Movement Disorders in Childhood

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[email protected] 66485438-66485457 Movement Disorders in Childhood

Harvey S. Singer, MD Professor of Neurology and Pediatrics Haller Professor of Pediatric Neurological Diseases Director of Pediatric Neurology The Johns Hopkins Hospital Baltimore, Maryland Jonathan W. Mink, MD, PhD Professor of Neurology, Neurobiology and Anatomy, and Pediatrics Chief, Child Neurology University of Rochester Medical Center Rochester, New york Donald L. Gilbert, MD Director, Movement Disorder Clinic and Tourette’s Syndrome Clinic Associate Professor of Pediatric Neurology Cincinnati Children’s Hospital Cincinnati, Ohio Joseph Jankovic, MD Professor of Neurology Director, Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, Texas [email protected] 66485438-66485457 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 MOVEMENT DISORDERS IN CHILDHOOD ISBN: 978-0-7506-9852-8 Copyright © 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current informa- Otion provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Authors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Previous editions copyrighted 2010 Library of Congress Cataloging-in-Publication Data Movement disorders in childhood / Harvey S. Singer … [et al.].—1st ed. Includes bibliographical references. ISBN 978-0-7506-9852-8 1. Movement disorders in children. I. Singer, Harvey S. [DNLM: 1. Movement Disorders. 2. Child. WS 340 M9354 2010] RJ496.M68M685 2010 618.92′683—dc22 2009034376

Acquisitions Editor: Adrianne Brigido Development Editor: Taylor Ball Publishing Services Manager: Anitha Raj Project Manager: Mahalakshmi Nithyanand Design Direction: Louis Forgione

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

[email protected] 66485438-66485457 We dedicate this book to our patients, mentors, students, fellows, and other trainees for their inspiration and to our wives and families for their enduring support.

[email protected] 66485438-66485457 [email protected] 66485438-66485457 [email protected] 66485438-66485457 Preface

Movement disorders are a relatively new area of special- Chapters 1 to 4, includes basal ganglia and cerebellar ization within child neurology. For many years, move- anatomy, physiology, and pharmacology; standard def- ment abnormalities affecting the pediatric population initions; and diagnostic approaches. Subsequent chap- received little attention in adult-oriented textbooks, ters are disease oriented, based on age of presentation, and chapters were frequently written by adult neu- predominant motor phenomenology (hypokinetic or rologists. Over the past several decades, child neurolo- hyperkinetic), or clinical etiology (static encephalopa- gists have assumed a greater role in the care of children thy, metabolic disease, etc). Where possible, chapters with movement disorders and the investigation of their share a common format consisting of an overview, underlying etiologies and mechanisms. definition, review of clinical characteristics, neuron- The decision to produce a high-quality text devoted atomic localization, and pathophysiology, followed to movement disorders in children was based on a per- by a discussion of individual diseases and disorders. ceived need for an informative, useful resource that Lastly, we have included appendices with information would benefit the care of affected individuals. In the of general relevance to a clinician managing a child process of attaining this ultimate goal, several working with a movement disorder. Appendix A covers com- aims were established. First and foremost, each chapter mon medications used in the treatment of movement would be written by a board-certified child neurologist disorders (doses, side effects, and drug interactions). with a strong clinical and scientific background in the Appendix B provides a guide for diagnosing herita- field. Second, the number of authors would be limited, ble movement disorders, with tips on the use of the in order to maintain an active dialogue and compre- Online Mendelian Inheritance in Man (OMIM) and hensive review of each chapter. Lastly, recognizing that Genetests websites. Appendix C provides legends to written descriptions of abnormal movements are often the videos. limited and that visual aides are an essential teaching For all, this was a labor of pleasure and one of contin- tool, the inclusion of videos was a requirement. ued learning. We believe that this book provides a fun- Chapters were written by Harvey Singer, Jonathan damental background of neuronal circuitry, an approach Mink, and Donald Gilbert and reviewed by all authors. to patient evaluation, and a comprehensive review of dis- Patient videos, designed to illustrate and enhance the orders that should be acceptable to readers at all levels of described phenomenology, were provided by Joseph experience. We fully recognize that advances in pediatric Jankovic, who also reviewed and edited all the chapters. movement disorders continue to proceed at a rapid pace The book is organized in sections. The first section, and that future updates may be required.

Harvey S. Singer, MD Jonathan W. Mink, MD, PhD Donald L. Gilbert, MD, MS Joseph Jankovic, MD Fall, 2009

vii [email protected] 66485438-66485457 [email protected] 66485438-66485457 Acknowledgments

The authors would like to thank the staff at Elsevier for their assistance and flexibility. In particular, we acknowledge the efforts of Taylor Ball and Mahalakshmi Nithyanand.

ix [email protected] 66485438-66485457 [email protected] 66485438-66485457 Basal Ganglia Anatomy, 1 Biochemistry, and Physiology O

Introduction Striatum and Subthalamic Nucleus are the Input Nuclei The basal ganglia are large subcortical structures comprising several interconnected nuclei in the forebrain, The striatum receives the bulk of extrinsic input to the diencephalon, and midbrain. Historically, the basal basal ganglia. The striatum receives excitatory input ganglia have been viewed as a component of the motor from virtually all of the cerebral cortex.1 In addition, system. However, there is now substantial evidence the ventral striatum (nucleus accumbens and rostroven- that the basal ganglia interact with all of the frontal tral extensions of caudate and putamen) receives inputs cortex and with the limbic system. Thus the basal gan- from the hippocampus and amygdala.2 The cortical glia likely have a role in cognitive and emotional func- input uses glutamate as its neurotransmitter and ter- tion in addition to their role in motor control. Indeed, minates largely on the heads of the dendritic spines of O 3 diseases of the basal ganglia often cause a combination medium spiny neurons. The projection from the cere- of movement, affective, and cognitive disorders. The bral cortex to the striatum has a roughly topographic motor circuits of the basal ganglia are better under- organization. It has been suggested that this topogra- stood than the other circuits, but because of similar phy provides the basis for a segregation of functionally organization of the circuitry, conceptual understand- different circuits in the basal ganglia.4 Although the ing of basal ganglia motor function can also provide topography implies a certain degree of parallel orga- a useful framework for understanding cognitive and nization, there is also evidence for convergence and affective function. divergence in the corticostriatal projection. The large dendritic fields of medium spiny neurons allow them 5 Components and Connections to receive input from adjacent projections, which arise of Basal Ganglia Circuits from different areas of cortex. Inputs to striatum from several functionally related cortical areas overlap and The basal ganglia include the striatum (caudate, puta- a single cortical area projects divergently to multiple men, nucleus accumbens), the subthalamic nucleus, striatal zones.6,7 Thus there is a multiply convergent the globus pallidus (internal segment, external seg- and divergent organization within a broader frame- ment, ventral pallidum), and the substantia nigra work of functionally different parallel circuits. This (pars compacta and pars reticulata) (Fig. 1-1). The organization provides an anatomic framework for the nucleus accumbens and the ventral portion globus integration and transformation of cortical information pallidus are limbic components of the circuitry and in the striatum. are not specifically shown in Figure 1-1. The stria- Medium spiny striatal neurons make up about tum and subthalamic nucleus receive the majority 95% of the striatal neuron population. They project of inputs from outside of the basal ganglia. Most of outside of the striatum and receive a number of inputs those inputs come from the cerebral cortex, but thal- in addition to the important cortical input, includ- amic nuclei also provide strong inputs to striatum. ing (1) excitatory glutamatergic inputs from the thala- The bulk of the outputs from the basal ganglia arise mus; (2) cholinergic input from striatal interneurons; from the globus pallidus internal segment, ventral pal- (3) gamma-aminobutyric acid (GABA), substance P, lidum, and substantia nigra pars reticulata. These out- and enkephalin input from adjacent medium spiny stri- puts are inhibitory to the pedunculopontine area in the atal neurons; (4) GABA input from small interneurons; brainstem and to thalamic nuclei that in turn project (5) a large input from dopamine-containing neurons to the frontal lobe. in the substantia nigra pars compacta (SNpc); and

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Cerebral Frontal cortex cortex

Glu Glu Glu Glu Glu Caudate/putamen

D2 ay D1 S IL O U GABA/ M VA/

GABA I A GABA n L

ENK dir VL/ e A

DA ct

p H MD y a T t a h w

w GPe

a h

t y GABA

a Hyperdirect pathw

c GABA

e GABA/DYN/ Glu Glu

i D SP GABA STN GPi Glu GABA SNpr

SNpc

GABA GABA

Excitatory PPA Inhibitory SC Exc/Inhib

Brainstem and spinal cord

Figure 1-1. Simplified schematic diagram of basal ganglia-thalamocortical circuitry. Excitatory connections are indicated by open arrows, inhibitory connections by filled arrows. The modulatory dopamine projection is indicated by a three-headed arrow. Abbreviations: dyn, dynorphin; enk, enkephalin; GABA, gamma-aminobutyric acid; glu, glutamate; GPe, globus pallidus pars externa; GPi, globus pallidus pars interna; IL, intralaminar thalamic nuclei; MD, mediodorsal nucleus; PPA, pedunculopontine area; SC, superior colliculus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; SP, substance P; STN, subthalamic nucleus; VA, ventral anterior nucleus; VL, ventral lateral nucleus.

(6) a more sparse input from the serotonin-containing on the type of dopamine receptor involved. Five types neurons in the dorsal and median raphe nuclei. of G protein–coupled dopamine receptors have been In recent years, there has been increasing recogni- described (D1 to D5).10 These have been grouped tion of the importance of the fast-spiking GABAergic into two families based on their linkage to adenyl striatal interneurons. These cells make up less than 5% cyclase activity and response to agonists. The D1 fam- of the striatal neuron population, but they exert power- ily includes D1 and D5 receptors and the D2 family ful inhibition on medium spiny neurons. Like medium includes D2, D3, and D4 receptors. The conventional spiny neurons, they receive excitatory input from the view has been that dopamine acts at D1 receptors to cerebral cortex. They appear to play an important role facilitate the activity of postsynaptic neurons and at in focusing the spatial pattern of medium spiny neuron D2 receptors to inhibit postsynaptic neurons.11 Indeed, activation.8 this is a fundamental concept for currently popular The dopamine input to the striatum terminates models of basal ganglia pathophysiology.12,13 However, largely on the shafts of the dendritic spines of medium the physiologic effect of dopamine on striatal neurons spiny neurons, where it is in a position to modulate is more complex. Whereas activation of dopamine D1 transmission from the cerebral cortex to the striatum.9 receptors potentiates the effect of cortical input to stri- The action of dopamine on striatal neurons depends atal neurons in some states, it reduces the efficacy of

[email protected] 66485438-66485457 4 Section 1 overview cortical input in others.14 Activation of D2 receptors techniques have demonstrated that many substances more consistently decreases the effect of cortical input such as substance P, dynorphin, and enkephalin have to striatal neurons.15 Dopamine contributes to focusing a patchy distribution that may be partly or wholly the spatial and temporal patterns of striatal activity. in register with the striosomes. The striosome-matrix In addition to short-term facilitation or inhibition organization suggests a level of functional segregation of striatal activity, there is evidence that dopamine can within the striatum that may be important in under- modulate corticostriatal transmission by mechanisms standing the variety of symptoms in a variety of move- of long-term depression (LTD) and long-term poten- ment disorders. tiation (LTP). Through these mechanisms, dopamine The subthalamic nucleus receives an excitatory, strengthens or weakens the efficacy of cortico- glutamatergic input from many areas of the frontal lobes, striatal synapses and can thus mediate reinforcement of with especially large inputs from motor areas of the cor- specific discharge patterns. LTP and LTD are thought tex.22 The STN also receives an inhibitory GABA input to be fundamental to many neural mechanisms of from the GPe. The output from the STN is glutamatergic learning and may underlie the hypothesized role of the and excitatory to the basal ganglia output nuclei, GPi, basal ganglia in habit learning.16 SNpc dopamine neu- VP, and SNpr. The STN also sends an excitatory pro- rons fire in relation to behaviorally significant events jection back to the GPe. There is a somatopic organiza- and rewards.17 These signals are likely to modify the tion in the STN23 and a relative topographic separation responses of striatal neurons to inputs that occur in of “motor” and “cognitive” inputs to the STN. conjunction with the dopamine signal, resulting in the GPi, VP, and SNpr are the Primary reinforcement of motor and other behavior patterns. Striatal lesions or focal striatal dopamine depletion Output Nuclei impairs the learning of new movement sequences,18 The primary basal ganglia output arises from the GPi, supporting a role for the basal ganglia in certain types a GPi-like component of ventral pallidum (VP), and of procedural learning. the SNpr. As described previously, the GPi and SNpr Medium spiny striatal neurons contain the inhibi- receive excitatory input from the STN and inhibitory tory neurotransmitter GABA and colocalized peptide input from the striatum. They also receive an inhibi- neurotransmitters.19 Based on the type of neurotrans- tory input from the GPe. The dendritic fields of GPi, mitters and the predominant type of dopamine receptor VP, and SNpr neurons span up to 1 mm diameter and they contain, the medium spiny neurons can be divided thus have the potential to integrate a large number of into two populations. One population contains GABA, converging inputs.24 The output from GPi, VP, and dynorphin, and substance P and primarily expresses SNpr is inhibitory and uses GABA as its neurotrans- D1 dopamine receptors. These neurons project to the mitter. The primary output is directed to thalamic basal ganglia output nuclei, GPi, and SNpr. The sec- nuclei that project to the frontal lobes: the ventrolat- ond population contains GABA and enkephalin and eral, ventroanterior, and mediodorsal nuclei. The thal- primarily expresses D2 dopamine receptors. These amic targets of GPi, VP, and SNpr project, in turn, to neurons project to the external segment of the globus the frontal lobe, with the strongest output going to pallidus (GPe).12 motor areas. Collaterals of the axons projecting to thal- Although there are no apparent regional differences amus project to an area at the junction of the midbrain in the striatum based on cell type, an intricate internal and pons near the pedunculopontine nucleus.25 Other organization has been revealed with special stains. output neurons (20%) project to intralaminar nuclei of When the striatum is stained for acetylcholinesterase the thalamus, to the lateral habenula, or to the superior (AChE), there is a patchy distribution of lightly staining colliculus.26 regions within more heavily stained regions.20 The The basal ganglia motor output has a somatotopic AChE-poor patches have been called striosomes and the organization such that the body below the neck is AChE-rich areas have been called the extrastriosomal largely represented in GPi and the head and eyes are matrix. The matrix forms the bulk of the striatal largely represented in SNpr. The separate representa- volume and receives input from most areas of the cere- tion of different body parts is maintained through- bral cortex. Within the matrix are clusters of neurons out the basal ganglia. Within the representation of with similar inputs that have been termed matrisomes. an individual body part, it also appears that there The bulk of the output from cells in the matrix is to is segregation of outputs to different motor areas of both segments of the GP, to VP, and to SNpr. The the cortex and that an individual GPi neuron sends striosomes receive input from the prefrontal cortex output via thalamus to just one area of the cortex.27 and send output to the SNpc.21 Immunohistochemical Thus GPi neurons that project via the thalamus to the

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motor cortex are adjacent to, but separate from, those Basal Ganglia Functional that project to the premotor cortex or supplementary Organization motor area. GPi neurons that project via the thalamus to the prefrontal cortex are also separate from those Although the basal ganglia intrinsic circuitry is com- projecting to motor areas and from VP neurons pro- plex, the overall picture is of two primary pathways jecting via the thalamus to the orbitofrontal cortex. through the basal ganglia from the cerebral cor- The anatomic segregation of basal ganglia-thalamo- tex with the output directed via the thalamus at the cortical outputs suggests functional segregation at the frontal lobes. These pathways consist of two disyn- output level, but other anatomic evidence suggests aptic pathways from the cortex to the basal ganglia interactions between circuits within the basal ganglia output (see Fig. 1-1). In addition, there are several (see previous discussion).28 multisynaptic pathways involving GPe. The two disynaptic pathways are from the cortex through (1) GPe is an Intrinsic Basal Ganglia Nucleus the striatum (the direct pathway) and (2) the STN The GPe, and the GPe-like part of the VP, may be (the hyperdirect pathway) to the basal ganglia out- viewed as intrinsic nuclei of the basal ganglia. Like the puts. These pathways have important anatomic and GPi and SNpr, the GPe receives an inhibitory projec- functional differences. First, the cortical input to the tion from the striatum and an excitatory one from the STN comes only from frontal lobe whereas the input STN. Unlike the GPi, the striatal projection to the GPe to striatum arises from virtually all areas of the cere- contains GABA and enkephalin but not substance P.12 bral cortex. Second, the output from STN is excit- The output of the GPe is quite different from the out- atory, whereas the output from striatum is inhibitory. put of the GPi. The output from the GPe is GABAergic Third, the excitatory route through STN is faster and inhibitory and the majority of the output projects than the inhibitory route through striatum.31 Finally, to the STN. The connections from the striatum to the the STN projection to the GPi is divergent and the GPe, from the GPe to the STN, and from the STN to striatal projection is more focused.32 Thus the two the GPi form the “indirect” striatopallidal pathway to disynaptic pathways from cerebral cortex to the basal the GPi29 (see Fig. 1-1). In addition, there is a mono- ganglia output nuclei, GPi and SNpr, provide fast, synaptic GABAergic inhibitory output from the GPe widespread, divergent excitation through the STN directly to the GPi and to the SNpr and a GABAergic and slower, focused, inhibition through the stria- projection back to the striatum.30 Thus GPe neurons tum. This organization provides an anatomic basis are in a position to provide feedback inhibition to neu- for focused inhibition and surround excitation of rons in the striatum and STN and feedforward inhibi- neurons in the GPi and SNpr (Fig. 1-2). Because the tion to neurons in the GPi and SNpr. This circuitry output of the GPi and SNpr is inhibitory, this would suggests that the GPe may act to oppose, limit, or result in focused facilitation and surround inhibition focus the effect of the striatal and STN projections to of basal ganglia thalamocortical targets. the GPi and SNpr, as well as focus activity in these A scheme of normal basal ganglia motor function has output nuclei. been developed based on the results of anatomic, physiological and lesion studies.22,33 In this scheme, the tonically Dopamine Inputs active inhibitory output of the basal ganglia acts as Dopamine input to the striatum arises from the sub- a brake on motor pattern generators (MPGs) in the stantia nigra pars compacta (SNpc) and the ventral cerebral cortex (via the thalamus) and brainstem. tegmental area (VTA). The SNpc projects to most of MPGs are networks of neurons which, when activated, the striatum; the VTA projects to the ventral striatum. produce a specific motor output. When a movement The SNpc and VTA are made up of large dopamine- is initiated by a particular MPG, basal ganglia out- containing cells. Both receive glutamatergic input from put neurons projecting to competing MPGs increase frontal cortex. The SNpc also receives input from the their firing rate, thereby increasing inhibition and striatum, specifically from the striosomes. This input is applying a “brake” on those generators. Other basal GABAergic and inhibitory. The SNpc and VTA dop- ganglia output neurons projecting to the generators amine neurons project to caudate and putamen in a involved in the desired movement decrease their dis- topographic manner,28 but with overlap. The nigral charge, thereby removing tonic inhibition and releas- dopamine neurons receive inputs from one striatal ing the brake from the desired motor patterns. Thus circuit and project back to the same and to adja- the intended movement is enabled and competing cent circuits. Thus they appear to be in a position to movements are prevented from interfering with the modulate activity across functionally different circuits. desired one.

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Cerebral cortex Rest Hyperdirect Th/Cx Activity pathway y (glu) Indirect (glu) x (GABA) pathway STN GPe Str (glu) (GABA) Hyperdirect Direct pathway pathway (GABA)

(glu) (GABA) GPi/SNr (GABA) Direct t pathway ABTh

Figure 1-2. A, Schematic diagram of the hyperdirect cortico-subthalamo-pallidal, direct cortico-striato-pallidal, and indirect cortico-striato-GPe-subthalamo-GPi pathways. Thin arrows represent excitatory glutamatergic (glu) and thick arrows represent inhibitory GABAergic (GABA) projections respectively. GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; Str, striatum; Th, thalamus. B, A schematic diagram explaining the activity change over time (t) in the thalamocortical projection (Th/Cx) following the sequential inputs through the hyperdiect cortico-subthalamo-pallidal (middle) and direct cortico-striato-pallidal (bottom) pathways. (Modified from Nambu A, Tokuno H, Hamada I, et al: Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey, J Neurophysiol 84:289–300, 2000.)

