential preceding psychogenic myo- JB Lippincott & Co., 1864. clonus: Clinical application of jerk-locked back aver- 38 Charcot JM. Hospice de la Salpêtrière. Clinique des aging. J Neurol Neurosurg Psychiat 1995; 58:745–7. maladies du système nerveux. Vol. 1. Paris: Progrès 54 Williams DR, Cowey M, Tuck K, Day B. Psychogenic Médical; 1892; p 95–116. propriospinal myoclonus. Mov Disord 2008 Jul 15; 39 Evans JA. Reflex sympathetic dystrophy. Surg Gynecol 23(9):1312–13. Obstet 1946; 82:36–43. 55 Baik JS, Lang AE. Gait abnormalities in psychogenic 40 Merskey H, Bogduk N. Relatively generalized syn- movement disorders. Mov Disord 2007 Feb 15; dromes. In Merskey H, Bogduk N (eds). Classification 22(3):395–9. of chronic pain. Description of chronic pain syndromes 56 Keane JR. Hysterical gait disorders: 60 cases. Neurol and definitions of pain terms. Seattle: IASP Press; 1989; 39:586–9. 1994; pp 40–3. 57 Hayes MW, Graham S, Helet al. A video review of the 41 Oaklander AL, Fields HL. Is reflex sympathetic dystro- diagnosis of psychogenic gait: Appendix and commen- phy/complex regional pain syndrome type I a small- tary. Mov Disord 1999; 14:914–21. fiber neuropathy? Ann Neurol 2009; 65:629–38. 58 Lang AE, Koller WG, Fahn S. Psychogenic parkinson- 42 Lang AE, Chen R. Dystonia in complex regional pain ism. Arch Neurol 1995; 52:802–10. syndrome type I. Ann Neurol 2010 Mar; 67(3):412–4. 59 Benaderette S, Fregonara PZ, Apartis E, et al. 43 Schott GD. The relation of peripheral trauma and pain Psychogenic parkinsonism: a combination of clinical, to dystonia. J Neurol Neurosurg Psychiat 1985; electrophysiological, and [(123)I]-FP-CIT SPECT scan 48:698–701. explorations improves diagnostic accuracy. Mov 44 Schott GD. Mechanisms of causalgia and related clinical Disord 2006 Mar; 21(3):310–317. conditions. The role of the central nervous and of the 60 Gaig C, Marti MJ, Tolosa E, et al. 123I-Ioflupane sympathetic nervous systems. Brain 1986; 109:717–38. SPECT in the diagnosis of suspected psychogenic 45 Scherokman B, Husain F, Cuetter A, et al. Peripheral Parkinsonism. Mov Disord 2006 Nov; 21(11):1994–8. dystonia. Arch Neurol 1986; 43:830–2. 61 Jankovic J. Psychogenic parkinsonism. J Neurol 46 Gordon MF, Brin MF, Giladi N, et al. Dystonia Neurosurg Psychiat 2011 (in press). precipitated by peripheral trauma. Mov Disord 1990; 62 Fekete R, Jankovic J. Psychogenic chorea associated 5(Suppl 1):67. with family history of Huntington disease. Mov Disord 47 Goldman S, Ahlskog JE. Posttraumatic cervical 2010; 25:503–4. dystonia. Mayo Clinic Proc 1993; 68:443–8. 63 Okuyama N, Kawakatsu S, Wada T, et al. Occipital 48 Sa DS, Mailis-Gagnon A, Nicholson K, Lang AE. hypoperfusion in a patient with psychogenic visual Posttraurnatic painful torticollis. Mov Disord 2003; disturbance. Psychiat Res 2002; 114(3):163–8. 18(12):1482–91. 64 Vuilleumier P, Chicherio C, Assal F, et al. Functional 49 Ibrahim NM, Martino D, van de Warrenburg BP, et al. neuroanatomical correlates of hysterical sensorimotor The prognosis of fixed dystonia: a follow-up study. loss. Brain 2001; 124:1077–90. Parkinsonism Relat Disord 2009 Sep; 15(8):592–7. 