The anatomic arrangement of the STN and stri- involuntary movements.22,33 Different involuntary atal inputs to the GPi and SNpr form the basis for a movements such as parkinsonism, chorea, dystonia, functional center-surround organization as shown in or tics result from different abnormalities in the basal Figure 1-3. When a voluntary movement is initiated ganglia circuits. Loss of dopamine input to the stria- by cortical mechanisms, a separate signal is sent to the tum results in a loss of normal pauses of GPi discharge STN, exciting it. The STN projects in a widespread during voluntary movement. Hence, there is excessive pattern and excites the GPi. The increased GPi activ- inhibition of motor pattern generators and ultimately ity causes inhibition of thalamocortical motor mecha- bradykinesia.34 Furthermore, loss of dopamine results nisms. In parallel to the pathway through the STN, in abnormal synchrony of GPi neuronal discharge and signals are sent from all areas of the cerebral cortex to loss of the normal spatial and temporal focus of GPi the striatum. The cortical inputs are transformed by activity.34–36 Broad lesions of the GPi or SNpr disinhibit the striatal integrative circuitry to a focused, context- both desired and unwanted motor patterns leading to dependent output that inhibits specific neurons in inappropriate activation of competing motor patterns, the GPi. The inhibitory striatal input to the GPi is but normal generation of the wanted movement. Thus slower, but more powerful, than the excitatory STN lesions of the GPi cause cocontraction of multiple mus- input. The resulting focally decreased activity in the cle groups and difficulty turning off unwanted motor GPi selectively disinhibits the desired thalamocorti- patterns, similar to what is seen in dystonia, but do cal MPGs. Indirect pathways from the striatum to the not affect movement initiation.37 Lesions of the SNpr GPi (striatum → GPe → GPi and striatum → GPe → cause unwanted saccadic eye movements that interfere STN → GPi) (Fig. 1-3) result in further focusing of with the ability to maintain visual fixation, but do not the output. The net result of basal ganglia activity dur- impair the initiation of voluntary saccades.38 Lesions ing a voluntary movement is the inhibition (braking) of the putamen may cause dystonia that is due to the of competing motor patterns and focused facilitation loss of focused inhibition in the GPi.33 Lesions of the (releasing the brake) from the selected voluntary move- STN produce continuous involuntary movements of ment pattern generators. the contralateral limbs (hemiballism or hemichorea).33 This scheme provides a framework for understand- Despite the involuntary movements, voluntary move- ing both the pathophysiology of parkinsonism22,34 and ments can still be performed. Although structural

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Cerebral cortex ganglia research over the past 15 years. If the success of a model is measured by the amount of research it stimulates, these schemes have been extraordinarily Striatum successful. In simple terms, these models proposed that hypokinetic movement disorders (e.g., parkinsonism) are distinguished from hyperkinetic movement disorders (e.g., chorea, dystonia, tics) based on the magnitude of basal ganglia output. Both clinical and basic research findings have required revision of the classic GPi model.22,33,39–41 New emphasis on (1) the importance of timing cortical input to the STN and the timing of STN input to GPi/SNpr,22,31 (2) the temporal-spatial organization of activity patterns in the different basal STN ganglia nuclei,22,33 and (3) the importance of spike train patterns36,39 reflect our improved understanding Thalamocortical and brainstem of basal ganglia function and dysfunction. It is our targets expectation that knowledge will continue to expand at Competing an impressive rate, with future revisions of the models motor patterns Desired to follow. motor pattern

Excitatory REFERENCES Inhibitory 1. Kemp JM, Powell TPS: The corticostriate projection in Figure 1-3. Schematic of normal functional organization of the monkey, Brain 93:525–546, 1970. the basal ganglia output. Excitatory projections are indicated 2. Fudge J, Kunishio K, Walsh C, et al: Amygdaloid pro- with open arrows; inhibitory projections are indicated with jections to ventromedial striatal subterritories in the filled arrows. Relative magnitude of activity is represented primate, Neuroscience 110:257–275, 2002. by line thickness. (Modified from Mink JW: Basal ganglia 3. Cherubini E, Herrling PL, Lanfumey L, Stanzione P: dysfunction in Tourette’s syndrome: a new hypothesis, Excitatory amino acids in synaptic excitation of rat stri- Pediatr Neurol 25:190–198, 2001.) atal neurones in vitro, J Physiol 400:677–690, 1988. 4. Alexander GE, DeLong MR, Strick PL: Parallel organi- lesions of the putamen, GPi, SNpr, or STN produce zation of functionally segregated circuits linking basal certain types of unwanted movements or behaviors, ganglia and cortex, Ann Rev Neurosci 9:357–381, 1986. they do not produce tics. Tics are more likely to arise 5. Wilson CJ, Groves PM: Fine structure and synaptic con- from abnormal activity patterns, most likely in the nections of the common spiny neuron of the rat neostriatum.33 striatum: a study employing intracellular injection of horseradish peroxidase, J Comp Neurol 194:599–614, Our scheme of basal ganglia function was devel- 1980. oped specifically for the motor circuits of the basal 6. Selemon LD, Goldman-Rakic PS: Longitudinal topog- 22 ganglia-thalamocortical system. However, it is likely raphy and interdigitation of corticostriatal projections in that the fundamental principles of function in the the rhesus monkey, J Neurosci 5:776–794, 1985. somatomotor, oculomotor, limbic, and cognitive 7. Flaherty AW, Graybiel AM: Corticostriatal transforma- basal ganglia circuits are similar. The basic scheme of tions in the primate somatosensory system. Projections facilitation and inhibition of competing movements from phsyiologically mapped body-part representations, can be extended to encompass more complex behav- J Neurophysiol 66(4):1249–1263, 1991. iors and thoughts. Thus, many features of basal gan- 8. Mallet N, Le Moine C, Charpier S, Gonon F: glia disorders can be explained as failed facilitation Feedforward inhibition of projection neurons by fast- of wanted behaviors, failed inhibition of unwanted spiking GABA interneurons in the rat striatum in vivo, J Neurosci 25(15):3857–3869, 2005. behaviors, or both. 9. Bouyer JJ, Park DH, Joh TH, Pickel VM: Chemical and The scheme presented here differs in emphasis structural analysis of the relation between cortical inputs from the now classic model of basal ganglia circuitry and tyrosine hydroxylase-containing terminals in rat that emphasizes opposing direct and indirect path- neostriatum, Brain Res 302:267–275, 1984. ways from striatum to GPi/SNpr.12,13 These models 10. Sibley DR, Monsma FJ: Molecular biology of dopamine have contributed substantially to advances in basal receptors, Trends Pharm Sci 13:61–69, 1992.

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11. Gerfen CR, Engber TM, Mahan LC, et al: D1 and D2 dop- distribution of pallidal axonal endings in the centre amine receptor-regulated gene expression of striatonigral median-parafascicular complex of macaques, Brain Res and striatopallidal neurons, Science 250:1429–1432, 473:181–186, 1988. 1990. 27. Hoover JE, Strick PL: Multiple output channels in the 12. Albin RL, Young AB, Penney JB: The functional anat- basal ganglia, Science 259:819–821, 1993. omy of basal ganglia disorders, Trends Neurosci 12:366– 28. Haber SN, Fudge JL, McFarland NR: Striatonigrostriatal 375, 1989. pathways in primates form an ascending spiral from the 13. DeLong MR: Primate models of movement disorders of shell to the dorsolateral striatum, J Neurosci 20:2369– basal ganglia origin, Trends Neurosci 13:281–285, 1990. 2382, 2000.

14. Hernandez-Lopez S, Bargas J, Surmeier DJ, et al: D1 29. Alexander GE, Crutcher MD: Functional architecture of receptor activation enhances evoked discharge in neo- basal ganglia circuits: neural substrates of parallel processing, striatal medium spiny neurons by modulating an L-type Trends Neurosci 13(7):266–271, 1990. Ca2+ conductance, J Neurosci 17(9):3334–3342, 1997. 30. Bolam JP, Hanley JJ, Booth PA, Bevan MD: Synaptic organ- 15. Nicola S, Surmeier J, Malenka R: Dopaminergic modu- isation of the basal ganglia, J Anat 196:527–542, 2000. lation of neuronal excitability in the striatum and nucleus 31. Nambu A, Tokuno H, Hamada I, et al: Excitatory corti- accumbens, Ann Rev Neurosci 23:185–215, 2000. cal inputs to pallidal neurons via the subthalamic nucleus 16. Jog M, Kubota Y, Connolly C, et al: Building neural rep- in the monkey, J Neurophysiol 84:289–300, 2000. resentations of habits, Science 286:1745–1749, 1999. 32. Parent A, Hazrati LN: Anatomical aspects of informa- 17. Schultz W, Romo R, Ljungberg T, et al: Reward-related tion processing in primate basal ganglia, Trends Neurosci signals carried by dopamine neurons. In Houk JC, et al, 16(3):111–116, 1993. editors: Models of information processing in the basal gan- 33. Mink J: The basal ganglia and involuntary movements: glia, Cambridge, 1995, MIT Press. impaired inhibition of competing motor patterns, Arch 18. Matsumoto N, Hanakawa T, Maki S, et al: Role of nigro Neurol 60:1365–1368, 2003. striatal dopamine system in learning to perform sequen- 34. Boraud T, Bezard E, Bioulac B, Gross CE: From single tial motor tasks in a predictive manner, J Neurophysiol extracellular unit recording in experimental and human 82:978–998, 1999. parkinsonism to the development of a functional con- 19. Penny GR, Afsharpour S, Kitai ST: The glutamate decar- cept of the role played by the basal ganglia in motor boxylase-, leucine enkephalin-, methionine enkephalin- control, Prog Neurobiol 66:265–283, 2002. and substance P-immunoreactive neurons in the 35. Tremblay L, Filion M, Bedard PJ: Responses of pallidal neostriatum of the rat and cat: evidence for partial popu- neurons to striatal stimulation in monkeys with MPTP- lation overlap, Neuroscience 17:1011–1045, 1986. induce parkinsonism, Brain Res 498:17–33, 1989. 20. Graybiel AM, Aosaki T, Flaherty AW, Kimura M: 36. Raz A, Vaadia E, Bergman H: Firing patterns and correla- The basal ganglia and adaptive motor control, Science tions of spontaneous discharge of pallidal neurons in the 265:1826–1831, 1994. normal and the tremulous 1-methyl-4-phenyl-1,2,3, 21. Gerfen CR: The neostriatal mosaic: multiple levels of 6-tetrahydropyridine Vervet model of parkinsonism, compartmental organization in the basal ganglia, Ann J Neurosci 20:8559–8571, 2000. Rev Neurosci 15:285–320, 1992. 37. Mink JW, Thach WT: Basal ganglia motor control. III. 22. Mink JW: The basal ganglia: focused selection and inhi- Pallidal ablation: normal reaction time, muscle cocon- bition of competing motor programs, Prog Neurobiol traction, and slow movement, J Neurophysiol 65:330– 50:381–425, 1996. 351, 1991. 23. Nambu A, Takada M, Inase M, Tokuno H: Dual somato- 38. Hikosaka O, Wurtz RH: Modification of saccadic eye topical representations in the primate subthalamic nucleus: movements by GABA-related substances. II. Effects of evidence for ordered but reversed body-map transforma- muscimol in monkey substantia nigra pars reticulata, tions from the primary motor cortex and the supplemen- J Neurophysiol 53(1):292–308, 1985. tary motor area, J Neurosci 16(8):2671–2683, 1996. 39. Vitek JL: Pathophysiology of dystonia: a neuronal model, 24. Percheron G, Yelnik J, Francois C: A Golgi analysis of Mov Disord 17:S49–S62, 2002. the primate globus pallidus. III. Spatial organization of 40. Hutchison WD, Lang AE, Dostrovsky JO, Lozano AM: the striato-pallidal complex, J Comp Neurol 227:214– Pallidal neuronal activity: implications for models of 227, 1984. dystonia, Ann Neurol 53:480–488, 2003. 25. Parent A: Extrinsic connections of the basal ganglia, 41. Hutchison WD, Dostrovsky JO, Walters JR, et al: Neuronal Trends Neurosci 13(7):254–258, 1990. oscillations in the basal ganglia and movement disor- 26. Francois C, Percheron G, Yelnik J, Tande D: A topo- ders: evidence from whole animal and human recordings, graphic study of the course of nigral axons and of the J Neurosci 24:9240–9243, 2004.

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Introduction between human genetics and animal models may eventually improve our therapeutics for these diseases. The objective of this chapter is to provide an overview The child’s cerebellar gray and white matter are of the basic anatomic and functional organization of both developing, resulting in the child learning to the cerebellum and its inflow and outflow pathways control eye movements, muscles of speech, axial relevant to medical decision making in children. This truncal muscles, and distal muscles.

information provides a context for understanding the At a gross structural level, one can think about the O symptoms of congenital, genetic, and acquired ataxias spectrum of cerebellar signs in terms of the three func- and aids in making decisions about a diagnostic assess- tional divisions of the cerebellum: (1) the vestibulocer- ment, particularly in cases where the initial clinical pre- ebellum, in the flocculonodular lobe, involved in axial sentation and neuroimaging findings are nonspecific. control and balance and positional reflexes; (2) the spi- Topics of more limited relevance to children, such as nocerebellum, in the vermis and intermediate part of the the circulatory system, are omitted. cerebellar hemispheres, involved in ongoing maintenance A number of challenges make diagnosis of cerebellar of tone, execution, and control of axial and proximal disorders and diseases more difficult in pediatric move- (vermis) and distal movements; and (3) the cerebrocere- ment disorders. First, in children these diagnoses are made bellum, in the lateral part of the hemisphere, involved in in the context of a developing motor system. Thus poten- initiation, motor planning, and timing of coordinated tially abnormal findings must be judged in the context of movements. Functional Anatomy of the Cerebellum the broad limits of normal motor development. Second, and Associated Signs are presented in Table 2-1. movement disorders in children are usually mixed, not pure. Multiple symptoms, including both involuntary Macroscopic to Microscopic movements from the basal ganglia and abnormal motor Cerebellar Structure control or coordination from the cerebellum, may be involved in the same disease process. Third, in the presence The cerebellum contains more than half of all neurons of epilepsy, cognitive dysfunction, or behavior problems, in the central nervous system.3 Its organization is hier- medications may be prescribed that precipitate, exacer- archic and highly regular. Understanding a simplified bate, or cause cerebellar (or basal ganglia) dysfunction. model of cerebellar neurotransmission and anatomy is This chapter provides merely an overview. helpful for understanding management of diseases and disorders causing ataxia. Understanding this system in Overview of Cerebellar Structure, greater detail may be useful for making more challeng- Function, and Symptoms ing diagnostic and treatment decisions, as well as for Our present, incomplete understanding of cerebellar understanding the direction future research and treat- function and disease has evolved over the last 100 years ments may take. through painstaking clinical and pathologic observation Cerebellar Structural “Threes” and ablational studies in animals.1,2 Neuroimaging of structure and function has vastly increased our under- Heuristically, three is a helpful mnemonic for remember- standing of the cerebellum in motor control, as well as ing cerebellar anatomy. The cerebellum has three major other functions. Neurophysiologic studies in animals anatomic components that may be affected by focal and humans continue to provide new information. pathologic processes; three major functional regions Genetic discoveries and the back-and-forth interplay that correspond moderately to these components and

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Table 2-1 Functional Anatomy of the Cerebellum Eye Movements Anatomy Vestibulocerebellum Vestibular system afferents to the cerebellar flocculus, paraflocculus, dorsal vermis Function Integration of both position and velocity information so that the eyes remain on target Signs Nystagmus—oscillatory, rhythmic movements of the eyes Impairment with maintaining gaze Difficulties with smooth visual pursuit Undershooting (hypometria) or overshooting (hypermetria) of saccades

Speech Anatomy Spinocerebellum—vermis Cerebrocerebellum Sensory afferents from face Corticocerebellar pathway afferents, via pons

Function Ongoing monitoring, control of facial muscles Signs Dysarthria, imprecise production of consonant sounds (“ataxic dysarthria”) Dysrhythmia of speech production Poor regulation of prosody; slow, irregularly emphasized (i.e., scanning) speech

Trunk Movements Anatomy Vestibulocerebellum Spinocerebellum Sensory, vestibular, and proprioceptive afferents

Function Integration of head and body position information to stabilize trunk and head Signs Unsteadiness while standing or sitting, compensatory actions such as use of visual input or stabilization with hands Titubation—characteristic bobbing of the head and trunk

Limb Movements Anatomy Spinocerebellum Cerebrocerebellum Sensory and proprioceptive afferents to the spinocerebellum Corticocerebellar pathway afferents via pons

Function Integration of input from above—cortical motor areas—about intended commands allows for control of muscle tone in the execution of ongoing movement The spinocerebellum monitors and regulates ongoing muscle activity to compensate for small changes in load during activity and to dampen physiologic oscillation The cerebrocerebellar pathway input contains information about intended movement Signs Hypotonia—diminished resistance to passive limb displacement Rebound—delay in response to rapid imposed movements and overshoot Pendular reflexes Imprecise targeting of rapid distal limb movements Delays in initiating movement Intention tremor—tremor at the end of movement seen on finger-to-nose and heel-to-shin testing Dyssynergia/asynergia—decomposition of normal, coordinated execution of movement—errors in the relative timing of components of complex multijoint movements Difficulties with spatial coordination of hand and fine fractionated finger movements Dysdiadochokinesia—errors in rate and regularity of movements, including alternating movements; the terms asynergia or dyssynergia refer to the inability to coordinate voluntary movements

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Table 2-1 Functional Anatomy of the Cerebellum—Cont’d Gait Anatomy Vestibulocerebellum Spinocerebellum Cerebrocerebellum

Function Maintenance of balance, posture, tone, ongoing monitoring of gait execution Signs Broad-based, staggering gait

subserve somewhat distinct functions; three sets of Hemisphere Vermis paired peduncles that carry information into and out of the cerebellum via the pons; three cortical cell layers Primary fissure Anterior that interconnect via predominantly glutamatergic and lobe Horizontal GABAergic signals; and three deep cerebellar output fissure Posterior nuclei that transmit cerebellar signal out to ascending lobe and descending tracts. The Three Anatomic Regions— Posterior fissure Structures and Afferent Connections Flocculonodular Flocculus lobe The cerebellum has surface gray matter, medullary white matter, and deep gray matter nuclei. Analogous Nodulus to cerebral gyri and sulci, folia make up the surface Figure 2-1. Schematic of the three lobes of the cerebellum of the cerebellum. Beneath the folia, the white mat- (anterior, posterior, flocculonodular) and three anatomic ter myelinates during childhood and is susceptible regions (hemispheres, vermis, nodulus). (From Kandel: to a wide variety of diseases affecting white matter. Principles of neuroscience, ed 4. McGraw Hill Medical, 2000.) Innermost are the deep cerebellar nuclei. The clefts between folia run transversely, demarcating the three main anatomic regions, the flocculonodular, Table 2-2 lobes and Pathways in the anterior, and posterior lobes, as shown in Figure 2-1 Cerebellum and described in Table 2-2. Anatomic The Three Cerebellar Functional Regions Region Structures Input Connect to Three Deep Cerebellar Nuclei Flocculonodular Flocculus—two Vestibular lobe small appendages Decades of clinical observations, laboratory animal inferiorly located ablation studies, and more recent imaging studies have Nodulus—inferior informed current views of the three functional regions vermis of the cerebellum. These regions subserve basic func- Anterior lobe A smaller region Spinal cord— tions of execution and integration of information about of the cerebellar spinocer- balance, body position and movement, and motor plan- hemispheres and ebellar ning and timing. Output from these regions goes to the vermis anterior pathways to the primary deep nuclei. The deep cerebellar nuclei, arranged medi- cerebellar fissure ally to laterally, are the fastigial, interposed, and dentate nuclei, with the interposed consisting of two nuclei, the Posterior lobe Largest, most Cerebrocor- globose and emboliform. Anatomy, output nuclei, and lateral, and tical, via phylogenetically pons function of these regions are described in Table 2-3. latest region of cerebellar The Three Cerebellar Peduncles hemispheres Three paired sets of peduncles carry fibers to and from the cerebellum. Unlike the basal ganglia, the and body (spinocerebellar) are ipsilateral. Cerebellar cerebellum has a direct connection to the spinal connections with the cerebrum (cerebrocerebellar, cord. Cerebellar connections with the spinal cord via dentate-rubral-thalamic tract) are contralateral.

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Table 2-3 Summary of Cerebellar Structure and Function Functional Anatomic Output Nuclei Function Vestibulocerebellum Flocculonodular Vestibular nuclei (medulla, Balance, vestibular reflex, not cerebellum) axial control Spinocerebellum Vermis Fastigial nuclei Motor control and execution, axial and proximal muscles

Medial aspect of cerebellar Interposed (globose plus Motor control and execution, hemispheres emboliform) nuclei distal muscles Cerebrocerebellum Lateral cerebellar Dentate nuclei Planning, timing coordinated hemispheres movements

That is, motor control of the right side of the body is con- To thalamus and red nucleus trolled by the left cerebrum with the right cerebellum. Corticopontine fibers Connections from the cerebrum to the cerebellum, via Superior cerebellar pons, therefore cross on entry and exit. Ascending con- peduncle nections from the spinal cord largely do not. Figure 2-2 Cerebellum shows a schema of the key pathways through the peduncles, and additional detail is provided in Table 2-4. Pons Types of Afferent Fibers Pontine To vestib. mossy nuclei There are two distinct types of afferent fibers that carry fibers Dentate excitatory signals, predominantly via the inferior and Interposed middle peduncles, into the cerebellum. These are the Middle Fastigial mossy and climbing fibers, as shown in Table 2-5. Both cerebellar peduncle of these fiber types send a few collateral axons to the deep cerebellar nuclei. The Three Layers of Cerebellar Cortex Inferior cerebellar peduncle 4 Three layers make up the cerebellar cortex. A schema Climbing fibers Proprioceptive of the predominant cells and their interactions is from inferior olive information from spinocerebellar tract shown in Figure 2-3, and additional detail about these (mossy fibers) layers and their predominant cell types and functional connections are shown in Table 2-6. Figure 2-2. Schematic of the three primary afferent (inferior peduncles and, middle peduncles) and efferent (superior Neurotransmitters in the Cerebellum peduncles) pathways of the cerebellum. (From Washington University School of Medicine: Neuroscience tutorial. Basal Understanding the neurotransmitter systems in basal ganglia ganglia and cerebellum. Retrieved from http://thalamus.wustl. allows for more rational decisions about pharmacotherapy. edu/course/cerebell.html, 21 September 2009.) See Table 2-4.

Table 2-4 Cerebellar Peduncles, Fiber Bundles, and Deep Cerebellar Nuclei Targets Peduncles Afferent and Efferent Fibers Inferior Afferent fibers (to cerebellum) from multiple sources: the vestibular nerve, the inferior olivary nuclei, the spinal cord (dorsal and rostral spinocerebellar, cuneocerebellar, and reticulocerebellar tracts) Efferent fibers (from cerebellum): fastigiobulbar tract projecting to vestibular nuclei, completing a vestibular circuit

Middle Afferent fibers: from pons (crossed fibers from cerebral cortex to pontine gray matter nuclei to middle peduncle) Superior Afferent fibers: few fibers from ventral spinocerebellar, rostral spinocerebellar, and trigeminocerebellar projections Efferent fibers: rubral, thalamic, reticular projections from deep cerebellar nuclei—dentate, interposed nuclei

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At present, this is much less true in the cerebellum because receptors. The ionotropic glutamate receptors are a diverse the main neurotransmitters in the cerebellum are gluta- group classified into three types—AMPA (alpha-amino- mate and gamma-aminobutyric acid (GABA).5 There are 3-hydroxy-5-methyl-4-isoxazolepropionic acid), NMDA limited therapeutic options involving glutamatergic and (N-methyl-d-aspartic acid), and kainate. These are GABAergic systems for improving ataxia. ligand-gated ion channels, meaning that when glutamate binds, charged ions pass through a channel in the recep- Glutamate tor center. Both basket and stellate cells in the molecular Glutamate, the main excitatory neurotransmitter in layer express presynaptic AMPA receptors, to which over- the brain, acts at both ionotropic and metabotropic flow glutamate from climbing fibers can bind.6 The metabotropic glutamate receptors, which are Table 2-5 Functional Anatomy of Mossy G-protein–coupled receptors acting via second mes- and Climbing Fibers sengers, are expressed in a developmentally dependent fashion in the cerebellum,7 with mGluR1 receptors Mossy fibers— Excitatory, originating from the primary multiple brainstem nuclei and playing a significant role in postsynaptic, Purkinje cell afferents spinocerebellar tracts, synapse signaling. Clinically, this is relevant in paraneoplastic at the granule cells, carry tactile and autoimmune cerebellar diseases.8 For example, and proprioceptive information mGluR1 antibodies, which can occur in Hodgkin’s Climbing Excitatory, originating from the disease, cause a combination of acute, chronic/plastic, fibers— inferior olivary nucleus in the and degenerative effects in Purkinje cells.9 afferent cerebellum, climb up to the outer, molecular layer and synapse on the Glutamate Transporters soma and dendrites of the Purkinje Glutamate transporters are important for glutamatergic cells; carry information critical for error correction neurotransmission, as well as excitatory neuropathology. Excitatory amino acid transporters (EAAT) 1, 2, and 3

Parallel Purkinje cell Parallel fiber Purkinje cell fiber

+ Molecular + + layer Molecular layer + +

Purkinje Purkinje cell layer cell layer Purkinje cell Granule + Granular cell layer Climbing fiber Mossy fiber Granular layer Cerebellar − Granule nuclear + cell cell Mossy + fiber Stellate To thalamus cell Basket Climbing Golgi cell and descending cell fiber motor tracts From From brainstem Purkinje inferior nuclei and spinal cord cell axon olive

Figure 2-3. Schematic of the three primary cell layers (granular, molecular, and Purkinje) of the cerebellum. (From Apps R, Garwicz M: Anatomical and physiological foundations of cerebellar information processing, Nature Rev Neurosci 6:297–311, 2005.)

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Table 2-6 Cerebellar Layers, Cell Types, and Function Layer Cells Input/Output and Function Innermost—granular cell Granule cells Densely packed granule cells receive excitatory input from layer ascending mossy fibers. Granule cells are the only excitatory cells within the cerebellum. Axons ascend toward outer, molecular layer where they synapse and form parallel fibers.

Golgi cells Receive excitatory, glutamatergic26 input from granule cells and provide negative GABAergic feedback to granule cells. Receive glycinergic and GABAergic input from the Lugaro cells.27

Lugaro cells Low prevalence interneurons, receive serotonergic input.19 Inhibit golgi cells.

Outermost—molecular Parallel fibers These are the bifurcated axons from granule cell layers. They layer have excitatory synapses directly on Purkinje cell dendrites and on stellate and basket interneurons.

Stellate and basket Excited by glutamatergic input from parallel fibers from granule cells cells. Output inhibitory on Purkinje cells. Middle—Purkinje Purkinje cells These cells have extensive dendrites in the molecular layer. cell layer Cell bodies are in a single layer. Output is inhibitory to deep cerebellar nuclei. are expressed in the motor cortex, but EAAT1 pre- in the molecular layer.17 Ethanol affects cerebellar dominates in the cerebellum,10 where it is expressed in function via GABA-a receptor binding, but may also Bergmann glial cell processes and is also known as the suppress responses in Purkinje cells to mGluR1 excita- glutamate aspartate transporter (GLAST). This plays tion from climbing fibers.18 an important role in glutamate reuptake shortly after Acetylcholine, Dopamine, synaptic release. Excitatory amino acid transporter 4 Norepinephrine, and Serotonin (EAAT4) is found on extrasynaptic regions of Purkinje cell dendrites and reduces spillover of glutamate to Acetylcholine, dopamine, norepinephrine, and sero- adjacent synapses.11 Colocalization of these transport- tonin19 and their receptors occur in the cerebellum. ers with perisynaptic mGluR1 receptors results in com- However, the clinical effects of these neurotransmitter petition for glutamate, and this interaction modulates systems in the cerebellum are poorly understood and at neuroplasticity in the cerebellum.12,13 this time seem not to be very helpful for ataxia. In general, the medications physicians use to suppress or modify Gamma-Aminobutyric Acid (GABA) movement disorders, or to improve mood or cognition, GABA is the major inhibitory neurotransmitter in the do not improve or worsen ataxia. Recognition, in mixed cerebellum, as well as the cerebrum. Its synthesis from movement disorders, of the cerebellar ataxia compo- glutamate is catalyzed by the enzyme glutamic acid nent can help with realistic assessment of the probable decarboxylase (GAD). Anti-GAD antibodies have been benefits of pharmacologic interventions. For example, reported in adults with ataxia.14 GABA acts via chlo- in mixed dystonia and ataxia, the dystonia may respond ride channels to hyperpolarize neurons. GABA recep- to anticholinergics but cerebellar symptoms will not. tors include GABA-A and GABA-C receptors, which Endocannabinoids are ionotropic, and GABA-B receptors, which are metabotropic, G-protein–coupled receptors. GABA-A Another important neurotransmitter system in the cer- receptors also have allosteric binding sites for other com- ebellum is the endocannabinoid (endogenous cannabi- pounds including barbiturates, ethanol, neurosteroids, noid) system.20,21 This system is involved in so-called and picrotoxin. Baclofen is a GABA-B agonist. retrograde signaling in the hippocampus, basal ganglia, GABA-A receptors are predominantly in the gran- and cerebellum, whereby postsynaptic neurons release ule cell layer,15 where they receive GABA input from endocannabinoids from their dendrites. These endo- the Golgi cells, and to a lesser extent they are present cannabinoids bind to cannabinoid receptor 1 (CB1) on the molecular layer interneurons, the basket and on the presynaptic terminal, resulting in a transient stellate cells.16 GABA-B receptors are predominantly suppression of presynaptic neurotransmitter release.

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Activation, on Purkinje cells, of metabotropic glutamate 12. Otis TS, Brasnjo G, Dzubay JA, Pratap M: Interactions receptors subtype 1 (mGluR1) reduces neurotransmitter between glutamate transporters and metabotropic glu- release from excitatory climbing fibers via this system. tamate receptors at excitatory synapses in the cerebellar In addition, it has recently been shown that GABAergic cortex, Neurochem Int 45:537–544, 2004. basket and stellate cells, in the molecular layer, regulate 13. Wadiche JI, Jahr CE: Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity, presynaptic neurotransmission from excitatory parallel Nature Neurosci 8:1329–1334, 2005. fibers, from the granule cells. This system is also 14. Manto MU, Laute MA, Aguera M, et al: Effects of anti- 22,23 involved in cerebellar neuroplasticity and may glutamic acid decarboxylase antibodies associated with thereby affect cerebellar contribution to learning. The neurological diseases, Ann Neurol 61:544–551, 2007. significance of pathology within this system in children 15. Palacios JM, Young WS 3rd, Kuhar MJ: Autoradiographic is currently unknown, although both active marijuana localization of gamma-aminobutyric acid (GABA) use and the exposure to cannabis prenatally may have receptors in the rat cerebellum, Proc Natl Acad Sci U S A adverse cognitive effects involving the cerebellum.24,25 77:670–674, 1980. 16. Trigo FF, Chat M, Marty A: Enhancement of GABA Conclusion release through endogenous activation of axonal GABA(A) receptors in juvenile cerebellum, J Neurosci This overview of cerebellar function provides a frame- 27:12452–12463, 2007. work for understanding cerebellar disorders and 17. Wilkin GP, Hudson AL, Hill DR, Bowery NG: diseases, including mixed movement disorders that Autoradiographic localization of GABA-B receptors in involve cerebellar function. rat cerebellum, Nature 294:584–587, 1981. 18. 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Arriza JL, Fairman WA, Wadiche JI, et al: Functional com- mGluR3, show unique postsynaptic, presynaptic and parisons of three glutamate transporter subtypes cloned from glial localizations, Neuroscience 71:949–976, 1996. human motor cortex, J Neurosci 14:5559–5569, 1994. 27. Dumoulin A, Triller A, Dieudonne S: IPSC kinetics at 11. Takayasu Y, Iino M, Kakegawa W, et al: Differential roles identified GABAergic and mixed GABAergic and glycin- of glial and neuronal glutamate transporters in Purkinje ergic synapses onto cerebellar Golgi cells, J Neurosci cell synapses, J Neurosci 25:8788–8793, 2005. 21:6045–6057, 2001.

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Introduction related condition? Does the movement disorder abate with sleep? Movement disorders are neurologic syndromes that In clinical practice, the diagnosis of a movement dis- involve impaired performance of voluntary movements, order requires a qualitative appreciation of the move- dysfunction of posture, the presence of abnormal invol- ment type and context. Abnormal movements can be untary movements, or the performance of normal- difficult to define. To best classify the disorder phenom- appearing movements at inappropriate or unintended enologically, one should describe the characteristics of times. The abnormalities of movement are not caused by the movements. Even under the best circumstances, weakness or abnormal muscle tone, but may be accom- movement disorders may be difficult to characterize. panied by weakness or abnormal tone. By convention, Chorea can resemble myoclonus. Dystonia can resem- Omovement disorders are divided into two major catego- ble spasticity. Paroxysmal movement disorders such ries. The first category is hyperkinetic movement dis- as dystonia and tics may resemble other paroxysmal orders, sometimes referred to as dyskinesias. This term neurologic problems, namely seizures. Movements refers to abnormal, repetitive, involuntary movements in some contexts may be normal and in others may and includes most of the childhood movement dis- indicate underlying pathology. Movements that are orders, including tics, stereotypies, chorea, dystonia, worrisome for a degenerative disorder in adolescents myoclonus, and tremor. The second category is hypo- (myoclonus) may be completely normal in an infant kinetic movement disorders, sometimes referred to as (benign neonatal myoclonus). It can be quite difficult akinetic/rigid disorders. The primary movement disorder to specifically diagnose a movement disorder without in this category is parkinsonism, manifest primarily in seeing the abnormal movements. Thus obtaining video adulthood as Parkinson’s disease or one of many forms examples of the child’s movement may be essential to of secondary parkinsonism. Hypokinetic disorders are making a correct diagnosis. The video atlas accom- relatively uncommon in children. Although weakness panying this book provides examples of the different and spasticity are characterized by motor dysfunction, types of movement disorders. by common convention these entities are not included Many classification schemes have been used to pro- among the category “movement disorders.” vide a taxonomy for the wide variety of movement When faced with a movement disorder, the first disorders. Disorders can be classified by phenom- step is to characterize the movement phenomena. Is the enology, based on the observed temporal and spatial pattern of movements normal or abnormal? Are there features of the movements themselves, along with char- excessive movements or is there a paucity of movement? acteristic clinical features. They can also be classified Is there decomposition or disorder of voluntary move- based on presumed etiology, anatomic localization, or ment trajectories? Is the movement paroxysmal (sud- neuropathologic features; by disease course; by genetic den onset and offset), continual (repeated again and or molecular criteria; or by other biologic factors.1–3 This again), or continuous (without stop)? Has the move- chapter is limited to classification based on phenome- ment disorder changed over time? Do environmental nology. The disorders are described alphabetically. stimuli or emotional states modulate the movement disorder? Can the movements be suppressed volun- Ataxia (Chapter 13) tarily? Is the abnormal movement heralded by a premonitory sensation or urge? Are there findings on the Ataxia literally means “without order.” It is defined as examination suggestive of focal neurologic deficit or an inability to generate a normal or expected volun- systemic disease? Is there a family history of a similar or tary movement trajectory that cannot be attributed

16 [email protected] 66485438-66485457 Chapter 3 Classification of Movement Disorders 17

to weakness or involuntary muscle activity about the Board of the Dystonia Medical Research Foundation affected joints.4 Ataxia can result from impairment of (www.dystonia-foundation.org) has adopted the fol- spatial pattern of muscle activity or from impairment lowing definition: “Dystonia is a syndrome of sustained of the timing of that activity, or both. Specific associ- muscle contractions, frequently causing twisting and ated deficits include dysmetria (inaccurate movement repetitive movements, or abnormal postures.” to a target – undershoot or overshoot), dyssynergia (decomposition of multijoint movements), and dysdi- Myoclonus (Chapter 11) adochokinesis (impaired rhythmicity of rapid alternat- refers to quick, shock-like movements of ing movements). Myoclonus O one or more muscles. The term is usually applied to Athetosis (Chapter 9) describe positive myoclonus: sudden, quick, involuntary muscle jerks caused by muscle contraction. In contrast, Athetosis literally means “without fixed position.” It is negative myoclonus refers to sudden, brief interruption defined as slow, writhing, continuous, involuntary of contraction in active postural muscles.7 Asterixis is a movements. There is some debate as to whether athetosis form of negative myoclonus. Both negative myoclonus should be considered as a discrete entity, or whether it and positive myoclonus occur in children, but through- is part of the spectrum of dystonia or chorea.5 Many out the chapter, myoclonus will mainly refer to posi- movement disorder specialists restrict the term athetosis tive myoclonus. Startle syndromes will also be discussed to describe a form of cerebral palsy. in Chapter 11. Startles are brief, generalized motor responses similar to myoclonus. Ballismus (Chapter 9) Ballismus or ballism refers to involuntary, high-ampli- Parkinsonism (Chapter 14) tude, flinging movements typically occurring proxi- Parkinsonism is a neurologic syndrome characterized mally. These movements may be brief or continual and by presence of two or more of the cardinal features of may occur in conjunction with chorea. Often, one side Parkinson’s disease, including tremor at rest, bradyki- of the body is affected, that is, hemiballism. In many nesia, rigidity, and postural instability. There are many cases, hemiballism becomes milder with time and causes of parkinsonism. evolves into chorea. It has been suggested that because the same lesions can produce both ballismus and cho- Stereotypies (Chapter 7) rea, ballismus is likely to be part of the spectrum of chorea and not a separate entity.6 Stereotypies are broadly defined as involuntary, patterned, coordinated, repetitive, nonreflexive movements Chorea (Chapter 9) that occur in the same fashion with each repetition. Often the movements are rhythmic. Chorea literally means “dance-like.” It refers to an involuntary, continual, irregular hyperkinetic dis- Tics (Chapter 6) order in which movements or movement fragments with variable rate and direction occur unpredictably Tics are involuntary, sudden, rapid, abrupt, repetitive, and randomly. Some movements may be flowing nonrhythmic, simple or complex movements or vocal- (similar to athetosis) or rapid (similar to myoclo- izations (phonic productions). Tics are classified into nus). All body parts may be involved, with certain two categories (motor and phonic), with each being distributions more characteristic of distinct diseases subdivided into a simple and complex grouping. Tics or disorders. are usually preceded by an uncomfortable feeling or urge that is relieved by carrying out the movement. Dystonia (Chapter 10) Tremor (Chapter 12) Dystonia is a syndrome of intermittent and sustained involuntary muscle contractions that produce abnor- Tremor refers to oscillating, rhythmic movements about mal postures and movements of different parts of the a fixed point, axis, or plane that occur when antagonist body.3 The term dystonia is used for the neurologic sign muscles contract alternately. Usually this involves oscil- of abnormal sustained twisting postures, for the clini- lation around a joint and produces a visible movement. cal syndrome of dystonia, or for specific diseases. In an Rhythmic palatal myoclonus is included by some effort to be uniform and specific, the Scientific Advisory authors as a form of tremor.

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REFERENCES 4. Sanger TD, Chen D, Delgado MR, et al: Definition and classification of negative motor signs in childhood, 1. Barbeau A, Duvoisin RC, Gerstenbrand F, et al: Pediatrics 118:2159–2167, 2006. Classification of extrapyramidal disorders. Proposal for an 5. Morris JG, Jankelowitz SK, Fung VS, et al: Atheto international classification and glossary of terms, J Neurol sis I: historical considerations, Mov Disord 17:1278– Sci 51:311–327, 1981. 1280, 2002. 2. Klein C: Movement disorders: classifications, J Inherit 6. Mink JW: The basal ganglia: focused selection and inhi- Metab Dis 28:425–439, 2005. bition of competing motor programs, Prog Neurobiol 3. Fahn S, Jankovic J: Principles and practice of movement 50:381–425, 1996. disorders, Philadelphia, 2007, Churchill Livingstone, 7. Shibasaki H: Pathophysiology of negative myoclonus and Elsevier. asterixis, Adv Neurol 67:199–209, 1995.

[email protected] 66485438-66485457 Diagnostic Evaluation of O 4 Children with O Movement Disorders

1–3 Introduction problems. In contrast, the rarest movement disorders will never be diagnosed by most neurologists. However, Diagnosis of movement disorders involves recognition the presentation of a child with some rare movement O and classification of phenomenology, as well as knowl- disorder is not a rare event in child neurology. These edge of neuroanatomy, as discussed in the first chapters diagnoses can be time-consuming for physicians, emo- of this book. By definition, movement disorders are not tionally difficult for families, and costly for the health (usually) the product of an interruption in the terminal care system. Parents want their physicians to make a pathway from the primary motor cortex to muscle. For diagnosis, even if no medical treatment is available. example, motor cortex strokes, spinal cord diseases, A systematic approach to diagnosis of both rare and anterior horn cell diseases, neuropathies, diseases at the common movement disorders is a pragmatic goal of this neuromuscular junction, and myopathies are not desig- chapter. The approach is based on knowledge of neu- nated as movement disorders, even though they interfere roanatomy, reviewed in the first two chapters, skill in with movement. Rather, movement disorders usually phenomenology classification, reviewed in the third, and involve subcortical and cerebellar structures and circuits knowing how to get the most information possible from “upstream” from the final common pathway from motor the clinical encounter. This chapter is not an encyclo- cortex to muscle. These circuits subserve planning, selec- pedia or a reference list of diagnoses, of variably present tion, timing, and inhibition of movement. clinical features, and of genes. That information is left for It is also helpful throughout the diagnostic process more detailed presentation in the phenomenology-based to recognize the importance of a normally functioning chapters. A better approach is to know how to obtain motor system to the patient and family. Full control over the most current information at the time the patient and one’s motor system for the execution of actions is taken family need it. With this foundation and the approach for granted by most persons during all waking hours. in this chapter, a provisional diagnosis, or at least a nar- Development of movement control is a basic expecta- rowed differential diagnosis, should be achieved for most tion of childhood, and loss of this control has psycho- children referred for movement disorders. logic consequences. Training in execution of particular, The skill of recognition of movement disorder phe- skilled actions may occupy hundreds or thousands of nomenology involves both visual pattern recognition hours in the lives of professional musicians, artists, or and conceptual understanding of classification systems. athletes. Any disease or disorder that interferes with the A unique challenge in children is that the nervous system execution of movements can cause substantial impair- is developing. Diseases manifest in different forms at dif- ment, psychologic distress, and reduced quality of life, ferent stages of motor system maturation. Also, of course, in children or adults. children may not communicate symptoms and will The most common movement disorders in childhood not always cooperate with the examination. Diagnosis will be seen by any general neurologist who evaluates through pattern recognition is greatly enhanced by clini- children. These diagnoses are relatively straightforward, cal experience but also by the study of case videos. requiring little time, effort, or health care resources. The This chapter is organized in the framework of a new diagnostic challenge for these conditions is recogni- clinic visit for a chief complaint of a movement disorder, tion of commonly co-occurring emotional or cognitive where the initial goal is diagnosis. The elements of a

19 [email protected] 66485438-66485457 20 Section 1 overview typical outpatient visit form the chapter sections. The communication about urgent visits. Recognizing both use of computer databases for diagnosis is discussed in real disability and overwhelming distress in some parents, the final section. it is important to have mechanisms in place to see appropriate patients quickly, either in clinic or as hospital con- Preclinic sultations. The primary physician should advocate for such patients with a phone call or an email to the spe- The Scheduling Process cialists. Parents often advocate directly for their children Some institutions support clinics devoted specifically to through phone calls or emails. An advantage of email is pediatric movement disorders. This requires an appro- that parents can provide chief complaint and history of priate triaging process where schedulers have a list of present illness data in advance. Some practices then also chief complaints. Essentially, the appropriate referrals email standard new visit intake questionnaires. are the list of chapter titles in this book. For children, this works well for common problems such as tremor or Gathering Data before the Visit tics that are readily recognized. Other problems, such Standardized intake questionnaires can yield essen- as ataxia or chorea, create greater difficulties because tial information for the diagnostic evaluation. Much referring physicians and office staff may not know how of this information can be effectively provided by par- to describe the problem or whether it is a movement ents before the visit. Emailing intake questionnaires disorder. However, once a clinic program becomes before the visit can be cost effective. Advance review established and with good physician communication, by the nursing staff can also help identify patients who the percentage of appropriate referrals improves. should be seen more promptly or arrange for testing to Urgent Referrals be done efficiently in concert with the visit. Videos can be sent in advance via email or websites. Most movement disorders are chronic. Therefore medically urgent scheduling is not typical. However, In Clinic some movement disorders, including those listed in Table 4-1, may emerge and become disabling fairly rap- The goal of the first clinic encounter is to arrive at a idly. Costly emergency department visits sometimes can diagnosis or to allow a plan to be put in place to find the be avoided with flexible scheduling and doctor-doctor etiology of the movement disorder. It is helpful to bear