65 Ghaffar O, Staines WR, Feinstein A. Unexplained 50 Monday K, Jankovic J. Psychogenic myoclonus. neurologic symptoms: an fMRI study of sensory Neurol 1993; 43:349–52. conversion disorder. Neurol 2006 Dec 12; 67(11): 51 Brown P. Clinical neurophysiology of myoclonus. In 2036–8. Hallett M, Fahn S, Jankovic J, Lang JE, Cloninger CR, 66 Voon V, Gallea C, Hattori N, et al. The involuntary Yudofsky SC, eds. Psychogenic Movement Disorders – nature of conversion disorder. Neurol 2010; Neurology and Neuropsychiatry, Philadelphia, 74(3):223–8. Lippincott Williams & Wilkins, 2006; pp 262–4. 67 Jankovic J, Cloninger CR, Fahn S, et al. Therapeutic 52 Thompson PD. The phenomenology of startle, latah, approaches to psychogenic movement disorders. In: and related conditions. In Hallett M, et al. (eds). Hallett M, et al. (eds). Psychogenic Movement Psychogenic Movement Disorders – Neurology and Disorders – Neurology and Neuropsychiatry. AAN Neuropsychiatry. Philadelphia, Lippincott Williams & Enterprises and Lippincott Williams & Wilkins, Wilkins, 2006; pp 48–52. Philadelphia, 2006; pp 323–8.

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Note: Page numbers in italics refer to Figures; those in bold to Tables

abdominal myoclonus amantadine, 44 autosomal recessive cerebellar ataxias vs. diaphragmatic myoclonus, 230 antiadrenergic drugs, 43 (ARCAs) surface EMG discharges, 230, 231 anticholinergic drugs, 43 chaperon protein deficiency symptoms, 230 anticonvulsants, 183 Charlevoix-Saguenay, spastic ataxia, acquired choreas antidopaminergic agents, 101–2 284 anticonvulsants, 183 anxiety relieving techniques, 46 MSS, 284 autoimmune disorders, 179–80 AOA1, see ataxia DNA repair defects description, 175 AOA2, see ataxia AT, 283 dopamine-blocking, 183 ARCAs, see autosomal recessive cerebellar AOA1, 283 dopamine-depleting agents, 183 ataxias (ARCAs) AOA2, 283 drug-induced choreas, 180–181 asterixis, 77 SCAN1, 283, 286–8 epidemiology, 176–7 ataxia hyperkinetic movement disorders, etiology, 177–8 ADCAs (see autosomal dominant 284, 289 glutamate NMDA-receptor cerebellar ataxias) mitochondrial dysfunction antagonists, 183 ARCAs (see autosomal recessive antioxidants, 280 immune modulators, 183 cerebellar ataxias) CoQ10 deficiency, 283 infectious, 181 cerebellar (see cerebellar ataxias) FA, 280–283 metabolic, 178–9 FA (see Friedreich ataxia (FA) ) frataxin, 280 non-medical therapies, 183–4 inherited (see inherited ataxias) histone deacetylase (HDAC) pathophysiology, 181 mitochondrial, 292 inhibitors, 280, 283 phenomenology, 175–6 movements, 267–8 idebenone, 283 post infectious, 181 with oculomotor apraxia 1 (AOA1), 283 mutations, 284 psychogenic, 181 with oculomotor apraxia type 2 vitamin E deficiency surgical therapies, 183 (AOA2), 283 abetalipoproteinemia, 284 treatment, 181, 183 with primary vitamin E deficiency ataxia with primary vitamin E action tremor, 29 (AVED), 284 deficiency (AVED), 284 acupuncture, RLS, 324–5 sporadic (see sporadic ataxias) CCA, 284 ADCAs, see autosomal dominant cerebellar telangiectasia (AT), 283 AVED, see ataxia ataxias (ADCAs) x-linked (see x-linked ataxias) ADHD, see attention deficit and athetosis, 8 belly dancer’s dyskinesia, 246–8 hyperactivity disorder (ADHD) attention deficit and hyperactivity disorder benign hereditary chorea (BHC), 165 adiadochokinesia, see dysdiadochokinesia (ADHD), 201, 202, 316 benign paroxysmal torticollis of infancy alternative therapy, RLS autoimmune disorders, 179–80 (BPTI), 370–371 acupuncture, 324–5 autosomal dominant cerebellar ataxias benzodiazepines, 43–4 deep brain stimulation (DBS), 325 (ADCAs) blepharospasm, 307 enhanced external counter pulsation genetic classification and nomenclature, botulinum neurotoxins (BoNTs) (EECP), 325 SCA hyperkinetic disorders, medical herbal therapy, 324 clinical and genetic diagnosis, 290 treatments, 44–6 infrared light, 325–6 epidemiology, 289–290 injections, HFS, 244 pallidotomy, 325 neuroimaging studies, 291 primary dystonias, 128 spinal cord stimulation, 325 Harding’s classification, 289 brainstem reticular reflex myoclonus, 33 transcutaneous electrical nerve hyperkinetic movement disorders, 289 brain-thyroid-lung syndrome, 165 stimulation, 325 pathogenic mechanisms, 291–2 branchial myoclonus, 225

385

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Cayman cerebellar ataxia (CCA), 284 thalamic, 86 rating scales, 303 cerebellar ataxias dentatorubral-pallidoluysian atrophy treatment, 304–6 hereditary, 279 (DRPLA), 163–4 kinesiogenic foot dystonia, 300 sporadic, 279, 292–4 developmental hyperkinesias non-motor symptoms, 308 symptomatic (secondary), 279 head nodding, 359 non-PD parkinsonian syndromes, 307 cerebellar cognitive affective syndrome shuddering, 359 punding activity, 308 (CCAS), 270–271 spasmus nutans, 359–60 risk factors, 302 cerebellar dysfunction diabetes mellitus, See tardive dyskinesia treatment algorithm, different types, cognitive deficits, 270–271 (TD) 304, 305 description, 259–60 diaphragmatic myoclonus dysmetria, 263–5 dysarthria, 263 clinical neurophysiology, 229 dystonia internal models, 272–3 description, 229 cerebellum–basal ganglia-cortex, 18–19 inverse models, 273–4 pathophysiology, 229 cortex–basal ganglia loops, 18 learning, 269–70 treatment, 230 description, 9 limb movement disturbances DNA repair defects, ARCAs dopamine dysfunction, 18 ataxic movements, 267–8 AT, 283 DYT1 and DYT6, links, 17–18 dysdiadochokinesia, 266 AOA1, 283 DYT6 and DYT3, links, 18 dysmetria, 263–5 AOA2, 283 molecular pathology, 15–17 hypotonia, 268 SCAN1, 283, 286–8 pathophysiology, integrative model, 20 impaired check, 268 dopamine agonist (DA), 41–2 peripheral nerve injuries tremor, 266–7 dopamine antagonists, 42 genetically-proven familial, 246 mutism, 263 dopamine receptor blockers, 42 post-traumatic cervical, 246 oculomotor disturbances, 262–3 neuroleptics, 42, 101, 161, 195, 248, treatment, 246–7 physiology, 260–262 320, 332 psychogenic movement disorders posture dopaminergic drug-associated dyskinesia, (PMDs), 379–80 gait ataxia, 269 PD sensorimotor disruption, 19 stance ataxia, 268–9 after transplantation, 306–7 surgical treatment, hyperkinetic theories, 271–2 clinical disorders, 54 cerebellar tremor syndromes, 97–8, impact, 302–3 tremor, 98–100, 117 see also Kinetic tremor rating scales, 303 DYT coding, 16–17, see also Dystonia chaperon protein deficiency, ARCAs epidemiology, 302 Charlevoix-Saguenay, spastic ataxia, 284 pathophysiology encephalitis lethargica pandemic, 200 MSS, 284 dopamine transporter, 303–4 endogenous opioid system, 317 childhood masturbation, 371 nigral degeneration, 303 end stage renal disease (ESRD), 316 chorea, see also acquired choreas; non-dopaminergic influence, 303–4 enhanced external counter pulsation Huntington disease (HD); phenomenology (EECP), 325 Sydenham’s chorea (SC) diphasic dyskinesia, 300–301 enhanced physiologic tremor (EPT), 27, 96 axonal transport, 36 OFF state, 300–301 epilepsia partialis