TABLE 4-1 Acute, Subacute Pediatric Movement Disorders That May Manifest Urgently Movement Disorder Most Common Etiology or Phenomenology Precipitant Comment Chorea Poststreptococcal (Sydenham), Usually causes significant functional other immune mediated interference Acute ataxia Postinfectious/postvaccine Usually causes significant functional interference Opsoclonus-myoclonus Postinfectious/postvaccine Usually causes significant functional interference Akathisia, ataxia, chorea, dyskine- Drug-induced Acute, chronic (tardive), or withdrawal sias, dystonia, tics, tremor while emergent symptoms taking psychiatric medications

Chorea/ballism Fever/illness in children with Can lead to rhabdomyolysis dyskinetic cerebral palsy

Tics Sometimes acute stressor Tic disorders may manifest dramatically or have severe, fairly sudden exacerbations; a specific precipitant is not always found Psychogenic tremor/shaking, Acute stressors often Early diagnosis is probably critical tics, gait disturbance, dystonia identified for improving prognosis

[email protected] 66485438-66485457 Chapter 4 Diagnostic Evaluation of Children with Movement Disorders 21 in mind that the most common movement disorder Many children are anxious in clinic and may be embar- complaints in children are emotionally distressing to rassed about their movement disorder, or excessive parents, but are not life-threatening or indicative of a anxiety may be part of their phenotype. Sensing this, progressive neurologic disease. Through history, exam- a clinician may set the child more at ease by indicating ination, and direct observation, the clinician should that he has observed the movements during the con- obtain an accurate impression of the movement phe- versation and that they resemble movements in some nomenology. Another important goal is to establish a other boys and girls. The reassured, less anxious child trusting relationship with the child and family to facili- may then be able to provide additional important infor- tate appropriate, beneficial long-term management. mation and cooperation during the examination. Data about the movement disorder to be obtained In the Waiting Room/Check-in by from the child include the following: Ancillary Personnel or Nursing • Awareness Some information about phenomenology can be gathered • Preceding urges or sensations before entry into the clinic room. One obvious example • Volition and suppressibility is loud vocal tics. However, more severe problems affect- • Effect of action ing gait or involuntary movements can be observed in • Other exacerbating or ameliorating factors the waiting room or when the nurse checks vitals. Staff • Associated pain can also gauge parental anxiety and may record the pri- • Functional interference with previously discussed mary movement disorder of concern to the family. Some fun activities parents may wish to discuss the chief complaint with the • Notice of the movement by previously discussed physician separately, without the child present. This is friends or teachers generally counterproductive, as it may reinforce or create • Associated social embarrassment/effect on peer anxiety in the child about the problem. relationships • Historical and subjective information for movement The First Physician Encounter in the disorder rating scales Clinic Room Interviewing the Parents/Guardians The first minutes of the clinic room encounter with the physician are very important for both the diagno- During the remainder of the history, the parents/ sis and the therapeutic alliance. After a brief introduc- guardians can provide complementary and usually tion to parents, the clinician should focus on the child. more detailed and accurate information. This may be This provides an important opportunity for observa- efficiently provided as well on a standardized intake tion, during which the chief complaint may be directly questionnaire. In particular, parents/guardians can observed. For an infant this can involve complimenting provide the following information: the child’s appearance and asking to hold him or her. • Verification of the details above, provided by the child For toddlers or older children who may be playing in • Past treatments the room, watching their play with toys can be useful. • Past diagnostic testing • Past school testing (e.g., test scores and reading Interviewing the Child ability) The diagnostic assessment is best served by opening • Emotional/behavioral and cognitive problems the conversation with topics such as fun after-school • Current and past medications activities, hobbies, sports, music participation, and • Past medical history best friends. An age-appropriate conversation about • Detailed prenatal and perinatal history including these topics helps make the child feel comfortable, so maternal health, diseases, medication or substance that the history and examination are more likely to be use, delivery, post-natal hospitalization, jaundice informative. This also provides essential information • Other medical diagnoses for assessing symptom-related impairment and making • Neurologic development treatment decisions later. Finally, parents and children • Skill acquisition—gross motor, fine motor, speech, usually appreciate kind and direct interaction by the and language physician with the child. • Academic performance During this conversation, continuous abnormal • Review of systems movements will be observed if present. Also, many inter- • Family history—movement disorders, neurologic, mittent or paroxysmal movements may be observed. psychiatric, or learning disorders and diseases

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• At least three generations (siblings; parents, aunts, The General Physical Examination uncles; grandparents) The goal of the general examination is to identify • Parent education and occupation additional features of the phenotype that provide • Social history/recent stressors/substance abuse history diagnostic clues and aid in medical decision making. • Information for rating scale scores Characteristic findings in other organs narrow the differential diagnosis. The eye examination may require The family history may be critical to identify- ophthalmology consultation. The presence of skin pig- ing the etiology. Neurologists must understand mentary abnormalities or dysmorphic face, trunk, limb patterns of inheritance: autosomal dominant and structures, thyroid enlargement, cardiac murmurs, and recessive, X-linked, and maternal/mitochondrial. organomegaly, for example, can also guide diagnosis. Other important concepts are penetrance, genetic anticipation, premutation status, copy number vari- The Neurologic Examination ation, and haplotype insufficiency See (Table 4-3). The neurologic examination should be thorough, with The examiner should be sensitive to the possibility the goal of the best possible neuroanatomic localiza- that parents may feel guilty or sad about the role of tion, as well as fully characterizing the phenotype. genetics in their child’s symptoms. It can be helpful A challenge is to interpret possibly abnormal findings to point out that many thousands of healthy, posi- in the context of the range of coordination and skills tive genes have been passed along to the children, in typically developing children. and that all parents naturally pass on at least a few Because of the dynamic, state-dependent nature genes they wish they had not. Inquiring about con- of movement disorders, a critical element is directly sanguinity can be important and requires extra tact. observing the motor system in states of rest, maintenance Ethnic backgrounds may also narrow the differential of postures, and actions. Specific useful maneuvers are diagnosis. described in the symptom-based chapters. Occasionally, The previously described history-taking pro- if an uncooperative child does not perform these in clinic, cess is usually sufficient to diagnose tic disorders and parents can be instructed in these maneuvers and to vid- stereotypies in otherwise healthy children. For these eotape the child at home. common, patterned, hyperkinetic movement disorders, Mental Status and General Cognitive and Emotional the general and neurologic examinations add little or Cerebral Function no specific diagnostic information.4 They may provide useful, nonspecific complementary information, for The mental status should essentially be screened example, about fine motor coordination. Occasionally, throughout the history-taking process. Additional the examination provides evidence of a secondary tic information is gained through observation during the disorder. However, another important purpose of the examination. As movement disorders often occur with examination is to reassure anxious parents. It is easier developmental and psychiatric disorders, including per- (and more appropriate) to convey reassurance about vasive disorders of development (PDD) (autistic spec- 5 the child’s neurologic health and development if there trum disorders), the clinician should be vigilant for this has been a moderately thorough neurologic examina- possibility. The physician concerned about the possibil- tion, even in cases where the examination adds no new ity of PDD should note presence of significant anxiety, information. In clinic settings where a trainee has been language, and social skills that are below expected for the initial examiner, it is important for the attending chronologic age, poor eye contact, repetitive behaviors physician to “lay on the hands” as well. When staffing and need for sameness, inability to understand jokes, the encounter, the attending physician should estab- and excessively concrete interpretations. Sometimes lish a friendly rapport with the parents and child and additional assessments may be employed. For example, repeat key portions of the motor examination, even if the Modified Checklist of Autism in Toddlers, available she or he trusts this has been competently performed at www.firstsigns.org/downloads/m-chat.pdf, is vali- by the trainee. dated for screening. For adolescents exhibiting concerning signs of cognitive impairment or memory loss, the Montreal Cognitive Assessment (www.mocatest.org/) The Physical and Neurologic Examination may be used. This is available free of charge for clinical The examination begins with observation and ideally purposes, is available in many languages, and may be may include observation in the waiting room, during used to assess cognition in older children. Simple writ- walking into the clinic room, and in all cases during the ing, reading, drawing Gesell figures, drawing freehand previously described interview. spirals, and math computations are also useful.

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Expressive and Receptive Language documented in the pediatric literature,14 this phe- This is gauged informally through conversation in nomenon is readily observed in clinics where chil- most cases. Expressive language is more likely to be dren with autistic spectrum disorders are evaluated. impaired than receptive. When language problems Cranial Nerves are present, it is important to obtain formal hearing evaluation. Sensorineural hearing loss may be a clue to Key points of this section of the examination include the diagnosis of genetic and mitochondrial diseases.6 the following: (1) brainstem signs of conditions affect- Children with speech disorders commonly have sub- ing the posterior fossa that may affect both cerebellar normal motor development.7 and brainstem function; (2) eye movements; and (3) Some of the more commonly described speech dif- weakness, as a portion of the general motor examina- ficulties and their relationship to movement and devel- tion (brain, brainstem, root, nerve, junction, muscle), opmental disorders include the following: as well as abnormal movements. Dystonia, chorea, myoclonus, and tics may all be manifest in the face. • Developmental dysarthria, with predominant prob- Nystagmus, other abnormal eye movements, slow sac- lems with articulation, is common and nonspecific. cades, saccadic pursuits, and oculomotor apraxia are Mistakes are usually consistent (e.g., difficulty with also important to characterize. certain consonants). The expected trajectory of language acquisition is delayed. A systematic, Cochrane Motor Examination evaluation of the benefits of speech therapy is under- way (http://mrw.interscience.wiley.com/cochrane/ Assessments of bulk, tone, strength, and reflexes are clsysrev/articles/CD006937/frame.html). standard. Many movement disorders are mixed, with • Developmental apraxia/dyspraxia of speech, manifested involvement of the corticospinal tract at some level. as difficulty generating speech sounds and putting Characterizing hypertonia in mixed spasticity and them together consistently in the correct order to dystonia can be challenging (see Chapter 17, Cerebral form words, is less common. There is some contro- Palsy). Children with generalized dystonia may become versy about formal criteria. It is usually diagnosed extremely dystonic in the stimulating clinic room set- by speech pathologists but should be suspected by ting. This level of extreme dystonia then masks underly- neurologists in the appropriate setting. In adults, ing tone and reflexes. The parental report of tone during this occurs in corticobasal degeneration8 or strokes sleep is helpful, as dystonic hypertonia disappears in involving areas supporting speech. In children, this sleep. Any procedures in which sedation is used offer a is usually nonlesional and nonspecific. It is often useful opportunity to examine such children in a state accompanied by fine motor skills problems.7 It is where dystonia is not present. In toddlers, the assess- seen in galactosemia with diffuse dysmyelination.9 ment of strength is mainly functional. For example, • Dysprosody/lack of prosody, alterations in speech inten- patterns of proximal and distal weakness in legs can be sity and pitch, speech rate, and pauses, is a component assessed through observation of rising from the floor, of speech abnormalities in Parkinson’s disease.10 In walking, running, and jumping. Other important children, dysprosody may be seen in autism. Infants maneuvers include tongue protrusion for darting tongue, rely on prosody for word recognition,11 and failure to sustaining grip for “milkmaid’s sign,” and arms and hands appreciate prosody or appropriately generate prosody up over head, for involuntary pronation (see Chapter 9). commonly occurs in autistic spectrum disorders. Sensory Examination • Abnormal speech cadence, dysrhythmic or abnormally timed speech, is classically affected in cerebellar The sensory examination has low yield in children. A syndromes. detailed multisensory examination may provide ambig- • Selective mutism, elective speech in some environ- uous or uninterpretable information, particularly when ments but not others, is usually related to anxiety.12 attempting to compare light touch or temperature • Cerebellar mutism, part of a syndrome of ataxia, between limbs. Young children may simply be unable reduced speech output, emotional lability, and hypo- to accurately interpret and describe sensations compar- tonia, is well described after midline cerebellar tumor ing distal versus proximal or left versus right. Generally, resections in children.13 young children can report presence of light touch and • Foreign accent syndrome is a condition involving vibration, and, with practice, may be able to report pro- development or acquisition of speech patterns and prioception. Older children with Tourette syndrome, pronunciation that fellow native language speakers obsessive-compulsive disorder, or neurotic personali- judge to be nonnative. Although this is only sparsely ties and sensory hypersensitivity may ruminate over

[email protected] 66485438-66485457 24 Section 1 overview

examination details and provide conflicting, nonana- • Ingestion/intoxication tomic reports. A detailed sensory examination need • Migrainous only be attempted when a specific hypothesis is being • Epileptic tested. • Traumatic • Vascular insult Cerebellar Examination • Metabolic/mitochondrial This is discussed extensively in Chapter 2. The clini- • Paroxysmal or episodic genetic diseases cian should have the full range of cerebellar bedside The phenomenology, the age of the child, and the tests at his or her disposal to be used in cases where history of present illness usually narrow this list sub- careful characterization of coordination and cerebellar stantially, and this guides diagnostic decision making. function is needed. In many cases, the diagnostic process will involve neu- Tremor Examination roimaging or laboratory testing. Acute and subacute diagnoses are discussed in the phenomenology-based The child should be observed at rest, in several postures chapters in this book. with hands outstretched, and on finger-to-nose testing. Additional discussion is found in the chapter on tremor. Strategy 3: Have a Stepwise, Organized Approach to More Difficult Chronic The Diagnosis Diagnoses This section reviews three general strategies for diagnosis, For more difficult diagnoses, many pieces of data can given the information obtained in the previous sections. be important, and sometimes arriving at the precise Strategy 1: Recognize Patterns Based on diagnosis requires days, months, or even years. Patients Phenomenology and Time Course with no molecular diagnosis for years may still acquire Experienced clinicians can correctly identify common one as clinical and basic science advance. and some rare diagnoses in clinic, using information The following is a useful, stepwise approach for described previously, without further medical diagnostic more difficult diagnoses: testing. Some diagnoses may literally be made in the door- 1. Classify the phenomenology. way to the clinic room. The most common diagnoses in 2. Identify the most likely anatomic substrate, bearing each chapter of this book are usually not difficult for neu- in mind that many disorders in children are mixed rologists to make. Particularly easy diagnoses include tic movement disorders, and that classic phenomenol- disorders, stereotypies, developmental tremor, and mild ogy/brain substrate relationships do not always apply. motor symptoms caused by static encephalopathies. 3. Review the time course: acute, subacute, paroxys- These diagnoses, although easy for the physician, mal, chronic static, chronic progressive, continuous may be very stressful for a family. It is important to but waxing and waning, relapsing and remitting. make the diagnosis confidently and steer families away 4. Use the family history to consider heritability and from obtaining unnecessary diagnostic tests. For exam- to narrow the differential diagnosis. ple, in most movement disorder cases, electroencepha- 5. Use other key features of the history or physical lograms (EEGs) will not provide useful information.15 examination. Education about the diagnosis, referrals to psychology 6. Use helpful online resources. For any suspected dis- for coping skills, and referrals to high-quality websites ease that is not clearly secondary or environmentally for education and advocacy are often very helpful. induced, there are an enormous number of genetic Strategy 2: Focus on Proximate Causes possibilities. Use of online resources, as described later as Possible Etiologies for Acute- and in this chapter and in Appendix B, is recommended. Subacute-Onset, Acquired Movement Note that the boundaries of the phenotypes of rare diseases are probably known only imprecisely. For Disorders example, the range of age of onset in rare diseases For acute and subacute manifestations, it is helpful to reflects ascertainment bias in the few reported cases. think in terms of categories: These six steps are considered in detail next. • Infectious • Inflammatory: postinfection, postvaccine, other Step 1: Classify the Phenomenology autoimmune Phenomenology classification is the critical first • Iatrogenic: drug-induced step. This is discussed in greater detail in Chapter 3.

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Classification aids in limiting the list of possible diag- example, family history of autoimmune, thrombotic, noses, based on probable anatomic substrate for symp- endocrine, or psychiatric diseases can be informative. toms. For example, dystonia or chorea often points The family history helps narrow the search. However, toward basal ganglia and ataxia toward cerebellum and the absence of a family history does not mean the dis- its inflow and outflow pathways. Most often, determi- ease is not heritable. nation of phenomenology is based on visual pattern Challenges to obtaining and interpreting the fam- recognition of movements observed spontaneously or ily history include genetic, neurologic, and social elicited during the examination. factors: In cases where several phenomenologic terms may • Diseases that are heritable, but most often due to seem appropriate, the determination may require sup- sporadic/new mutations plementation of visual impressions by details from the • Incomplete penetrance history or careful examination. After clinic, review of • Genetic anticipation—because the child may be videotape of the child’s movements may clarify or cor- symptomatic but not the parent carrying the disease rect impressions from the real-time observation. A par- • Age-related disease expression—the child’s pheno- tial list of overlapping phenomena that can be difficult type may differ because of younger age of onset to distinguish visually appears in Table 4-2. • X-linked diseases or those with greater pene- Step 2: Identify the Anatomic Substrate trance in males, such that carrier mother may be asymptomatic Anatomic substrate, that is, localization of the lesion, • Single-gene diseases with substantial intrafamilial is based on the phenomenology and neurologic exam- variability in phenotype ination in most cases. Neuroimaging is sometimes • Unknown but important modifier genes needed. Additional information about anatomy is • Environmental or epigenetic factors discussed in the first two chapters. Mixed movement • Mitochondrial diseases with heteroplasmy disorders pose a special challenge, as do movement dis- • Nonpaternity orders in infancy, because the examination is relatively • Absence of information on one or both biologic insensitive at that stage of neurodevelopment. Once parents the clinician has localized the disease, it is important • Guilt/denial leading to inaccurate reporting not to be too dogmatic in narrowing the differential • Prior misdiagnoses or lack of precise knowledge of diagnosis. The examination in children can be diffi- problems in family members. As our understanding cult to interpret, and diseases manifest in uncommon of disease inheritance and genotype/phenotype or unexpected ways. For example, Huntington’s disease interactions has evolved, a simple understanding of in young children manifests with dystonia and parkin- Mendelian genetics has become insufficient for neu- sonism, not chorea. Spinocerebellar ataxias and ataxia rologists. An abbreviated list of important and rela- telangiectasia may manifest with chorea or dystonia, tively recent genetic concepts is found in Table 4-3. not ataxia. Step 5: Identify and Consider Nonneurologic, Key Step 3: Incorporate the Time Course into the Features of History or Physical Examination Diagnostic Process Involvement of other organ systems in the disease may Time course includes age of onset and acute, subacute, assist in identifying the diagnosis. For example, short paroxysmal, waxing and waning, chronic-static, or stature, migraine, and hearing loss may narrow the chronic-progressive history. These assist with identify- search to mitochondrial disease. Dysmorphic features ing probable etiologic categories for primary and sec- may also provide useful clues. Any clinical feature can ondary movement disorders. be extremely helpful when using computer resources to Step 4: Use the Family History of Neurologic and make more difficult diagnoses. Psychiatric Conditions Step 6: Use of Online Resources: OMIM and When heritability is suspected, a three-generation fam- Genetests ily pedigree, including cousins and siblings of parents Two linked websites are ideal for assistance in diagnosis and grandparents, can clarify an inheritance pattern. in nearly all possibly genetic movement disorders: Examples of common inheritance patterns are shown in Figure 4-1. 1. Online Mendelian Inheritance in Man (OMIM) In selected situations, presence of nonneurologic (www.ncbi.nlm.nih.gov/omim) diseases is also worth noting on the pedigree. For 2. Genetests (www.genetests.org)

[email protected] 66485438-66485457 26 Section 1 overview

TABLE 4-2 Selected Challenging Classifications Movement Disorders with Overlapping Phenomenologies Keys to Differentiation Based on History, Examination Brief tics; myoclonus Tics: The child interview is critical. The child should be aware of some tics and of urges to perform tics, particularly when stressed or in other predictable situations. Tics are usually at least partly suppressible. Both tics and subcortical myoclonus may diminish during purposeful activity, but this is more universally characteristic of tics. Myoclonus: The child may be unaware of movement. If aware, the child experiences myoclonus as involuntary. Action may enhance myoclonus.

Complex tics; compulsions; Tics: The child should sometimes be aware of an urge to perform the tic. stereotypies Tics usually begin with simple movements, after age 3 years, with waxing and waning and increasing complexity over time. Young children with complex tics often ultimately manifest obsessive-compulsive disorder (OCD). Compulsions: The urge to perform these commonly corresponds to an obsession (e.g., obsession with germs/compulsions with washing, obsessions with safety/compulsions with checking). This is not always true in children who may have compulsions and rituals but not articulate a fear or obsession. Stereotypies: Complex, patterned, with earlier onset than tics, usually before age 3. Characteristic of autism and a relatively small number of serious neurologic diagnoses, but occurs often in typical children.

Multifocal and truncal Myoclonus of muscles of limbs and trunk, when frequent, may fairly myoclonus; truncal ataxia continuously move the trunk, creating an appearance of titubation. This and titubation; jerky chorea is particularly true in toddlers. Myoclonus may occur at multiple levels of the neuraxis, so detailed neurologic examination may provide additional clues. Opsoclonus is an ominous finding. Titubation and ataxia are characteristic of cerebellar disease, for which other cerebellar findings and nystagmus may be clues. Jerky chorea, as in benign hereditary chorea, may be difficult to distinguish from ataxia or myoclonus. Expert consensus cannot always be achieved in individual cases.

Akathisia; chorea Akathisia is characterized by restless movements and subjective sensory hypersensitivity and discomfort. It most often occurs as a side effect of psychiatric medication. Chorea is involuntary restlessness, with jerky or flowing, random-appearing movement fragments occurring fairly continuously. It causes aggravation but not sensory discomfort. Both movement disorders may be drug-induced but subacute chorea is more likely autoimmune.

Ataxic gait; choreic gait; Ataxic gait: Fairly consistently broad-based. Other signs including positive progressive spastic gait Romberg, dysmetria on heel to shin and finger to nose often present. Choreic gait: Less consistently broad-based. Choreic intrusions may lead to lurching intermittently rather than a stably broad-based gait. Upper limb chorea should be readily distinguishable from ataxia. Spastic gait: Can be difficult to characterize in gradually progressive parapareses and leukodystrophies. When scissoring/hip adduction is not prominent, consistent or intermittent hypertonic extensions during walking may produce broad-based gait and poor balance mimicking ataxia. Careful motor examination often clarifies the picture.

Seizure; Not-Seizure: Clonic Simple partial seizures brief patterned clonic movements may occur, with movements and automatisms preserved consciousness. These cannot be suppressed by the patient or in simple and complex partial observer. seizures vs. paroxysmal movement Epileptic Automatisms Blinking, patterned movements may resemble tics. disorders Awareness is limited or absent. In contrast to tics, there is no urge to perform these and no ability to suppress. These cannot be interrupted by the observer, in contrast to stereotypies, which can be interrupted. Paroxysmal Movement Disorders – dyskinesias, tics, stereotypies – no loss of consciousness, no “post ictal” confusion or fatigue; phenomenology, subjective experience, interruptibility all help distinguish from epilepsies. [email protected] 66485438-66485457 Chapter 4 Diagnostic Evaluation of Children with Movement Disorders 27

B A Diagnosis = known carrier Diagnosis = affected

Figure 4-1. Patterns of inheritance. Individuals affected by the disease are indicated by darker colors; squares = males; circles = females. A, Autosomal dominant (AD): Autosomal—the disease-causing gene is located on an “autosome” (chromosomes 1 through 22) and not a sex chromosome (X, Y). Males and females are equally likely to inherit and pass on these genes. Dominant—one copy of the disease-causing gene suffices to produce disease. Probability that an affected parent will pass the disease-causing gene to each child is 50%. Note that in pedigrees for diseases with incomplete penetrance such as DYT1 (i.e., some individuals have the disease-causing gene but remain unaffected), there will be more disease-gene carriers than affected individuals. AD heritability may be suspected when males or females in multiple generations are affected, including pedigrees with male-to-male or male-to-female transmission. B, Autosomal recessive (AR): Recessive—one copy of the disease-carrying gene does not suffice to produce disease. Individuals with one copy are not affected and usually are unaware of the presence of the gene. They are designated as “carriers.” Two copies of the disease-carrying gene yield the disease, in either males or females. The probability that a child of two carrier-parents will be homozygous for the disease-carrying gene and have the disease is 25%. AR heritability may be suspected when siblings in one generation only are affected. C, X-linked recessive (XR): the disease-causing gene is on the X chromosome. No male-to-male transmission is possible. Only males may be affected, or carrier females may have mild phenotype. Probability that a male child of a carrier-mother will inherit the disease-carrying gene is 50%. XR heritability may be suspected when only males, related through common females, are affected. D, Mitochondrial DNA (mtDNA): The disease-causing gene is located in mitochondrial DNA. Mitochondria are passed to children through the egg, not the sperm, so affected males cannot pass on mtDNA diseases. Affected females can pass diseases on to some or all male or female offspring. Note that mitochondria contain multiple copies of DNA, and cells contain multiple mitochondria, so there is a mixture of more than one type of mtDNA within cells, a phenomenon referred to as heteroplasmy. Sorting of disease-causing mtDNA occurs during cell division, meaning there is vast potential for variability in organ involvement as well as age of onset of mitochondrial diseases. MtDNA inheritance may be suspected when both males and females in multiple generations are affected, with no male-to-offspring transmission. [email protected] 66485438-66485457 28 Section 1 overview

Table 4-3 Definitions of Genetic Terms Related to Variability in Disease Expression Term Definition Example

Penetrance The frequency of expression of The penetrance of DYT1 mutations is 30%; 30% an allele when it is present in the of persons carrying mutations in the DYT1 gene genotype; the frequency with develop dystonia which a heritable trait occurs in individuals carrying the principal gene(s) for that trait

Genetic When genetically transmitted The biological basis for genetic anticipation in anticipation diseases manifest earlier or more Huntington’s Disease is expansion of trinucleotide severely in successive generations. CAG repeats in the Huntingtin Gene, leading to increasingly dysfunctional protein/earlier onset

Premutation A genetic variation that increases Based on the number of CGG repeats in the FMR-1 Status the risk of disease in subsequent gene, the status of individuals may be classified as generations healthy, pre-mutation, or full mutation. Normal: Fewer than 54 CGG repeats. Premutation: male or female carrier with 54–200 CGG repeats; premutation females are unaffected or mildly affected cognitively but are at risk for affected sons with full mutation. Premutation males over age 50 are at risk for Fragile X Tremor Ataxia Syndrome (FXTAS). Full-Mutation: trinucleotide CGG expansion over 200 causing Fragile X Syndrome with autism, mental retardation.

Haplo- When a mutation occurs in one Haplo-insufficiency has been suggested to play a role insufficiency/ gene, and the amount of in forms of disease expression related to potassium Haplotype protein produced by the other gene channel subunits and to mitochondria-regulating Insufficiency is insufficient for healthy function. polymerase gamma1 (POLG1) This concept that disease symptoms may depend on gene dosage/ protein dosage may partially explain differences in penetrance and disease severity in autosomal dominant, single gene diseases Copy Number In comparative genome studies, Copy number variation has been suggested to play Variation (CNV) segments of DNA have been a role in susceptibility to Autism, Schizophrenia, identified where duplications, Tourette Syndrome, and Parkinson’s Disease deletions, inversions, or translocations have resulted in changes in copy number. These CNVs are heritable and may affect gene expression.

Further details on a search strategy using the OMIM More difficult cases may require a review of rele- and Genetests websites is found in Appendix B. vant neuroanatomy, as presented in the first two chapters of this book, or as reviewed on useful websites or Summary other textbooks. There are myriad opportunities for Diagnosis begins with a careful history and a thor- second opinions from colleagues through in-person ough physical examination, with the goal of classify- clinic visits, teleconferences, meeting presentations, ing the phenomenology first. Even experts may fail to or emailing videos. Repeated searching of databases reach consensus in some clinical situations.16 Advances such as OMIM, as described in this chapter, is also in molecular understanding can ultimately provide helpful, because these are regularly updated based on clarification,17,18 although there are still cases where a new discoveries. Once a diagnosis is made, treatment molecular diagnosis remains elusive.19–21 remains, in most cases, at best symptomatic. However, [email protected] 66485438-66485457 Chapter 4 Diagnostic Evaluation of Children with Movement Disorders 29 it is hoped that increasing knowledge of the molecular 11. Johnson EK, Seidl AH: At 11 months, prosody still out- basis of disease will eventually yield more rational and ranks statistics, Dev Sci 12(1):131–141, 2009. effective therapies. 12. Sharp WG, Sherman C, Gross AM: Selective mutism and anxiety: a review of the current conceptualization of the disorder, J Anxiety Disord 21(4):568–579, 2007. REFERENCES 13. Robertson PL, Muraszko KM, Holmes EJ, et al: Incidence and severity of postoperative cerebellar mut- 1. Dooley JM, Brna PM, Gordon KE: Parent perceptions ism syndrome in children with medulloblastoma: a of symptom severity in Tourette’s syndrome, Arch Dis prospective study by the Children’s Oncology Group, Child 81(5):440–441, 1999. J Neurosurg 105(6):444–451, 2006. 2. Gilbert DL: Treatment of children and adolescents with 14. Marien P, Verhoeven J, Wackenier P, et al: Foreign accent tics and Tourette syndrome, J Child Neurol 21:690–700, syndrome as a developmental motor speech disorder, 2006. Cortex 45(7):870–878, 2009. 3. Mahone EM, Bridges D, Prahme C, Singer HS: Repetitive 15. Gilbert DL, Gartside P: Factors affecting the yield of arm and hand movements (complex motor stereotypies) pediatric EEGs in clinical practice, Clin Pediatr (Phila) in children, J Pediatr 145(3):391–395, 2004. 41:25–32, 2002. 4. Dooley JM, Gordon KE, Wood EP, et al: The utility 16. Schrag A, Quinn NP, Bhatia KP, Marsden CD: Benign of the physical examination and investigations in the hereditary chorea—entity or syndrome? Mov Disord pediatric neurology consultation, Pediatr Neurol 28(2): 15(2):280–288, 2000. 96–99, 2003. 17. Breedveld GJ, Percy AK, MacDonald ME, et al: Clinical 5. Canitano R, Vivanti G: Tics and Tourette syndrome in and genetic heterogeneity in benign hereditary chorea, autism spectrum disorders, Autism 11(1):19–28, 2007. Neurology 59(4):579–584, 2002. 6. Leveque M, Marlin S, Jonard L, et al: Whole mito- 18. Breedveld GJ, van Dongen JW, Danesino C, et al: chondrial genome screening in maternally inherited Mutations in TITF-1 are associated with benign heredi- non-syndromic hearing impairment using a microar- tary chorea, Hum Mol Genet 11(8):971–979, 2002. ray resequencing mitochondrial DNA chip, Eur J Hum 19. Edlefsen KL, Tait JF, Wener MH, Astion M: Genet 15(11):1145–1155, 2007. Utilization and diagnostic yield of neurogenetic 7. Visscher C, Houwen S, Scherder EJ, et al: Motor profile testing at a tertiary care facility, Clin Chem 53(6): of children with developmental speech and language dis- 1016–1022, 2007. orders, Pediatrics 120(1):e158–e163, 2007. 20. Gilbert DL, Leslie EJ, Keddache M, Leslie ND: A 8. Zadikoff C, Lang AE: Apraxia in movement disorders, novel hereditary spastic paraplegia with dystonia Brain 128(pt 7):1480–1497, 2005. linked to chromosome 2q24–2q31, Mov Disord 24 9. Ridel KR, Leslie ND, Gilbert DL: An updated review (3):364–370, 2009. of the long-term neurological effects of galactosemia, 21. Wong LJC: Diagnostic challenges of mitochondrial Pediatr Neurol 33(3):153–161, 2005. DNA disorders, Mitochondrion 7(1–2):45–52, 2007. 10. Skodda S, Rinsche H, Schlegel U: Progression of dysprosody in Parkinson’s disease over time—a longitudinal study, Mov Disord 24(5):716–722, 2009.

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Introduction axial or facial muscles can be seen. The myoclonus can be focal, multifocal, unilateral, or bilateral. The move- The presence of a movement disorder in a child usu- ments can be rhythmic or nonrhythmic. Typically, the ally raises concerns about an underlying serious, pro- movements occur in clusters of jerks at 1 to 5 Hz over a gressive, degenerative, or metabolic disease. However, period of several seconds. Benign neonatal sleep myo- many movement disorders are benign and related to clonus typically begins during the first week of life, normal stages of development. In fact, it may be dif- diminishes in the second month, and is usually gone Oficult to justify the term disorder in describing many before 6 months of age, but has been reported to per- of these movements. The developing nervous system sist as long as 3 years in one patient.3 Ictal and interictal may produce a variety of motor patterns that would be electroencephalograms (EEGs) are typically normal.4 pathologic in older children and adults, but are sim- The movements are most likely to occur during quiet ply a manifestation of central nervous system immatu- (non–rapid eye movement) sleep.5 They can also be rity. Like many of the neonatal reflexes (e.g., grasping, triggered by noise. Waking the baby causes the move- rooting, placing, tonic neck reflexes), these motor pat- ments to cease. Episodes of myoclonus can be exacer- terns disappear as neuron connectivity and myelina- bated by treatment with benzodiazepines.6 Treatment tion matures. Examples include the minimal chorea is not required and neurologic outcome is normal. of infants, the mild action dystonia commonly seen in toddlers, and the overflow movements that are commonly seen in young children. Other transient Benign Myoclonus of Early Infancy or developmental movement disorders may be mani- (Benign Infantile Spasms) festations of abnormal neural function, but do not Benign myoclonus of early infancy (BMEI) is charac- correlate with serious underlying pathology. These terized by episodes of myoclonic spasms involving flex- are typically associated with complete resolution of ion of the trunk, neck, and extremities in a manner the abnormal movements and ultimately normal resembling the infantile spasms of West syndrome.7,8 development and neurologic function. Most of these The myoclonic spasms typically occur in clusters. conditions occur during infancy or early childhood In some cases they involve a shuddering movement of (see Table 5-1). It is important to recognize these tran- the head and shoulders, and in others the movements sient developmental movement disorders, distinguish of the trunk and limbs are extensor.9 There is no change them from more serious disorders, and be able to pro- in consciousness during the spells. Unlike benign neo- vide reassurance when appropriate. natal sleep myoclonus, the movements in BMEI only occur in the waking state. The onset of these spells is usually between ages 3 and 9 months, but they may Benign Neonatal Sleep Myoclonus begin in the first month of life. The spells usually cease Benign neonatal sleep myoclonus is characterized by within 2 weeks to 8 months of onset,10 but may persist repetitive myoclonic jerks occurring during sleep.1,2 for 1 to 2 years.7 Both ictal and interictal EEGs are The myoclonic jerks typically occur in the distal more normal, distinguishing this entity from infantile than proximal limbs and are more prominent in the spasms. Treatment is not required. Development and upper than the lower extremities. In some cases, jerks of neurologic outcome are normal. 32 [email protected] 66485438-66485457 Chapter 5 Transient and Developmental Movement Disorders in Children 33

Table 5-1 Transient Movement Disorders of Infancy and Childhood Disorder Age at onset Age at resolution Treatment Benign Neonatal Less than 1 month Six months Reassurance Sleep Myoclonus

Benign Myoclonus of 3–9 months typically by 15 months Reassurance Early Infancy O Jitteriness 1st week of life Typically before 6 months Reassurance Shuddering Infancy, early childhood Unknown Reassurance Paroxysmal Tonic First year of life Usually age 1–4 years Levodopa may Upgaze of Infancy be effective

Spasmus Nutans Age 3–12 months Within a few months, Reassurance but subtle nystagmus may persist for years

Head Nodding Before age 3 years May persist for years Reassurance Benign Paroxysmal First year of life By 5 years Reassurance Torticollis

Benign Idiopathic Before 5 months By age 1 year Reassurance Dystonia of Infancy Infantile masturbation Age 3–12 months Reassurance

Jitteriness 100 times per day. During a spell, there is no change in consciousness. Ictal and interictal EEGs are normal. The Jitteriness is a movement disorder that is commonly preservation of consciousness and normal EEG distin- observed in the neonatal period. Jitteriness manifests guish this entity from seizures. Shuddering attacks may as generalized, symmetric, rhythmic oscillatory move- be differentiated from neonatal jitteriness in that shud- ments that resemble tremor or clonus. Up to 50% of dering attacks last only a few seconds and jitteriness is term infants exhibit jitteriness during the first few days often more prolonged in duration. Jitteriness typically of life, especially when stimulated or crying. Jitteriness involves the limbs more than the trunk and neck, can be usually disappears shortly after birth, but can persist for suppressed with passive limb flexion, and is more likely 11,12 months or recur after being gone for several weeks. to occur in neonates.16 Similarity to BMEI has been Persistent jitteriness has been associated with hypoxic- suggested.9,15 Shuddering attacks are similar to BMEI in ischemic injury, hypocalcemia, hypoglycemia, and their frequency, duration, and clinical course; however, drug withdrawal. Jitteriness is highly stimulus sensi- they differ in the semiology of the events. Shuddering tive. It can be precipitated by startle and suppressed attacks typically consist of fine tremor. In contrast, by gentle passive flexion of the limb. Unlike seizures, BMEI typically involves paroxysms of myoclonic limb there are no associated abnormal eye movements or contractions often associated with an atonic head drop 13 autonomic changes. Idiopathic jitteriness is usually that mimics the infantile spasms of West syndrome. associated with normal development and neurologic There may be similarity or overlap between shudder- outcome. The outcome of infants with symptomatic ing episodes and stereotypies (see Chapter 7). Typical jitteriness depends on the underlying cause. stereotypies are rhythmic, patterned, and repetitive involuntary movements such as body rocking, hand flapping Shuddering or clapping, or head nodding. Parallels to shuddering Shuddering episodes are characterized by periods of attacks include their age of onset in infancy and early rapid tremor of the head, shoulders, and arms that childhood, their rhythmic component, and the presence resemble shivering.14,15 Shuddering is often accompa- of facial grimacing. However, the movement frequency is nied by facial grimacing. Onset is in infancy or early usually lower in stereotypies,the duration of stereotypies childhood, but can occur as late as 10 years of age. tends to be longer (up to minutes), and stereotypies tend The episodes last several seconds and can occur up to to persist into late childhood or longer.

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Shuddering episodes typically abate as the child (up to 15 Hz) and low amplitudes (0.5 to 3 degrees) grows older. The prognosis for development and neu- and is most commonly dysconjugate.27 When the child rological function is uniformly good. Some inves- is looking at an object, the nodding may increase. If the tigators, however, have suggested that “shuddering head is held, the nystagmus typically increases. These attacks” of infancy might be the initial manifestation of observations have led to the suggestion that the head essential tremor.9,17 nodding is compensatory for the nystagmus.28 Spasmus nutans generally resolves within several months, but Paroxysmal Tonic Upgaze the majority of patients continue to have a fine, sub- of Infancy clinical, nystagmus until at least 5 to 12 years of age.29 Paroxysmal tonic upgaze of infancy is a disorder char- Long-term outcome for visual acuity is good. Spasmus nutans must be distinguished from con- acterized by repeated episodes of upward gaze devia- 30 18,19 genital nystagmus. Indeed, head nodding has been tion, although downward gaze has also been 31 reported.20 Onset is usually in the first year of life. This reported in association with congenital nystagmus. In condition is characterized by episodes of variably sus- those cases, it appears that the head nodding serves no tained conjugate upward deviation of the eyes that is function. Congenital nystagmus usually begins in the often accompanied by neck flexion. The gaze deviation newborn period before 6 months of age. Congenital can be sustained or intermittent during an episode. The nystagmus is usually bilaterally symmetric whereas typical episode lasts for hours, but can persist for a few spasmus nutans is often asymmetric. Congenital nystagmus persists beyond a few months. Visual acuity is days. Attempts to look downward are accompanied by abnormal in about 90% of children with congenital down-beating nystagmus. Horizontal eye movements nystagmus. Although these features are useful in distin- are normal during an episode. Spells may resolve with guishing congenital nystagmus from spasmus nutans, sleep and be aggravated by fatigue or infection. Some some children who clinically appear to have spasmus infants may have ataxia during some episodes. nutans at the time of presentation have been found to Paroxysmal tonic upgaze is usually idiopathic, 32,33 Thus ophthalmologic but has been reported to have autosomal dominant have retinal abnormalities. evaluation is recommended for children with spas- inheritance. Paroxysmal upgaze has been reported in mus nutans. Neuroimaging abnormalities, including association with mutation in CACNA1A in a large tumor and aplasia of the cerebellar vermis, have been family that also had members affected by episodic 21 described in patients with spasmus nutans, but this is ataxia or benign paroxysmal torticollis. It is uncom- 32,34,35 monly associated with structural lesions, but reported an uncommon association. Routine neuroimaging conditions have included hypomyelination,22 periven- in the absence of other evidence for intracranial pathol- tricular leukomalacia, vein of Galen malformation, ogy has limited yield but is probably reasonable given 19 difficulties of neurological examination at this age and or pinealoma. In the absence of other neurologic 36 signs or symptoms, imaging is unlikely to be reveal- the low incidence of this disorder. ing. There is no specific treatment, but there have been a few reports of improvement with levodopa Head Nodding treatment.18,23 There is a report of paroxysmal tonic upgaze developing in relation to valproate treatment Head nodding without accompanying nystagmus can 24 occur as paroxysmal events in older infants and tod- of absence seizures. The condition typically remits 37 spontaneously and completely within 1 to 4 years.25 dlers. These head movements can be lateral (“no- Outcome is good in most cases, but persistent ataxia, no”), vertical (“yes-yes”), or oblique. The episodes may cognitive impairment, and residual minor oculomotor occur several times a day. The frequency (1 to 2 Hz) disorders have been reported.19 is slower than that of shuddering. The movements do not occur when the child is lying, but can occur in the sitting or standing position. The movements typically Spasmus Nutans resolve within months, but can persist longer. Some Spasmus nutans is a condition beginning in late infancy children with head nodding have a prior history of (3 to 12 months) that is characterized by a slow head shuddering spells; others may have a family history of tremor (approximately 2 Hz) that can be horizontal essential tremor.16 However, it is unclear whether there (“no-no”) or vertical (“yes-yes”). The head movements is any etiologic relationship with these other condi- are accompanied by a small-amplitude nystagmus that tions. An unusual head-nodding epileptic syndrome can be dysconjugate, conjugate, or uniocular.26 The has been described in sub-Saharan Africa. This head- nystagmus is typically pendular with high frequencies nodding epilepsy syndrome appears to be associated