continua, 77 description, 6 peak-dose dyskinesia, 300, 301 epilepsy excitotoxicity, 35 run-away dyskinesias, disorders, 370 mitochondrial dysfunction, 36 neurotransplantation, 301 medications, 44, 45 molecular pathology, 35 ON state, 300 episodic ataxias, 368, 369 pathophysiology, 34–5 treatment episodic focal lingual spasms, 249 surgical treatment, hyperkinetic antidyskinetic drugs, 305–6 EPM, see essential palatal myoclonus disorders, 52–3, 54–5 aspect, 304–5 (EPM) transcriptional dysregulation, 35–6 stereotactic surgery, 306 essential palatal myoclonus (EPM), 222 cigarettes, 102 dopaminergic drug-induced syndromes, essential tremor (ET), see also Kinetic clonazepam, 103 46, 47 tremor clonidine, 324 dopamine transporter (DAT), 77 benign essential tremor, 73 clonus, 77 dopa-responsive dystonia (DRD), 122–3 description, 73 coenzyme Q10 (CoQ10) deficiency, 283 DRPLA, see dentatorubral-pallidoluysian epidemiology complex regional pain syndrome (CRPS), 34 atrophy (DRPLA) incidence, 81 muscle spasms, 245–6 dysarthria, 263 mortality, 82 comprehensive behavioral intervention for dysdiadochokinesia, 266 prevalence, 81 tic (CBIT), 194 dyskinesia pathophysiology, 83–4 compulsions, 354 blepharospasm, 307 pharmacological agents, 85 cortical stimulation, 63 dopaminergic drug-associated phenomenology culturally determined startle syndromes, after transplantation, 306–7 associated findings, 80–81 242–3 clinical impact, 302–3 clinical diagnostic criteria, 78 epidemiology, 302 differential diagnosis, 76–7 deafness, see hearing loss pathophysiology, 303–4 kinetic arm tremor, 74 deep brain stimulation (DBS), 306, 325 phenomenology, 300–301 laboratory workup, 77

Albanese_bindex.indd 386 12/24/2011 7:36:07 AM Index 387

medical history, 74–5 hereditary hyperekplexia, 241–2 phenomenology, 209–12 physical examination, 73 HFS, see hemifacial spasm (HFS) PME/PMA, 217 tremor assessment, 78 Holmes tremor, 100–101, see also Kinetic treatment, 214 risk factors and etiology, 82–3 tremor intentional tremor, 95, see also Kinetic surgical treatment Huntington disease (HD), see also Chorea tremor gamma knife thalamotomy, 87 behavioral manifestations, 152–3 iron deficiency, 316 stereotactic thalamotomy, 87 cognitive manifestations, 153 thalamic deep brain stimulation, 87 epidemiology, 153 jerks surgical treatment, hyperkinetic genetic causes episodic focal lingual spasms, 249 disorders, 52, 53 BHC, 165 hereditary hyperekplexia, 241–2 treatment DRPLA, 163–4 jumpy stumps syndrome, 247 considerations, 84–5 HDLs, 164 Latah syndrome, 241–2 pharmacological agents, 85–6 neuroacanthocytosis, 164 myoclonias, 236–41 ethanol, 44 neurodegeneration, brain iron painful hands syndrome, 248–9 exaggerated startle syndromes, see accumulation, 165 painful legs syndrome, 248 hyperekplexia imaging, 159–60 peripheral nerve injuries, 243–7 excitotoxicity, 35 motor manifestations, 149–52 jumpy stumps syndrome, 247 exercise-induced paroxysmal dyskinesias neuropathology, 158–9 description, 367 pathogenesis, 154–8 kinetic tremor, 29 epidemiology, 368 phenomenology, 149 etiology, 368 premanifestation, 149–50 Lafora body disease, 217 pathophysiology, 368 psychiatric manifestations, 152–3 Latah syndrome, 242–3 phenomenology, 367 psychogenic chorea, 165 l-dopa-induced dyskinesia, see tardive treatment, 368 treatment dyskinesia (TD) cell-based therapy, 161 levodopa-induced