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with hippocampal sclerosis and may be related to posture is of shoulder abduction, pronation of the infection with onchocerca volvulus.38 Head nodding forearm, and flexion of the wrist. The posture occurs may also occur as a benign stereotypy that can persist when the infant is at rest and goes away completely through adolescence (see Chapter 7). Developmental with volitional movement. Occasionally, both arms, an and neurologic outcomes are benign in idiopathic head arm and leg on one side of the body, or the trunk can nodding. be involved. In some infants the posture is only apparent with relaxation or in certain positions. In others it Benign Paroxysmal Torticollis may be present during all waking hours. The rest of the neurologic examination is normal, and the develop- Benign paroxysmal torticollis is an episodic disorder mental and neurologic outcome is normal. Exclusion starting in the first year of life. It typically manifests as of progressive dystonia, brachial plexus injury, infantile a head tilt to one side for a few hours or days. It may hemiplegia, and orthopedic abnormalities is impor- not be affected by sleep. Spells can last as little as 10 tant, but can be based on history and examination. minutes or as long as 2 months, but this is uncommon.39 The torticollis may occur without any asso- Sandifer Syndrome ciated symptoms, or may be accompanied by pallor, vomiting, irritability, or ataxia. Episodes typically recur Sandifer syndrome involves flexion of the neck, arch- with some regularity, up to twice a month initially and ing of the back, or opisthotonic posturing, associated becoming less frequent as the child grows older. The with either gastroesophageal reflux or the presence of spells abate spontaneously, usually by 2 to 3 years of hiatal hernia. Sandifer syndrome was first described by age but always by age 5. The child is normal between Kinsbourne46 as “hiatus hernia with contortions of the spells. Interictal and ictal EEGs are normal. neck.” In the initial report, five patients ranging in age It has been suggested that benign paroxysmal tor- from 4 to 14 years had abnormal head and neck pos- ticollis is a migraine variant.40 There is often a family tures with neck extension, rotation, and side flexion history of migraine. Some older children complain of worsened by eating. All patients had subjective swal- headache during a spell, and many children go on to lowing difficulties and weight loss, but were otherwise develop typical migraine after they have “outgrown” neurologically normal. These patients were found to the paroxysmal torticollis.41,42 Two patients with have hiatus hernia and the movements were thought benign paroxysmal torticollis have been reported from to be associated in some way with the hernia.46 It was a kindred with familial hemiplegic migraine linked later found that the syndrome occurred with gastroe- to a CACNA1A mutation.39 and another family with sophageal reflux and esophagitis, even in the absence CACNA1A mutation has been reported with members of hiatus hernia.47,48 manifesting benign paroxysmal torticollis, paroxysmal The exact incidence is not known, but in chil- tonic upgaze, or episodic ataxia.21 dren with gastroesophageal reflux, Sandifer syndrome The differential diagnosis is broad, and diagnosis occurred in 7.9% of cases.49 In a study of paroxysmal of benign paroxysmal torticollis is one of exclusion. nonepileptic events in children, Sandifer syndrome Torticollis can be seen as an acute dystonic reaction to was diagnosed in 15% of children under 5 years of medication, as a symptom of a posterior fossa or cervical age.50 Diagnosis is often delayed and children often cord lesion, or cervical vertebral abnormalities. In undergo extensive investigations before the diagnosis the case of structural lesions, the torticollis tends to is reached. be persistent and not paroxysmal. Torticollis can also In the original five cases, surgical repair of the hia- be a sign of IVth nerve palsy. Congenital muscular tor- tus hernia led to complete resolution of the involuntary ticollis is present from birth, is nonparoxysmal, and neck movements.46 In subsequent patients, medical is associated with palpable tightness or fibrosis of the treatment of the gastroesophageal reflux and esophagi- sternocleidomastoid muscle unilaterally.43 tis relieved symptoms.47,48 Treatment of gastroesophageal reflux disease by medical or surgical means results Benign Idiopathic Dystonia in resolution of the symptoms in 94% of patients.51 of Infancy Posturing during Masturbation Benign idiopathic dystonia of infancy is a rare disorder characterized by a segmental dystonia, usually of Masturbation is a normal behavior that occurs in the one upper extremity, that can be intermittent or persis- majority of both boys and girls. Although masturba- tent.44,45 The syndrome usually appears before 5 months tion occurs at all ages and has even been observed in of age and disappears by 1 year of age. The characteristic utero, it is most common at about 4 years of age and

[email protected] 66485438-66485457 36 section 2 developmental Movement Disorders during adolescence.52 Masturbation in young children 3. Egger J, Grossmann G, Auchterlonie IA: Lesson of the may involve unusual postures or movements,53 which week: benign sleep myoclonus in infancy mistaken for may be mistaken for abdominal pain or seizures.54,55 epilepsy, BMJ 326:975–976, 2003. Masturbatory movements in boys are usually obvi- 4. DiCapua M, Fusco L, Ricci S, Vigevano F: Benign neo- ous to the observer, due to direct genital manipula- natal sleep myoclonus: clinical features and videopoly- graphic recordings, Mov Disord 8:191–194, 1993. tion. In girls, they are more subtle and often involve 5. Resnick TJ, Moshe SL, Perotta L, Chambers HJ: Benign adduction of the thighs, or sitting on a hand or foot neonatal sleep myoclonus. Relationship to sleep states, and rocking. When the movements are accompanied Arch Neurol 43:266–268, 1986. by posturing of the limbs they are often mistaken for 6. Reggin J, Johnson M: Exacerbation of benign sleep myoclo- paroxysmal dystonia. Several characteristic features of nus by benzodiazepine treatment, Ann Neurol 26:455, 1989. masturbating girls have been identified: (1) onset after 7. Lombroso C: Early myoclonic encephalopathy, early infan- 2 months of age and before 3 years of age; (2) ste- tile epileptic encephalopathy, and benign and severe infantile reotyped posturing with pressure applied to the pubic myoclonic epilepsies: a critical review and personal contri- area; (3) quiet grunting, diaphoresis, or facial flushing; butions, J Clin Neurophysiol 7:380–408, 1990. (4) episode duration of less than 1 minute to several 8. Lombroso C, Fejerman N: Benign myoclonus of early hours; (5) no alteration of consciousness; (6) normal infancy, Ann Neurol 1:138–148, 1977. 9. Pachatz C, Fusco L, Vigevano F: Benign myoclonus of findings on examination; and (7) cessation with dis- early infancy, Epileptic Disord 1:57–62, 1999. traction or engagement of the child in another activ- 10. Maydell BV, Berenson F, Rothner AD, et al: Benign 54,56 ity. Unnecessary diagnostic tests are commonly myoclonus of early infancy: an imitator of West’s performed before the true nature of the behavior is syndrome, J Child Neurol 16:109–112, 2001. recognized. No imaging or laboratory evaluation is 11. Kramer U, Nevo Y, Harel S: Jittery babies: a short term required if the movements abate when the child is dis- follow-up, Brain Dev 16:112–114, 1994. tracted, the movements involve irregular rocking, the 12. Shuper A, Zalzberg J, Weitz R, Mimouni M: Jitteriness child remains interactive, there is some degree of voli- beyond the neonatal period: a benign pattern of move- tional control, direct genital stimulation is involved, ment in infancy, J Child Neurol 6:243–245, 1991. and the neurologic and physical examinations are nor- 13. Volpe J: Neurology of the newborn, Philadelphia, 1995, mal. There appears to be no association with sexual WB Saunders. 14. Holmes G, Russman B: Shuddering attacks. Evaluation thoughts in the child. Instead, it is probably better to using electroencephalographic frequency modulation view these movements on the spectrum of other self- radiotelemetry and videotape monitoring, Am J Dis comforting behaviors such as thumb sucking or rock- Child 140:72–73, 1986. ing, which have no concerning connotations for the 15. Kanazawa O: Shuddering attacks—report of four parents.56,57 Masturbation is a normal human behav- children, Pediatr Neurol 23:421–424, 2000. ior, so there is no expectation that this behavior will 16. DiMario FJ: Childhood head tremor, J Child Neurol cease as the child grows older. However, the frequency 15:22–25, 2000. of the behavior usually decreases as the child gets 17. Vanasse M, Bedard P, Andermann F: Shuddering attacks older, and the behavior is less likely to occur under the in children: an early clinical manifestation of essential observation of the parents. Neurologic and develop- tremor, Neurology 26:1027–1030, 1976. mental outcome is normal. No treatment is required, 18. Ouvrier R, Billson F: Benign paroxysmal upgaze of childhood, J Child Neurol 3:177–180, 1988. but it is important to educate the parents about the 19. Ouvrier R, Billson F: Paroxysmal tonic upgaze of child- behavior. Reassurance for the family is the key to man- hood—a review, Brain Dev 27:185–188, 2005. agement, with redirection should the behavior prove 20. Wolsey DH, Warner JE: Paroxysmal tonic downgaze in two 52,54,57 embarrassing for the family or occur in public. healthy infants, J Neuroophthalmol 26:187–189, 2006. The parents should be educated that this is a normal 21. Roubertie A, Echenne B, Leydet J, et al: Benign paroxys- behavior resulting from random exploration of the mal tonic upgaze, benign paroxysmal torticollis, episodic body by the infant. ataxia and CACNA1A mutation in a family, J Neurol 255:1600–1602, 2008. 22. Blumkin L, Lev D, Watemberg N, Lerman-Sagie T: REFERENCES Hypomyelinating leukoencephalopathy with paroxysmal tonic upgaze and absence of psychomotor development, 1. Coulter D, Allen R: Benign neonatal myoclonus, Arch Mov Disord 22:226–230, 2007. Neurol 39:191–192, 1982. 23. Campistol J, Prats J, Garaizar C: Benign paroxysmal tonic 2. Paro-Panjan D, Neubauer D: Benign neonatal sleep upgaze of childhood with ataxia. A neuroophthalmological myoclonus: experience from the study of 38 infants, Eur syndrome of familial origin? Dev Med Child Neurol J Paediatr Neurol 12:14–18, 2008. 35:436–439, 1993.

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24. Luat AF, Asano E, Chugani HT: Paroxysmal tonic upgaze 40. Al-Twaijri W, Shevell M: Pediatric migraine equiva- of childhood with co-existent absence epilepsy, Epileptic lents: occurrence and clinical features in practice, Pediatr Disord 9:332–336, 2007. Neurol 26:365–368, 2002. 25. Verrotti A, Trotta D, Blasetti A, et al: Paroxysmal tonic 41. Deonna T, Martin D: Benign paroxysmal torticollis in upgaze of childhood: effect of age-of-onset on prognosis, infancy, Arch Dis Child 56:956–959, 1981. Acta Paediatr 90:1343–1345, 2001. 42. Roulet E, Deonna T: Benign paroxysmal torticollis in 26. Anthony J, Ouvrier R, Wise G: Spasmus nutans, a mis- infancy, Dev Med Child Neurol 30:409–410, 1988. taken entity, Arch Neurol 37:373–375, 1980. 43. Collins A, Jankovic J: Botulinum toxin injection for con- 27. Weissman BM, Dell’Osso LF, Abel LA, Leigh RJ: genital muscular torticollis presenting in children and Spasmus nutans. A quantitative propsective study, Arch adults, Neurology 67:1083–1085, 2006. Ophthalmol 105:525–528, 1987. 44. Deonna T, Ziegler A, Nielsen J: Transient idiopathic 28. Gottlob I, Zubcov A, Wizov S, Reinecke R: Head nod- dystonia in infancy, Neuropediatrics 22:220–224, 1991. ding is compensatory in spasmus nutans, Ophthalmology 45. Willemse J: Benign idiopathic dystonia in the first year 99:1024–1031, 1992. of life, Dev Med Child Neurol 28:355–363, 1986. 29. Gottlob I, Wizov S, Reinecke R: Spasmus nutans. 46. Kinsbourne M: Hiatus hernia with contortions of the A long-term follow-up, Invest Ophthalmol Vis Sci 36: neck, Lancet 13:1058–1061, 1964. 2768–2771, 1995. 47. Bray PF, Herbst JJ, Johnson DG, et al: Childhood gas- 30. Gottlob I, Zubcov A, Catalano R, et al: Signs distinguish- troesophageal reflux. Neurologic and psychiatric syn- ing spasmus nutans (with and without central nervous dromes mimicked, JAMA 237:1342–1345, 1977. system lesions) from infantile nystagmus, Ophthalmology 48. Murphy WJ, Gellis SS: Torticollis with hiatus hernia 97:1166–1175, 1990. in infancy. Sandifer syndrome, Am J Dis Child 131: 31. Carl JR, Optican LM, Chu FC, Zee DS: Head 564–565, 1977. shaking and vestibulo-ocular reflex in congenital 49. Shepherd RW, Wren J, Evans S, et al: Gastroesophageal nystagmus, Invest Ophthalmol Vis Sci 26:1043–1050, reflux in children. Clinical profile, course and outcome 1985. with active therapy in 126 cases, Clin Pediatr (Phila) 32. Kiblinger GD, Wallace BS, Hines M, Siatkowski RM: 26:55–60, 1987. Spasmus nutans-like nystagmus is often associated with 50. Kotagal P, Costa M, Wyllie E, Wolgamuth B: Paroxysmal underlying ocular, intracranial, or systemic abnormali- nonepileptic events in children and adolescents, Pediatrics ties, J Neuroophthalmol 27:118–122, 2007. 110:e46, 2002. 33. Smith D, Fitzgerald K, Stass-Isern M, Cibis G: 51. Leape LL, Ramenofsky ML: Surgical treatment of gastro Electroretinography is necessary for spasmus nutans esophageal reflux in children. Results of Nissen’s fundopli- diagnosis, Pediatr Neurol 23:33–36, 2000. cation in 100 children, Am J Dis Child 134:935–938, 34. Kim JS, Park SH, Lee KW: Spasmus nutans and congen- 1980. ital ocular motor apraxia with cerebellar vermian hypo 52. Leung AKC, Robson WLM: Childhood masturbation, plasia, Arch Neurol 60:1621–1624, 2003. Clin Pediatr 32:238–241, 1993. 35. Unsold R, Ostertag C: Nystagmus in suprasellar tumors: 53. Bower B: Fits and other frightening or funny turns in recent advances in diagnosis and therapy, Strabismus young people, Practitioner 225:297–304, 1981. 10:173–177, 2002. 54. Fleisher DR, Morrison A: Masturbation mimicking 36. Arnoldi K, Tychsen L: Prevalence of intracranial lesions abdominal pain or seizures in young girls, J Pediatr in children initially diagnosed with disconjugate nystag- 116:810–814, 1990. mus (spasmus nutans), J Pediatr Ophthalmol Strabismus 55. Nechay A, Ross LM, Stephenson JB, O’Regan M: 32:296–301, 1995. Gratification disorder (“infantile masturbation”): a 37. Nellhaus G: Abnormal head movements of young review, Arch Dis Child 89:225–226, 2004. children, Dev Med Child Neurol 25:384–389, 1983. 56. Yang ML, Fullwood E, Goldstein J, Mink JW: 38. Winkler AS, Friedrich K, Konig R, et al: The head nod- Masturbation in infancy and early childhood presenting ding syndrome—clinical classification and possible as a movement disorder: 12 cases and a review of the lit- causes, Epilepsia 49:2008–2015, 2008. erature, Pediatrics 116:1427–1432, 2005. 39. Giffin NJ, Benton S, Goadsby PJ: Benign paroxysmal torti- 57. Mink J, Neil J: Masturbation mimicking paroxysmal collis of infancy: four new cases and linkage to CACNA1A dystonia or dyskinesia in a young girl, Mov Disord 10: mutation, Dev Med Child Neurol 44:490–493, 2002. 518–520, 1995.

[email protected] 66485438-66485457 [email protected] 66485438-66485457 [email protected] 66485438-66485457 6 Tics and Tourette Syndrome O 6 Introduction movements, and an array of nonspeech motor behaviors (eye blinking or deviation, head jerks, limb and Tourette syndrome (TS) is named after the French trunk movements) in individuals who stutter.7 Some physician Georges Gilles de la Tourette, who in 1885 complex motor tics may be repetitive and appear stereo- reported nine patients with chronic disorders charac- typic. Features of catatonia, including classic negative terized by the presence of involuntary motor and pho- symptoms such as immobility, staring, and posturing, nic tics.1 This syndrome, however, represents only one are referred to as “blocking” tics.8 Nontic movements entity in a spectrum of disorders that have tics as their that need to be distinguished include those that are cardinal feature, ranging from a mild transient form drug-induced (akathisia, dystonia, stereotypy, parkin- to Tourettism. In addition to tics, children with tic sonism), associated with common comorbidities such disorders often suffer from a variety of concomitant as OCD, ADHD, impulsive and antisocial behaviors, psychopathologies, including attention-deficit/hyper- or are motor stereotypies.9,10 Oactivity disorder (ADHD), obsessive-compulsive disor- Tics have several characteristics that are useful in der (OCD), anger outbursts, learning difficulties, sleep confirming their presence. A waxing and waning pat- abnormalities, and other behaviors. tern, the intermixture of new and old tics, and a fluctuating frequency and intensity are expected. Brief Tic Phenomenology exacerbations are often provoked by stress,11,12 anxiety, Formal definitions of tics include involuntary, sud- excitement, anger, fatigue, or infections, although the den, rapid, abrupt, repetitive, nonrhythmic, simple mechanism for prolonged tic exacerbations, whether or complex movements or vocalizations (phonic pro- environmental or biologic, remains to be deter- ductions). Nevertheless, observation either directly in mined. Although stress influences tics, the onset of the office or via homemade video is essential for the TS is not related to stressful life events or to an inter- correct diagnosis. Tics are classified into two catego- action between stressful life events and personality.13 ries (motor and phonic) with each being subdivided Tic reduction often occurs when the affected individ- into a simple and complex grouping. Brief rapid ual is concentrating, focused, emotionally pleased, or movements that involve only a single muscle or local- sleeping. The absence of tics during sleep is commonly ized group are considered “simple” (eye blink, head reported by observers/parents. Polysomnograms of jerk, shoulder shrug), whereas complex tics involve TS subjects, however, demonstrate tics in all phases either a cluster of simple actions or a more coordi- of sleep.14 About 90% of adults15 and 37% of chil- nated sequence of movements. Complex motor tics dren16 report a premonitory urge/sensation just before can be nonpurposeful (facial or body contortions), a motor or phonic tic, vaguely defined as an urge, appear purposeful but actually serve no purpose tension, pressure, itch, or feeling.17 Attempts to vol- (touching, hitting, smelling, jumping, echopraxia, untarily suppress tics often trigger an exacerbation of copropraxia), or have a dystonic character. Simple premonitory sensations or a sense of increased internal phonations include various sounds and noises (grunts, tension. Both of these conditions resolve when the tic barks, sniffs, and throat clearing), whereas complex is permitted to occur. vocalizations involve the repetition of words, that Misdiagnoses are common; for example, eye blink- is, syllables, phrases, echolalia (repeating other peo- ing tics may be thought to stem from ophthalmologic ple’s words), palilalia (repeating one’s own words), or problems, ocular tics are confused with opsoclonus, coprolalia (obscene words). throat-clearing tics are thought to be due to sinusitis Unique tics have included vomiting and retch- or allergic conditions, involuntary sniffing frequently ing,2 anterior-posterior displacement of the external results in referral to an allergist, and a chronic persistent ear,3 sign language tics,4 air swallowing,5 palatal cough-like bark is called asthma.

40 [email protected] 66485438-66485457 Chapter 6 Tics and Tourette Syndrome 41

Tic Disorders Tourette Syndrome and Tourette’s Disorder The diagnosis of a tic disorder is based on historical features and a clinical examination that confirms their pres- Formal criteria for Tourette syndrome based on ence and eliminates other conditions. There is no currently the definition provided by the Tourette Syndrome available blood test, brain scan, or genetic screen. Tourette Classification Study Group18 are similar to, but have syndrome represents only one entity in a spectrum of minor differences from, Tourette’s disorder, as outlined disorders that have tics as their cardinal feature, ranging by the DSM-IV.21 The DSM-IV criteria for Tourette’s from a mild transient form to TS.18 The Diagnostic and disorder reduce the age of onset to less than 18 years O Statistical Manual of Mental Disorders, Fourth Edition and require that no tic-free interval can be greater (DSM-IV), classifies tics into four major categories than 3 months’ duration. Coprolalia, one of the most including Transient tic disorder (TTD), Chronic motor socially distressing symptoms, is not a diagnostic or vocal tic disorder (CMVTD), Tourette’s disorder criterion, and studies have suggested that possibly fewer (TD), and Tic disorders, not otherwise specified (Tic than 10% of patients exhibit this symptom.22 disorder-NOS). Recognizing that formal DSM modi- Tic Disorder; Not Otherwise Specified fications are currently under review, several diagnostic guidelines are suggested based on the following principles: This category as currently defined includes all individuals a) a duration of tics for greater than 12 months is required who do not meet the criteria for TD, CMVTD, or TTD. for a chronic disorder (i.e., Tourette syndrome, TD, However, in recognition of the fact that this category or CMVTD); b) a tic disorder of less than 12 months could contain subjects with ongoing tics that have been duration should be considered a Provisional tic disorder present for less than one year, a new provisional category (or Tic disorder-diagnosis deferred); c) Tourette has been provided. Tic disorder-NOS also includes indi- syndrome/TD requires the presence of both motor and viduals with tics associated with other neurological condi- vocal tics; d) tic disorders have appeared after 18-21 years tions. An alternate terminology for this latter group would (adult onset); and e) tic disorders may occur in association be Tourettism, Tourette-like, or Secondary disorder. with other medical conditions (Tic disorder-NOS or Tourettism, Tourette-like, or Secondary Tourettism/Secondary). Tic Disorder Transient Tic Disorder These are terms are suggested for tic syndromes that do The mildest and most common tic disorder, requires not meet the criteria for TS because they are associated that tics be present for at least 4 weeks, resolve before with another medical condition,23 such as infection,24–27 1 year, typically after several months’ duration. Since drugs,28–30 toxins,31 stroke,32,33 head trauma,34–36 periph- transient tic disorder requires a duration of tics for less eral trauma,37 and surgery,38,39 or found in association than 1 year, the diagnosis is strictly retrospective. with a variety of sporadic, genetic, and neurodegenerative disorders, such as neuroacanthocytosis, Provisional Tic Disorder (Tic Disorder- Huntington’s disease, and Creutzfeldt-Jakob disease.40–42 Diagnosis Deferred) This category would also include the subset of children These terms are used to designate an individual with who have the abrupt onset and repeated exacerbation ongoing fluctuating tics that have been present for less of tics associated with evidence of group A β-hemolytic than 1 year. A provisional diagnosis is required because streptococcal infections, designated pediatric autoim- it is impossible to predict whether an individual’s tics mune neuropsychiatric disorders associated with strepto- 43,44 will persist for the requisite one-year time interval coccal infection (PANDAS). required for a “chronic” designation or fall into the Tardive Tourette is the term for individuals who 45 transient category. develop tics following the use of neuroleptics. Chronic Motor or Phonic Tic Disorder Epidemiology (CMVTD) Tourette syndrome occurs worldwide with increas- CMVTD requires that tics be present for more than ing evidence for common features in all cultures and 1 year and individuals have either entirely motor or, races. The current prevalence figure (number of cases less commonly, solely vocal tics. Several studies have in population at a given time) for tics in childhood is documented that chronic motor tic disorder represents about 6% to 12% (range 4% to 24%).46–48 The pre- a mild form of Tourette syndrome and both are trans- cise prevalence of chronic motor and vocal tics (TS) mitted as inherited traits in the same family.19,20 is unknown, but the estimate for moderately severe

[email protected] 66485438-66485457 42 section 3 Paroxysmal Movement Disorders cases is 1 to 10 per 1000 children and adolescents with problems has expanded, it has become clear that psy- an additional 10 to 30 per 1000 children and adoles- chopathology is more pervasive than previously cents having mild unidentified “true” cases.46,49,50 TS is thought and its clinical impact may be more significant more common in males than in females (more than than the tics.68 For example, health-related quality of 3:1), the mean age of onset is typically between 5 and life (HR-QOL), as measured by HR-QOL scales, con- 7 years, and most patients develop tics before their firms that outcome is predicted by comorbidities such teenage years.47,48,51 Tic phenomenology and severity as ADHD and OCD rather than tic severity.69,70 Hence, appear to be similar between children and adults.52 it is essential that the physician caring for an individual Adult-onset tic disorders have been reported and are with a tic disorder be aware of potential psychopathol- often associated with potential environmental triggers, ogies, be able to differentiate comorbidities from tics, severe symptoms, greater social morbidity, and a poorer and be part of a comprehensive treatment program. response to medications.53 TS is common in children with autism, Asperger syndrome, fragile X syndrome,54 Attention-Deficit Hyperactivity Disorder 55 and other autistic spectrum disorders, but its pres- ADHD is characterized by impulsivity, hyperactivity, ence appears to be unrelated to the severity of autistic and a decreased ability to maintain attention. Symptoms 56 symptoms. Tics and related behaviors have not been usually precede the onset of tics by 2 to 3 years. ADHD found to be overrepresented among adult inpatients is reported to affect about 50% (range 21% to 90%) of 57 with psychiatric illnesses. Neurologic examination referred cases with TS.71 Attentional impairments in TS + and neuroradiographic studies are typically normal. ADHD subjects differ from those with ADHD only, the “Soft” signs, including abnormalities of coordination latter having greater impairment on tests that measure and fine motor performance, synkinesis, and motor visual search and mental flexibility, slower reaction times, restlessness, are often observed in affected children— and fewer corrective responses on simple and choice especially those with ADHD. reaction time tasks.72 In patients with tics, the addition of ADHD symptoms correlates with increased psychoso- Outcome cial difficulties, disruptive behavior, emotional problems, Although TS was originally proposed to be a lifelong functional impairment, learning disabilities, and school disorder, its course can be highly variable, with most problems.73–76 TS and ADHD are not alternate pheno- patients having a spontaneous remission or marked types of a single underlying genetic cause but there is improvement over time. The maximum severity of tics likely an overlap in their underlying neurobiology.77 tends to be between ages 8 and 12 years.58 Long term, most studies support a decline in symptoms during the Obsessive-Compulsive Disorder teenage–early adulthood years.59,60 The “rule of thirds,” that is, one third disappear, one third are better, and Obsessions are recurrent ideas, thoughts, images, or one third continue, is a reasonable estimate of out- impulsions that intrude on conscious thought, are per- come.61 Although tic resolution is reported by many sistent, and are unwelcome (egodystonic). Compulsions adults, whether they fully resolve has been questioned.62 are repetitive, seemingly purposeful behaviors usually Proposed predictors of severity and longevity remain performed in response to an obsession, or in accord with controversial.63 Included in this list are factors such certain rules, or in a stereotyped fashion. Obsessive- as tic severity, fine motor control, and the volumetric compulsive behaviors (OCBs) become obsessive-com- size of brain regions such as caudate and subgenual pulsive disorder (OCD) when activities are sufficiently areas.64,65 The presence of coexisting neuropsychiatric severe to cause marked distress, take up more than 1 hour issues has a significant effect on impairment; indi- of the day, or have a significant impact on normal routine, function, social activities, or relationships. A genetic asso- viduals solely with chronic tics are less impaired 78–80 than those with OCD, ADHD, mood disorders, ciation has been identified between OCD and TS. OCBs generally emerge several years after the onset and other associated behaviors.66,67 of tics, usually during early adolescence. Behaviors Associated Behaviors and occur in 20% to 89% of patients with TS and typically become more severe at a later age.81–83 Two sub- Psychopathologies in Tic Disorders types of OCD, based on differences in prevalence in Georges Gilles de la Tourette, in his early descriptions, age-groups and implied etiologic relationships, have noted the presence of a variety of comorbid neuro-behav- been proposed: a juvenile subtype and one related to ioral problems, including obsessive compulsive symp- tics.84,85 In patients with TS, OCBs usually include a toms, anxieties, and phobias.1 As the list of associated need for order or routine and a requirement for things

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to be symmetric or “just right,” for example, arrang- disabilities, or medications.97 For example, poor arith- ing, ordering, hoarding, touching, tapping, rubbing, metic performance was found only in children with TS counting, checking for errors, and performing activi- who had attentional deficits.75 Individuals with TS typ- ties until things are symmetric or feel/look just right ically have normal intellectual functioning, although (“evening-up” rituals). In contrast, OCD subjects there may be concurrent executive dysfunction, dis- without tics typically have fear of contamination and crepancies between performance and verbal IQ test- cleaning compulsions. Differentiating OCBs from tics ing, impairment of visual-perceptual achievement, and may be difficult, with clues favoring OCB including decrease in visual-motor skills.66,98–101 the following: a cognitive-based drive and need to per- Sleep Disorders form the action in a particular fashion, that is, a certain number of times, until it feels “just right,” or equally Problems associated with sleep have been reported on both sides of the body. in about 20% to 50% of children and young adults with TS. Common symptoms include difficulties Anxiety and Depression falling asleep, difficulties staying asleep, restless sleep, The incidence of generalized anxiety disorder in TS increased movement-related arousals, and parasom- subjects ranges from 19% to 80%.86,87 TS patients are nias.14,102 Sleep deficits may be associated with the pres- likely to be more depressed than controls, and depres- ence of other comorbidities such as ADHD, anxiety, sion has correlated positively with earlier onset and mood disorders, or OCD.103,104 longer duration of tics.86,87 Genetic studies show that major depressive disorder (MDD) is genetic but that Etiology TS and MDD are unrelated.88 Genetic Basis Episodic Outbursts (Rage) and Despite Georges Gilles de la Tourette’s suggestion of an Self-Injurious Behavior inherited nature for TS, the precise pattern of transmis- Rage attacks, difficulty with aggression, and self-inju- sion and the identification of the gene remain elusive. rious behaviors are common in patients with TS.89,90 The strongest support for a genetic disorder are studies Whether these behaviors are due to the presence of of monozygotic twins, which show an 86% concor- other disruptive psychopathology, such as obsessions, dance rate with chronic tic disorder compared with 105,106 compulsions, ADHD-related impulsivity, risk-taking 20% in dizygotic twins. A complex genetic etiology behaviors, or affective disorders, is unclear. is also supported by a study of at-risk children free of tics at baseline who subsequently developed a tic disorder.107 Other Psychopathologies A multifactorial inheritance with at least one major locus 108,109 Antisocial behaviors, oppositional behaviors, and per- seems likely. Although susceptibility loci have been sonality disorders are more frequent in TS, but the identified in TS, it is possible that no causative gene has 110 cause of this increase may be attributed to childhood been identified because of phenotypic heterogeneity. ADHD, OCD, family, or economic issues.91 Schizotypal Several approaches have been used to identify the traits are relatively common in TS.92 A variety of other genetic site, including linkage analysis, cytogenetics, 111 behavioral/emotional problems have been identified in candidate gene studies, and molecular genetic studies. patients with TS. For example, in studies based on the Linkage analyses have suggested a number of chromo- Child Behavior Checklist (CBCL), up to two thirds somal locations, but without a clear reproducible locus of TS subjects had abnormal scores, with clinical or convergence of findings. One analysis performed in problems including OCBs, aggressiveness, hyperactiv- 238 affected sibling pair families and 18 multigenera- ity, immaturity, withdrawal, and somatic complaints.93–95 tional families identified significant evidence for link- 112 Antisocial personality, coupled with impulsivity, occasion- age to a marker on chromosome 2p23.2, but studies ally leads to actions that involve the legal system, although remain inconsistent. Suggestions of an association with 113 there is no evidence that TS patients are more likely to SLITRK1 have not been confirmed in additional 114 engage in criminal behavior than those without TS.96 TS populations. The possible effects of genomic imprinting (sex of the transmitting parent affects the clinical phenotype), bilineal transmission (genetic con- Academic Difficulties tribution from both sides of the family),115–117 genetic Poor school performance in children with tics can heterogeneity, epigenetic factors, and gene–environ- be secondary to several factors, including severe tics, ment interactions further complicate the understand- psychosocial problems, ADHD, OCD, learning ing of TS genetics. Potential epigenetic risk factors

[email protected] 66485438-66485457 44 section 3 Paroxysmal Movement Disorders that have been suggested include timing of perinatal Pathophysiology of Tic Disorders care, severity of mother’s nausea and vomiting during the pregnancy, low proband birth weight, the Apgar Neuroanatomic Localization 118 score at 5 minutes, thimerosal, nonspecific maternal A series of parallel cortico-striatal-thalamocortical 119 120 emotional stress, and prenatal maternal smoking. (CSTC) circuits provide a unifying framework for Further replication of these latter studies is necessary understanding the interconnected neurobiologic rela- before any significance can be truly claimed. It has also tionships that exist between movement disorders and been suggested that TS is not genetic but rather repre- associated behaviors.140–142 The motor circuit, proposed 121 sents a common disorder in the general population. to be abnormal in the production of tic symptoms, orig- Autoimmune Disorder inates primarily from the supplementary motor cortex and projects to the putamen in a somatotopic distri- Several investigators have proposed that, in a subset bution. The oculomotor circuit, possibly influencing of children, tic symptoms are caused by a preceding ocular tics, begins principally in the frontal eye fields group A β-hemolytic streptococcal infection and connects to the central region of the caudate. The 44,122 (GABHS). Labeled as pediatric autoimmune dorsolateral prefrontal circuit links Brodmann’s areas 9 neuropsychiatric disorder associated with streptococ- and 10 with the dorsolateral head of the caudate and cal infection (PANDAS), proposed criteria include appears to be involved with “executive functions” (flex- the following: the presence of OCD and/or tic dis- ibility, organization, constructional strategy, verbal and order; prepubertal age at onset; sudden, “explosive” design fluency) and “motor planning” (sequential and onset of symptoms and/or a course of sudden exac- alternating reciprocal motor tasks). The lateral orbito- erbations and remissions; a temporal relationship frontal circuit originates in the inferior lateral prefron- between symptoms and GABHS; and the presence of tal cortex (areas 11 and 12) and projects to the ventral neurologic abnormalities, including hyperactivity and medial caudate. This circuit is associated with obses- choreiform movements. On the basis of a model pro- sive-compulsive behaviors, personality changes, mania, posed for Sydenham’s chorea, it has been hypothesized disinhibition, and irritability. The anterior cingulate that the underlying pathology in PANDAS involves circuit arises in the cingulate gyrus and projects to the an immune-mediated mechanism with molecular mim- ventral striatum, which also receives input from the 44 icry. The PANDAS hypothesis remains controversial amygdala, hippocampus, medial orbitofrontal cortex, on both clinical grounds and failure to confirm an entorhinal, and perirhinal cortex. Hence, as described, 123–128 immune process. For example, in many individuals a variety of behavioral problems may be linked to this 129,130 the diagnosis is based on incomplete criteria, stud- circuit. Although direct and indirect evidence suggests ies do not consistently support an epidemiologic link that components of CSTC circuits are involved in the 131 to GABHS, family histories are similar to individu- expression of tic disorders, identification of the primary 132 als with standard tic disorders, neuropsychological abnormality remains an area of active research. functioning is similar to subjects without an infectious background,133 and the presence of proposed Striatum putative pathologic antibodies134,135 does not convey Associations between basal ganglia dysfunction and either a distinct phenotypical difference136 or structural movements in other disorders, as well as numerous abnormality of gray or white matter.137 Further, a lon- neuroimaging studies,64,143–150 have led some investiga- gitudinal study in children with PANDAS has shown tors to emphasize the striatal component. Diffusion- little association between GABHS and symptom tensor magnetic resonance imaging (DT-MRI), exacerbation138 and no correlation between exacerbation sensitive to the diffusion of water, has been used to of symptoms and changes in antineuronal antibodies, monitor microstructural abnormalities in TS sub- antilysoganglioside GM1 antibodies, or cytokines.127 jects. Reduced white matter integrity of subcortical Last, it is emphasized that the required steps to confirm structures has been suggested based on increased autoimmunity as the basis for tic disorder have not mean water diffusivity bilaterally in the putamen and been fulfilled, that is, the consistent identification of decreased uneven diffusion (anisotropy) in the right autoantibodies, the presence of immunoglobulins thalamus.151 One hypothesis suggests a striatal com- at the pathologic site, a positive response to immu- partment abnormality at the level of striosome-matrix nomodulatory therapy, the induction of symptoms organization based on anatomic, physiologic, and with autoantigens, and the ability to passively transfer lesion studies,152,153 the clinical response to dopamine the disorder to animal models with the induction of receptor agonists,154 and the association of stereotypies behavioral symptoms.139 with variations in the inducibility of immediate-early

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genes for the Fos/Fra family of transcription fac- a single MRI study has shown increased left midbrain tors within the striosomes and matrix.155 Recent gray matter volume in TS patients as compared with post-mortem investigations have compared the density controls.175 of parvalbumin-staining inhibitory interneurons in Neurotransmitter Abnormalities TS. A reduced number and density of parvalbumin positive neurons were observed in caudate and globus Neurochemical hypotheses tend to be based on clinical pallidus externa, and a higher number in globus palli- responses to specific classes of medications; from cere- dus interna, in TS brains suggesting inhibitory deficits brospinal fluid (CSF), blood, and urine studies in rela- in basal ganglia.257 Other investigators have focused tively small numbers of patients; from neurochemical on the ventral striatum, based on its role in sequen- assays on a few postmortem brain tissues; and from tial learning and habit formation156 and imaging PET or single-photon emission computed tomogra- studies indicating monoaminergic hyperinnervation. phy (SPECT) studies.176 Although the dopaminergic For example, positron emission tomography (PET) system may play a dominant role, the serotoninergic, imaging studies have demonstrated a ventral-to-dorsal glutamatergic, GABAergic, cholinergic, noradrenergic, gradient of increased striatal dopaminergic innervation and opioid neurotransmitter systems may have using a ligand for type-2 vesicular monoamine trans- additional important effects. porters (VMAT2).157 PET studies with 11C-raclopride and amphetamine have also shown robust increases in Dopamine dopamine release in the ventral striatum of TS subjects With some variations, studies of the striatum have as compared with controls.158 shown a slight increase in the number of striatal177 or cortical173,174 dopamine receptors, greater binding Cortical to dopamine transporters (DAT),178–180 altered DAT- There is persuasive evidence to support cortical binding ratio after methylphenidate,181 an increased dysfunction in TS. Children with TS have executive release of dopamine following amphetamine stimu- dysfunction,99,100 cognitive inhibitory deficits,159 larger lation,158,182 and altered D2 receptor availability in dorsolateral prefrontal regions on volumetric MRI,160 mesolimbocortical areas.183 These findings have led larger hippocampal regions,161 controversial alterations to a potentially unifying hypothesis involving the of amygdala volume and morphology,161,162 increased tonic-phasic release of dopamine,158,182 first proposed cortical white matter in the right frontal lobe163 or by Grace for schizophrenia.184,185 The phasic DA decreases in the deep left frontal region,164 and alter- hypothesis is further supported by clinical findings, ations in size of the corpus callosum.165,166 DT-MRI including (1) the exacerbation of tics by stimulant studies of the corpus callosum in TS have shown lower medications, likely secondary to enhanced dopamine fractional anisotrophy, suggesting reduced white mat- release from the axon terminal; (2) tic exacerbation ter connectivity in this interhemispheric pathway.167 by environmental stimuli, such as stress, anxiety, and Imaging has identified frontal and parietal cortical thin- medications, events shown to increase phasic bursts ning, most prominent in ventral portions of the sensory of dopamine; and (3) tic suppression with very low and motor homunculi.168 Additional suggestions of doses of dopamine agonists, likely due to presynap- possible fronto-parietal control network abnormalities tic reduction of phasic dopamine release. Although have been based on measures of MRI resting-state the dopaminergic tonic-phasic model hypothesis functional connectivity.169 Functional MRI studies could exist in either the cortex or striatum, a frontal suggest that tic suppression involves the prefrontal cor- dopaminergic abnormality is favored based on the tex,170 event-related PET techniques reveal correlations presence of dopaminergic abnormalities in this between tics and cortical brain activity,149 and transcra- area.173,174 An association has been identified between nial magnetic stimulation studies demonstrate several a polymorphism of the dopamine transporter gene, forms of reduced inhibition in motor cortex.171,172 DAT DdeI, and TS.186 Direct evidence also comes from semiquantitative immunoblot investigations on postmortem tissue Serotonin that showed a greater number of changes in prefron- Direct evidence for a serotoninergic role in TS comes tal centers (BA9) than in caudate, putamen, or ventral from serum studies in TS patients that show decreased striatum.173,174 levels of serum serotonin and tryptophan.187 Although Last, some have suggested that the primary dysfunc- 5-HIAA (a serotonin metabolite) levels in TS subjects tion lies not in these circuits but rather in the midbrain. were normal in the cortex,188 levels in basal ganglia189 For example, building on early work by Devinsky,26 and CSF190 were found to be decreased. Investigators

[email protected] 66485438-66485457 46 section 3 Paroxysmal Movement Disorders have reported a negative correlation between vocal tics specialists to focus on the patient’s immediate needs and [123I]βCIT binding to the serotonin transporter more effectively. A health-related quality of life scale (SERT) in the midbrain thalamus,191 indicating that has been developed and validated in patients with serotoninergic neurotransmission in the midbrain and TS.69 Therapy should be targeted and reserved for serotoninergic or noradrenergic neurotransmission in those problems that are functionally disabling and the thalamus may be important factors in the expression not remediable by nondrug interventions. Providing of TS. [123I]βCIT and SPECT studies investigating sero- clear and accurate information and allowing adequate tonin transporter binding capacity in TS patients also time for questions and answers enhances the ability show reduced binding in TS, but findings appear to be of patients and family members to cope with issues associated with the presence of OCD.191 The finding of surrounding this disorder. For many, education about the diminished serotonin transporter and elevated serotonin diagnosis, outcome, genetic predisposition, underlying 2A receptor binding in some patients has suggested a pathophysiologic mechanisms, and availability of tic- possible serotonergic modulatory effect.158 Positron suppressing pharmacotherapy often obviates or delays emission tomography of tryptophan metabolism has the need for medication. The treatment of a child with demonstrated abnormalities in cortical and subcortical TS requires a chronic commitment and often a compre- regions.192 The finding of increased dopamine release, hensive multidisciplinary approach, especially in those decreased SERT binding potential, and possible eleva- individuals with academic or psychiatric difficulties. tion of 5-HT2A receptor binding in individuals with TS + OCD has suggested a condition of increased pha- Tic Suppression sic dopamine release modulated by low 5-HT in TS + There is no cure for tics, and all pharmacotherapy is 158 OCD. Polymorphic variants of tryptophan hydroxy- symptomatic. Physicians considering pharmacologic 193 lase 2 have been postulated to be associated with TS. treatment should be aware of the natural waxing and waning course of tics and the influence of psychopathologies Glutamate on outcome. Specific criteria for initiating tic-suppress- Glutamate is the primary excitatory neurotransmitter ing medication include the presence of psychosocial in the mammalian brain, with approximately 60% of (i.e., loss of self-esteem; peer problems; difficulty par- brain neurons using glutamate as their primary neu- ticipating in academic, work, family, social, and after- 194 rotransmitter. Several lines of evidence suggest that school activities; and disruption of classroom settings) a dysfunction of the glutamatergic system may have a and/or musculoskeletal/physical difficulties. The goal of role in TS: reduced levels of this amino acid have been treatment is not complete suppression of tics, but rather identified in the globus pallidus interna (GPi), glo- their reduction to a level where they no longer cause bus pallidus externa (GPe), and substantia nigra pars significant psychosocial or physical disturbances. reticulata (SNpr) regions of four TS brains195; glutamate has an essential role in pathways involved with Nonpharmacologic Treatments cortico-striatal-thalamocortical circuits189 there is an A variety of behavioral treatments (conditioning tech- extensive interaction between the glutamate and dop- niques, massed negative practice, relaxation training, amine neurotransmitter systems254-258,; and glutamate- biofeedback, awareness training, habit reversal, and alterng medications have a beneficial therapeutic effect hypnosis) have been proposed as alternative therapeutic on obsessive-compulsive symptoms.254–255 approaches for tics, but few have been adequately evaluated. Massed negative practice (deliberately repeating Treatment the tic alternating with periods of rest) was suggested to be somewhat effective, but additional studies showed General Principles that the long-term benefit was minimal.196,197 Exposure The initial step in establishing a therapeutic plan for and response prevention, consisting of exposure to pre- individuals with tic disorders is the careful evalua- monitory sensory experiences during prolonged tic tion of all potential issues and the determination of suppression, has been reported to be beneficial.198,199 their resulting impairment. In conjunction with the Self-monitoring (subject taught to recognize and record patient, family, and school personnel, it is essential tics) reduced symptoms in a few isolated reports, pos- to identify whether tics or associated problems, for sibly by increasing patient awareness of these behav- example, ADHD, OCD, school problems, or behaviors.200,201 Awareness training is usually combined ioral disorders, represent the greatest handicap. The with other behavioral instructions, either competing discussion of tics and comorbid symptoms as sepa- response therapy (tensing muscles that are incompat- rate entities frequently enables families and health care ible with the tic) or with a more comprehensive habit