dyskinesias (LID), see FA, see Friedreich ataxia (FA) disease-modifying therapy, 160–161 dyskinesia factitious disorder, 376 symptomatic therapy, 161–3 limb movement disturbances familial cortical myoclonic tremor with weight loss, 153 ataxic movements, 267–8 epilepsy (FCMTE), 31, 32 hyperekplexia dysdiadochokinesia, 266 fixed dystonia, 117 hereditary, 241–2 dysmetria, 263–5 focal myoclonus, peripheral nerve injuries, Latah syndrome, 242 hypotonia, 268 244–5 major, 241 impaired check, 268 formes frustes, 117 minor, 241 tremor, 266–7 fragmentary myoclonus, 236, 237 secondary, 242 limb-shaking transient ischemic attacks, Friedreich ataxia (FA), 280–283 treatment, 243 370 hyperkinesias, see developmental gait disorder, 381 hyperkinesias malingering, 376–7 gamma-aminobutyric acid (GABA) hypertension, 315 Marinesco-Sjögren syndrome (MSS), 284 receptor agonists, 43–4 hypnic myoclonus, 236, 237 medical treatments, hyperkinetic disorders gamma knife thalamotomy, 87 hypotonia, 268 amantadine, 44 genetic choreas, see Huntington disease antiadrenergic drugs, 43 (HD) immune modulators, 183 anticholinergic drugs, 43 Gilles de la Tourette syndrome (TS), immunity, 317 anxiety relieving techniques, 46 20–22, see also Tics; Tourette inflammation, 317, 318–20 botulinum toxins (BoNTs), 44–6 syndrome (TS) inherited ataxias dopamine agonist (DA), 41–2 globus pallidus (GPi), 60–62, 63 cerebellar ataxias dopamine antagonists, 42 glutamate NMDA-receptor antagonists, hereditary, 279 ethanol, 44 183 sporadic, 279, 292–4 GABA receptor agonists, 43–4 symptomatic (secondary), 279 motor phenotypes, 40 HCF–1-binding motif (HBM), 18 hereditary cerebellar ataxias pathophysiology, 41 head nodding, 359 ADCAs, 289–92 phenotypes, 41 health-related quality of life (HRQoL), 79 ARCAs, 280–289 surgical treatments, 46 hearing loss, 137 mitochondrial ataxias, 292 tetrabenazine (TBZ), 42–3 hemifacial spasm (HFS) x-linked ataxias, 292 topiramate, 44 bilateral cases, 243 OMIM number, 280 mitochondrial ataxias, 292 BoNT injections, 244 sporadic ataxias, 292–4 mitochondrial dysfunction, ARCAs oral treatment, 244 inherited myoclonus syndromes coenzyme Q10 (CoQ10), 283 pathophysiology, 243 characteristics, 215 FA, 280–283 sporadic disorder, 243 description, 209 monoclonal gammopathy of undetermined surgical treatment, 244 epidemiology, 212 significance (MGUS), 106 vascular compression, 243 etiology, 212–13 motor phenotypes, 40 herbal therapy, RLS, 324 pathophysiology, 213–14 movement disorder society, 78

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multiple sclerosis (MS), see Cerebellar pathophysiology, 223–4 paroxysmal tonic upgaze (PTU), 371 tremor syndromes treatment, 224–5 parvalbumin-positive neurons, 21 myoclonus palatal tremor (PT), 29, 103 pediatric autoimmune neuropsychiatric cortical, 31–3 pallidotomy, 306, 325 disorder associated with streptococcus definition, 236 paramyoclonus multiplex, 4 (PANDAS), 200, 201 description, 8 Parkinson disease (PD) peripheral myoclonus, 34 essential tremor, differential diagnosis, dopaminergic drug-associated, peripheral nerve injuries 76 dyskinesia dystonia, 246–7 etiologic classifications, 236 after transplantation, 306–7 focal myoclonus, 244–5 familial cortical myoclonic tremor with clinical impact, 302–3 guidelines/criteria, 243 epilepsy (FCMTE), 32 epidemiology, 302 HFS, 243–4 other physiologic myoclonias, 237 pathophysiology, 303–4 surgical treatment, hyperkinetic periodic myoclonus, 240 phenomenology, 300–301 disorders, 63 peripheral, 34 rating scales, 303 peripheral neuropathy, 137–8 post-anoxic myoclonus, 240 treatment, 304–6 position-specific tremor, 96 psychogenic movement disorders dyskinesia positron emission tomography (PET), 21 (PMDs), 380 blepharospasm, 307 post-traumatic tremor, 105–6 singultus/hiccups, 237 goal, objective measures, 303 postural tremor, 96, see also sleep kinesiogenic foot dystonia, 300 Action tremor fragmentary myoclonus, 236, 237 non-motor symptoms, 308 primary dystonias hypnic myoclonus, 236, 237 non-PD parkinsonian syndromes, 307 botulinum neurotoxins (BoNTs), 128 spinal, 33–4 punding activity, 308 classification, 116–17 subcortical, 33 risk factors, 302 deep brain stimulation, 128–9 symptomatic/secondary, 237–41 treatment algorithm, different types, epidemiology, 117 myoclonus-dystonia (M-D) syndrome, 33, 304, 305 etiology 123–4, see also inherited myoclonus psychogenic movement disorders DYT5, 122–3 syndromes (PMDs), 381 DYT11, 123–4 secondary dystonias, 138–9 DYT12, 124 negative myoclonus, see Asterixis tremor, 96–7 DYT16, 124 neuroacanthocytosis, 164 paroxysmal dyskinesias DYT1 dystonia, 119–21 neurodegeneration associated with brain childhood disorders, 370–371 DYT6 dystonia, 121–2 iron accumulation type 1 (NBIA-1), epileptic disorders, 370 mapped loci, 124 202 episodic ataxias, 368, 369 genetically unclassified dystonia neuroleptics exercise-induced syndromes description, 42 description, 367 classified phenotypes, 125 drug- and toxic-induced tremors, 101 epidemiology, 368 unclassified phenotypes, 125–6 Huntington disease, 161 etiology, 368 pathophysiology, 126–7 painful legs and moving toes, 248 pathophysiology, 368 phenomenology RLS, 320 phenomenology, 367 cardinal features, 117–18 tardive dyskinesias, 332 treatment, 368 diagnostic algorithm, 118–19 Tourette syndrome treatment, 195 kinesigenic features, 118 neuropathic tremor, 30, 106–7 description, 363 systemic treatments, 128 neurotransmitter dysfunction, 357 epidemiology, 364 treatments, 127–8 non-parkinsonian syndromes, 307 etiology, 364–5 primary writing tremor, 104 pathophysiology, 365 primidone, 85 obsessive-compulsive disorder (OCD), 200, phenomenology, 363–4 progressive dementia, 139 201 therapy, 365 prominent orobulbar involvement, 136 oculofacialmasticatory myorhythmia, 225 limb-shaking transient ischemic attacks, propriospinal myoclonus (PSM), 34, 231 opsoclonus-myoclonus syndrome, 240 370 psychogenic movement disorders (PMDs) orthostatic myoclonus, 33 non-kinesigenic clinical examination, 377–8 orthostatic tremor (OT), 30, 102–3 description, 365 clinical features, 378 oscillations epidemiology, 366 diagnosis, 375–6 central generator(s), 26–7 etiology, 366 dystonia, 379–80 mechanical, 26 pathophysiology, 366–7 gait disorder, 381 reflex, 26 phenomenology, 365–6 historical, 377 treatment, 367 myoclonus, 380 painful hands syndrome, 248–9 psychogenic paroxysmal movement parkinsonism, 381 palatal myoclonus disorders (P-PMDs), 370 physiologic brain changes, 381 clinical neurophysiology, 222–3 superior oblique muscle (SOM) psychiatric classification, 376–7 diagnosis and evaluation, 222 myokymia, 370 treatment, 381–2 EPM vs. SPM, 222 tonic spasms, 370 tremor, 378–9

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psychogenic paroxysmal movement SCAN1, see spinocerebellar ataxia with somatoform disorder, 376 disorders (P-PMDs), 370 axonal neuropathy (SCAN1) spasmus nutans, 359–60 punch drunk syndrome, 105 SCGE gene, 18 spinal cord stimulation, RLS, 325 Purkinje cells, 83, 259 secondary dystonias spinal myoclonus, 33–4 clinical features, 135 spinal segmental myoclonus quality of life in essential tremor description, 135 causes, 225, 226 questionnaire (QUEST), 79 phenomenology clinical neurophysiology, 226–7 hearing loss, 137 diagnosis and evaluation, 225–6 rapid-onset dystonia parkinsonism (RDP), neuroimaging features, 139–41 pathophysiology, 227–8 124 ocular motor signs, 136–7 treatment, 228 re-emergent tremor, 96 parkinsonism, 138–9 spinocerebellar ataxia with axonal reflex sympathetic dystrophy (RSD), 106 peripheral neuropathy, 137–8 neuropathy (SCAN1), 283, 286–8 restless legs syndrome (RLS) progressive dementia, 139 SPM, see symptomatic palatal myoclonus alternative therapies prominent orobulbar involvement, (SPM) acupuncture, 324–5 136 sporadic ataxias deep brain stimulation (DBS), 325 symptoms, 136 acquired ataxias, 292–3 enhanced external counter pulsation unusual distribution, 136 non-genetic degenerative ataxias (EECP), 325 prevalence and etiology, 141–2 multiple system atrophy (MSA), herbal therapy, 324 treatment, 142 293 infrared light, 325–6 secondary myoclonias sporadic adult-onset cerebellar ataxia pallidotomy, 325 causes, 237–9 (SAOA), 293 spinal cord stimulation, 325 cortical, 240 sporadic olivopontocerebellar atrophy transcutaneous electrical nerve treatment, 240–241 (sporadic OPCA), 293–4 stimulation, 325 secondary/symptomatic hyperekplexia, startles, see jerks antibiotic treatment, 326 242 stereotypies, see also developmental attention deficit hyperactivity disorder, secondary tics hyperkinesias 316 chromosomal abnormalities, 203 central nervous system surgery, 50–51 childhood RLS, 316 drugs, 201–2 description, 9–10 clinical features, 311–15 infections pathophysiology, 356–8 description, 311 SC, 201 phenomenology, 353–5 dopamine agonist (DA) drugs, 41 von Economo disease, 200 primary, 355 dopaminergics, 321–3 working diagnostic criteria, prognosis, 358–9 endogenous opioid system, 317 200–201 secondary, 355–6 end stage renal disease (ESRD), 316 management, 203 thalamotomy, 87 epidemiology, 315 neurodegenerative disorders, 202–3 treatment, 358 etiology, 316 psychogenic tics, 203 stroke-induced tremor, 104 gastrointestinal disease, 316 structural lesions, 202 subcortical myoclonus, 33 hypertension, 315 second line treatments, RLS superior oblique muscle (SOM) immunity, 317 anticonvulsants, 324 myokymia, 370 inflammation, 317, 318–20 benzodiazepines, 324 surgical treatment, hyperkinetic disorders iron opioids, 323–4 chorea, 52–3, 54–5 deficiency, 316 segmental myoclonus, 33 cortical stimulation, 63 therapy, 323 abdominal/truncal myoclonus, description, 49–50 pathophysiology 230–231 dystonia, 54 dopamine, 317 branchial myoclonus, 225 essential tremor, 52, 53 iron, 316–17 classical clinical appearance, 221 globus pallidus (GPi), 60–62, 63 pneumatic compression devices, 326 definition, 221–2 peripheral nervous system surgery, 63 second line treatments, 323–4 diaphragmatic myoclonus, 229–30 phenomenology, 50 supplements oculofacialmasticatory myorhythmia, physiology, 50 folate, 326 225 procedures, 51–2 magnesium, 326 palatal myoclonus, 222–5 stereotactic central nervous system third line treatment, 324 propriospinal myoclonus, 231 surgery, 50–51 treatment, 320–321 spinal, 225–8 Tourette syndrome, 55–7, 57 rest tremor sensorimotor disruption, dystonia, 19 transmagnetic cranial stimulation anatomical pathways, 28, 29 sensory deprivation, 356 (TMS), 63–4 characteristic symptoms, 27 SGCE gene, 213 ventralis intermedius nucleus, 57, 58, description, 95 shuddering, 359 59, 63 Rett syndrome, 356 single positron emission computerized SWEDD, see Palatal tremor tomography (SPECT) Sydenham’s chorea (SC), 175, 201 Sandifer syndrome (SS), 371 acquired choreas, 178 symptomatic myoclonias, see secondary SC, see Sydenham’s chorea (SC) tics, 21 myoclonias

Albanese_bindex.indd 389 12/24/2011 7:36:08 AM 390 Index

symptomatic palatal myoclonus (SPM) pathophysiology, 192–3 psychogenic movement disorders abnormality, 223 phenomenology, 188–91 (PMDs), 378–9 causes, 222 surgical treatment, hyperkinetic research group, 78 coronal illustration, brainstem nuclei disorders, 55–7, 57 rest, 27–9, 95 and pathways, 223, 224 treatment, 193–6 stroke-induced, 104 dorsolateral reticular formation, 224 tourettism, see secondary tics SWEDD, 29 vs. EPM, 222, 223 transcriptional dysregulation, 35–6 systemic disorders, 104–5 systemic disorders, 104–5 transcutaneous electrical nerve task-specific, 95, 104 stimulation, 325 truncal myoclonus, see abdominal tardive dyskinesia (TD), 176 transmagnetic cranial stimulation (TMS), myoclonus description, 331 63–4 TS, see Gilles de la Tourette syndrome epidemiology, 331–4 tremor, see specific types etiology, 337 action, 29 ubiquinone, see coenzyme Q10 deficiency metoclopramide, 341, 343–4 central generator(s), 26–7 unified dyskinesia rating scale (UDRS), pathophysiology, 337–9 cerebellar tremor syndromes, 97–8 303 phenomenology, 334–6 characteristics, 27 Unverricht Lundborg disease, 217 predisposing factors, 336–7 classification, 95 treatment, 340–341, 342, 343 description, 5–6, 26, 95 ventralis intermedius nucleus, 57, 58, task-specific tremor, 95, 104 diagnosis, 95 59, 63 tetrabenazine (TBZ), 42–3, 195 drug-and toxic-induced, 101–2 vesicular monoamine transmitter-2 thalamic deep brain stimulation, 87 dystonic tremor syndromes, 98–100 (VAMT-2), 43 thanatos-associated protein (THAP), 17 enhanced physiologic, 96 vestibulo-ocular reflex (VOR), 262 tics, see also Tourette syndrome (TS) essential (see Essential tremor (ET) ) vitamin E deficiency description, 4, 6–8, 20 Holmes, 100–101 ARCAs genetic aspects, 20–21 intentional, 95 abetalipoproteinemia, 284 histological studies, 21 kinetic, 29–30 AVED, 284 imaging studies, 21 limb movement disturbances, 266–7 CCA, 284 pathophysiology, integrative mechanisms, 26 von Economo disease, see encephalitis model, 22 neuropathic, 30, 106–7 lethargica pandemic titubation, see Cerebellar tremor orthostatic, 102–3 syndromes palatal, 103 Washington Heights-Inwood genetic tonic spasms, 370 Parkinson disease, 96–7 study, 79 topiramate, 44 peripheral mechanical-reflex whiplash tics, 190 Tourette syndrome (TS) oscillations, 26 Whipple’s disease, 225 description, 188 physiological, 96 whispering dystonia, 136 epidemiology, 191 position-specific, 96 etiology, 191–2 post-traumatic, 105–6 x-linked ataxias, 292

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