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reversal protocol.202–204 Habit reversal training signifi- Only two medications, pimozide and haloperidol, are cantly improved tics as compared with a supportive approved by the Food and Drug Administration (FDA) therapy group, and the beneficial effect persisted to for tic suppression. The extent of supporting evidence for the time of a 10-month follow-up evaluation.201,205–207 many of the medications has been documented.216,217 Relaxation training (biofeedback, progressive muscle Tier One Medications relaxation, deep breathing, visual imagery, auto- genic training, and producing postures and activities In general, there is fair evidence for the use of alpha- characteristic of a relaxed state) reduced tic severity in adrenergics for tic suppression as initial medications for a formally trained group after 6 weeks of individual tic suppression. Medications in this category include 218 219 instruction, but values failed to reach statistical signifi- clonidine, guanfacine. Anticonvulsants, such as 222,260 223 cance and improvement was short-lived.208 topiramate and levetiracetam, have been tried, 216,224,225 Preliminary studies using repetitive transcranial mag- although data are either limited or controversial. netic stimulation (rTMS) have been beneficial when the A recent placebo controlled study, although small, pro- supplemental motor area is targeted,209 but of little success vided more support for tic suppressing benefit from 259 stimulating motor or premotor regions.210,211 In two topiramate. There is minimal evidence for use of 220 221 patients, transcranial direct current stimulation was bene- baclofen and long term clonazepam for use for ficial.212 Reports have suggested a worsening of symptoms tic suppression. associated with caffeinated beverages213 and a beneficial Tier Two Medications tic response to the use of alternative dietary therapies (i.e., Medications in this category include those that act vitamin B , magnesium),214 but, to date, there is no sci- 6 as dopamine receptor antagonists (antipsychotics). entific evidence to support the use of diets, food restric- Although often effective tic-suppressing agents, side tions, or general use of minerals or vitamin preparations. effects from the use of typical and atypical neuroleptics 215 Acupuncture was beneficial in a single study, but has frequently limit their usefulness. The sequence of drug not received much attention in the scientific literature. usage varies among physicians, and the order listed in Pharmacotherapy Figure 6-1 represents that of the authors. Pimozide and A two-tiered approach is recommended: for milder tics, fluphenazine are preferred to haloperidol, because of nonneuroleptic medications (tier 1), and for more severe reduced side effects. Atypical neuroleptics (risperidone, tics, typical and atypical neuroleptics (tier 2) (Figure 6-1). olanzapine, ziprasidone, quetiapine) are characterized Therapeutic agents should be prescribed at the lowest by a relatively greater affinity for 5HT2 receptors than effective dosage and the patient carefully followed with for D2 receptors and a reduced potential for extrapy- periodic determinations made about the need for contin- ramidal side effects. In this group, risperidone has 226,227 Several small stud- ued therapy. Generally, after several months of successful been studied most extensively. ies have confirmed the clinical effectiveness of olan- treatment, consider a gradual taper of the medication dur- zapine,228–230 ziprasidone,231,232 quetiapine,233,234 and ing a nonstressful time, typically during vacation time. If aripiprazole.235,236 Tetrabenazine, a benzoquinolizine significant symptoms reemerge, treatment is reinstituted. derivative that depletes the presynaptic stores of cate- TREATMENT OF TICS cholamines and blocks postsynaptic dopamine receptors, may also be effective.237,238 Sulpiride and tiapride, sub- Education stituted benzamides, have been beneficial in European Behavioral approaches Pharmacotherapy trials, but neither is available in the United States. Other Medications and Botulinum Toxin 1st tier 2nd tier Other Clonidine Pimozide Dopamine agonists The dopamine agonists pergolide and ropinirole, pre- Guanfacine Fluphenazine Tetrabenazine scribed at lower doses than used in treating Parkinson’s Baclofen Risperidone Botulinum toxin Topiramate Aripiprazole disease, have been beneficial, but ergot-containing medi- Levetiracetam Olanzapine cations should be avoided because of side effects.154,239 Clonazepam Haloperidol Delta-9-tetrahydrocannabinol, the major psychoactive Ziprasidone 240,241 Quetiapine ingredient of marijuana, has been effective, but it Sulpiride is unlikely that this compound, illegal in multiple coun- Tiapride tries, will have widespread use. Botulinum toxin (Botox), which reduces muscle activity by inhibiting acetylcholine Deep brain stimulation release at neuromuscular junctions, has had a beneficial Figure 6-1 approaches to the Treatment of Tics. effect on both dystonic motor and vocal tics.242–247

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Surgical Approaches 12. Hoekstra P, Steenhuis M, Kallenberg C, Minderaa R: Deep brain stimulation (DBS), a stereotactic treatment, Association of small life events with self reports of tic sever- has had preliminary success in treating tics.248–250 Target ity in pediatric and adult tic disorder patients: a prospective longitudinal study, J Clin Psychiatry 65:426–431, 2004. sites for high-frequency stimulation have included the 13. Horesh N, Zimmerman S, Steinberg T, et al: Is onset of centromedian-parafascicular complex of the thalamus, Tourette syndrome influenced by life events? J Neural the globus pallidus interna, and the anterior limb of the Transm 115:787–793, 2008. internal capsule.251 Although this technique has several 14. Cohrs S, Rasch T, Altmeyer S, et al: Decreased sleep advantages over other neurosurgical approaches, pend- quality and increased sleep related movements in patients ing determination of patient selection criteria and the with Tourette’s syndrome, J Neurol Neurosurg Psychiatry outcome of carefully controlled clinical trials, a cau- 70:192–197, 2001. tious approach is recommended.252 Other neurosurgical 15. Kwak C, Dat Vuong K, Jankovic J: Premonitory sen- approaches, with target sites including the frontal lobe sory phenomenon in Tourette’s syndrome, Mov Disord (bimedial frontal leucotomy and prefrontal lobotomy), 18:1530–1533, 2003. limbic system (anterior cingulotomy and limbic leuco- 16. Banaschewski T, Woerner W, Rothenberger A: Premoni- tory sensory phenomena and suppressibility of tics in tomy), cerebellum, and thalamus, have been tried in Tourette syndrome: developmental aspects in children 253 attempts to reduce severe tics. and adolescents, Dev Med Child Neurol 45:700–703, 2003. 17. Prado HS, Rosario MC, Lee J, et al: Sensory phenom- REFERENCES ena in obsessive-compulsive disorder and tic disorders: a review of the literature, CNS Spectr 13:425–432, 2008. 1. Gilles de la Tourette G: Étude sur une affection nerveuse 18. Tourette Syndrome Classification Study Group: caractérisée par l’incoordination motrice accompagnée Definitions and classification of tic disorders, Arch d’écholalie et de copralalie, Arch Neurol 9:19–42, Neurol 50:1013–1016, 1993. 158–200, 1885. 19. Diniz JB, Rosario-Campos MC, Hounie AG, et al: 2. 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197. Evers RA, van de Wetering BJ: A treatment model for 213. Muller-Vahl KR, Buddensiek N, Geomelas M, Emrich motor tics based on a specific tension-reduction tech- HM: The influence of different food and drink on nique, J Behav Ther Exp Psychiatry 25:255–260, 1994. tics in Tourette syndrome, Acta Paediatr 97:442–446, 198. Wetterneck CT, Woods DW: An evaluation of the effec- 2008. tiveness of exposure and response prevention on repeti- 214. Garcia-Lopez R, Romero-Gonzalez J, Perea-Milla E, et al: tive behaviors associated with Tourette’s syndrome, [An open study evaluating the efficacy and secu- J Appl Behav Anal 39:441–444, 2006. rity of magnesium and vitamin B(6) as a treatment 199. Verdellen CW, Hoogduin CA, Kato BS, et al: of Tourette syndrome in children], Med Clin (Barc) Habituation of premonitory sensations during expo- 131:689–692, 2008. sure and response prevention treatment in Tourette’s 215. Wu L, Li H, Kang L: 156 cases of Gilles de la Tourette’s syndrome, Behav Modif 32:215–227, 2008. syndrome treated by acupuncture, J Tradit Chin Med 200. Wright KM, Miltenberger RG: Awareness training in 16:211–213, 1996. the treatment of head and facial tics, J Behav Ther Exp 216. Scahill L, Erenberg G, Berlin CM Jr, et al: Contemporary Psychiatry 18:269–274, 1987. assessment and pharmacotherapy of Tourette syndrome, 201. Wilhelm S, Deckersbach T, Coffey BJ, et al: Habit NeuroRx 3:192–206, 2006. reversal versus supportive psychotherapy for Tourette’s 217. Shprecher D, Kurlan R: The management of tics, Mov disorder: a randomized controlled trial, Am J Psychiatry Disord 24:15–24, 2009. 160:1175–1177, 2003. 218. Gaffney GR, Perry PJ, Lund BC, et al: Risperidone 202. Miltenberger RG, Fuqua RW: A comparison of con- versus clonidine in the treatment of children and ado- tingent vs non-contingent competing response practice lescents with Tourette’s syndrome, J Am Acad Child in the treatment of nervous habits, J Behav Ther Exp Adolesc Psychiatry 41:330–336, 2002. Psychiatry 16:195–200, 1985. 219. Scahill L, Chappell PB, Kim YS, et al: A placebo-con- 203. Woods D, Miltenberger R, Lumley V: Sequential trolled study of guanfacine in the treatment of children application of major habit reversal components with tic disorders and attention deficit hyperactivity to treat motor tics in children, J Appl Behav Anal disorder, Am J Psychiatry 158:1067–1074, 2001. 29:483–493, 1996. 220. Singer HS, Wendlandt J, Krieger M, Giuliano J: 204. Azrin NH, Peterson AL: Habit reversal for the treat- Baclofen treatment in Tourette syndrome: a double- ment of Tourette syndrome, Behav Res Ther 26:347– blind, placebo-controlled, crossover trial, Neurology 351, 1988. 56:599–604, 2001. 205. Woods DW, Twohig MP, Flessner CA, Roloff TJ: 221. Gonce M, Barbeau A: Seven cases of Gilles de la Treatment of vocal tics in children with Tourette syn- Tourette’s syndrome: partial relief with clonazepam: drome: investigating the efficacy of habit reversal, a pilot study, Can J Neurol Sci 4:279–283, 1977. J Appl Behav Anal 36:109–112, 2003. 222. Abuzzahab FS, Brown VL: Control of Tourette’s 206. Himle MB, Woods DW, Piacentini JC, Walkup JT: Brief syndrome with topiramate, Am J Psychiatry 158: review of habit reversal training for Tourette syndrome, 968, 2001. J Child Neurol 21:719–725, 2006. 223. Awaad Y, Michon AM, Minarik S: Use of levetiracetam 207. Deckersbach T, Rauch S, Buhlmann U, Wilhelm S: to treat tics in children and adolescents with Tourette Habit reversal versus supportive psychotherapy in syndrome, Mov Disord 20:714–718, 2005. Tourette’s disorder: a randomized controlled trial 224. Smith-Hicks CL, Bridges DD, Paynter NP, Singer HS: and predictors of treatment response, Behav Res Ther A double blind randomized placebo controlled trial 44:1079–1090, 2006. of levetiracetam in Tourette syndrome, Mov Disord 208. Bergin A, Waranch HR, Brown J, et al: Relaxation ther- 22:1764–1770, 2007. apy in Tourette syndrome: a pilot study, Pediatr Neurol 225. Hedderick E, Morris CM, Singer HS: A double-blind, 18:136–142, 1998. crossover study of clonidine and levetiracetam in 209. Mantovani A, Leckman JF, Grantz H, et al: Repetitive Tourette syndrome, Pediatr Neurol 40:420–425, 2009. transcranial magnetic stimulation of the supplementary 226. Scahill L, Leckman JF, Schultz RT, et al: A placebo- motor area in the treatment of Tourette syndrome: report controlled trial of risperidone in Tourette syndrome, of two cases, Clin Neurophysiol 118:2314–2315, 2007. Neurology 60:1130–1135, 2003. 210. Munchau A, Bloem BR, Thilo KV, et al: Repetitive 227. Dion Y, Annable L, Sandor P, Chouinard G: Risperidone transcranial magnetic stimulation for Tourette syn- in the treatment of Tourette syndrome: a double-blind, drome, Neurology 59:1789–1791, 2002. placebo-controlled trial, J Clin Psychopharmacol 22:31– 211. Orth M, Kirby R, Richardson MP, et al: Subthreshold 39, 2002. rTMS over pre-motor cortex has no effect on tics in 228. Stephens RJ, Bassel C, Sandor P: Olanzapine in the patients with Gilles de la Tourette syndrome, Clin treatment of aggression and tics in children with Neurophysiol 116:764–768, 2005. Tourette’s syndrome—a pilot study, J Child Adolesc 212. Mrakic-Sposta S, Marceglia S, Mameli F, et al: Transcranial Psychopharmacol 14:255–266, 2004. direct current stimulation in two patients with Tourette 229. Budman CL, Gayer A, Lesser M, et al: An open- syndrome, Mov Disord 23:2259–2261, 2008. label study of the treatment efficacy of olanzapine

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for Tourette’s disorder, J Clin Psychiatry 62:290–294, 245. Marras C, Andrews D, Sime E, Lang AE: Botulinum 2001. toxin for simple motor tics: a randomized, double-blind, 230. McCracken JT, Suddath R, Chang S, et al: Effectiveness controlled clinical trial, Neurology 56:605–610, 2001. and tolerability of open label olanzapine in children and 246. Trimble MR, Whurr R, Brookes G, Robertson MM: Vocal adolescents with Tourette syndrome, J Child Adolesc tics in Gilles de la Tourette syndrome treated with botuli- Psychopharmacol 18:501–508, 2008. num toxin injections, Mov Disord 13:617–619, 1998. 231. Sallee FR, Kurlan R, Goetz CG, et al: Ziprasidone treat- 247. Vincent DA Jr: Botulinum toxin in the management of ment of children and adolescents with Tourette’s syn- laryngeal tics, J Voice 22:251–256, 2008. drome: a pilot study, J Am Acad Child Adolesc Psychiatry 248. Ackermans L, Temel Y, Visser-Vandewalle V: Deep brain 39:292–299, 2000. stimulation in Tourette’s syndrome, Neurotherapeutics 232. Sallee FR, Gilbert DL, Vinks AA, et al: 5:339–344, 2008. Pharmacodynamics of ziprasidone in children and ado- 249. Servello D, Porta M, Sassi M, et al: Deep brain stimulation lescents: impact on dopamine transmission, J Am Acad in 18 patients with severe Gilles de la Tourette syndrome Child Adolesc Psychiatry 42:902–907, 2003. refractory to treatment: the surgery and stimulation, 233. Mukaddes NM, Abali O: Quetiapine treatment of chil- J Neurol Neurosurg Psychiatry 79:136–142, 2008. dren and adolescents with Tourette’s disorder, J Child 250. Neuner I, Podoll K, Janouschek H, et al: From psycho- Adolesc Psychopharmacol 13:295–299, 2003. surgery to neuromodulation: Deep brain stimulation 234. Copur M, Arpaci B, Demir T, Narin H: Clinical effec- for intractable Tourette syndrome, Biological Psychiatry tiveness of quetiapine in children and adolescents with 65:e5–6, 2009. Tourette’s syndrome: a retrospective case-note survey, 251. Shields DC, Cheng ML, Flaherty AW, et al: Clin Drug Investig 27:123–130, 2007. Microelectrode-guided deep brain stimulation for 235. Yoo HK, Kim JY, Kim CY: A pilot study of aripiprazole Tourette syndrome: within-subject comparison of dif- in children and adolescents with Tourette’s disorder, ferent stimulation sites, Stereotact Funct Neurosurg J Child Adolesc Psychopharmacol 16:505–506, 2006. 86:87–91, 2008. 236. Seo WS, Sung HM, Sea HS, Bai DS: Aripiprazole treat- 252. Mink JW, Walkup J, Frey KA, et al: Patient selection ment of children and adolescents with Tourette disorder and assessment recommendations for deep brain stim- or chronic tic disorder, J Child Adolesc Psychopharmacol ulation in Tourette syndrome, Mov Disord 21:1831– 18:197–205, 2008. 1838, 2006. 237. Kenney CJ, Hunter CB, Mejia NI, Jankovic J: 253. Temel Y, Visser-Vandewalle V: Surgery in Tourette Tetrabenazine in the treatment of Tourette syndrome, syndrome, Mov Disord 19:3–14, 2004. J Pediatr Neurol 5:9–13, 2007. 254. Singer HS, Morris CM, Grados M: Glutamatergic 238. Porta M, Sassi M, Cavallazzi M, et al: Tourette’s syn- modulatory therapy for Tourette syndrome, Medical drome and role of tetrabenazine: review and personal Hypotheses, In Press. experience, Clin Drug Investig 28:443–459, 2008. 255. Kushner MG, Kim SW, Donahue C, et al: D-cycloserine 239. Anca MH, Giladi N, Korczyn AD: Ropinirole in augmented exposure therapy for obsessive-compulsive Gilles de la Tourette syndrome, Neurology 62:1626– disorder. Biological Psychiatry 62:835–838, 2007. 1627, 2004. 256. Kalanithi PS, Zheng W, Kataoka Y, et al: Altered par- 240. Muller-Vahl KR, Schneider U, Prevedel H, et al: Delta valbumin-positive neuron distribution in basal ganglia 9-tetrahydrocannabinol (THC) is effective in the treat- of individuals wth Tourette Syndrome. Proc Natl Acad ment of tics in Tourette syndrome: a 6-week random- Sci USA, 102(37):13307–13312, 2005. ized trial, J Clin Psychiatry 64:459–465, 2003. 257. Canales ��JJ, Capper-Loup ��C, Hu ��D��, et al: Shifts in stri- 241. Muller-Vahl KR, Schneider U, Koblenz A, et al: atal responsivity evoked by chronic stimulation of dop- Treatment of Tourette’s syndrome with delta 9-tetra- amine and glutamate systems. Brain, 125:2353–2363, hydrocannabinol (THC): a randomized crossover trial, 2002. Pharmacopsychiatry 35:57–61, 2002. 258. Wu Y, Pearl SM, Zigmond MJ, Michael AC: Inhibitory 242. Awaad Y: Tics in Tourette syndrome: new treatment glutamatergic regulation of evoked dopamine release in options, J Child Neurol 14:316–319, 1999. striatum. Neuroscience, 96:65–72, 2000. 243. Kwak C, Jankovic J: Tics in Tourette syndrome and 259. Jankovic J, Jimez-Shahed J, Brown L: A Randomized, botulinum toxin, J Child Neurol 15:631–634, 2000. Double-Blind, Placebo-Controlled Study of Topira 244. Kwak CH, Hanna PA, Jankovic J: Botulinum toxin mate in the Treatment of Tourette Syndrome. Journal in the treatment of tics, Arch Neurol 57:1190–1193, of Neurology, Neurosurgery, and Psychiatry (EPUB ahead 2000. of Print) 2009.

[email protected] 66485438-66485457 7 Motor Stereotypies O Introduction Motor stereotypies typically begin in the first several years of life. Movements occur in bursts, last Although historically, stereotypic movement disorder has from seconds to minutes, appear many times per day, been linked to autism and impaired cognitive deficiency, it have a fixed pattern, and are associated with periods commonly occurs in typically developing children. Motor of engrossment, excitement, stress, fatigue, or bore- stereotypies can be classified into two groups: primary, dom. Each child typically has his or her own repertoire indicating a physiologic basis, and secondary, for those involving a wide range of simple or complex move- associated with other neurodevelopmental problems. ments. Vocalizations may accompany the patterned Both types of stereotypies usually begin in early child- movements. Stereotypies can be readily suppressed by hood, frequently persist into adulthood, and are often a sensory stimulus or distraction, especially in chil- a source of concern for parents. Previously considered dren with normal cognition. There are no associated psychogenic behaviors, there is increasing evidence sensory phenomena, and occasionally patients report Oto suggest a biologic mechanism even for the primary that they enjoy their movements or it makes them stereotypies. Behavioral and pharmacologic treatments feel good. They are frequently distressing for parents have been used with variable success. but are usually of little concern for the patient, whose daily activities are rarely affected. The incidences of Definition attention-deficit/hyperactivity disorder (ADHD), Stereotypies are broadly defined as involuntary, patterned, obsessive-compulsive behaviors, and tics are increased coordinated, repetitive, often rhythmic, nonreflex- in typically developing children with complex motor 9 ive movements that are goal directed and occur in the stereotypies. same fashion with each repetition.1 Other investigators have supplemented these criteria by adding the terms Differentiating Stereotypies from involuntary, rhythmic, seemingly purposeful, suppressible, Other Disorders or serve no obvious adaptive function.2–6 According to The diagnosis of stereotypies, as stated in the DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, requires the exclusion of several other conditions. Fourth Edition, Text Revision (DSM-IV TR) criteria, these repetitive, nonfunctional behaviors must be pres- 1. Mannerisms are gestures or individual flourishes/ ent for at least 4 weeks and markedly interfere with embellishments that are attached to a normal activity normal activities or possibly cause self-injury, which (e.g., a baseball player’s routine while awaiting a pitch). excludes mild, nontroublesome, forms of stereotypies. These movements tend to be unique to the individual Stereotypic movements come in a variety of forms (e.g., can be repetitive, do not appear in clusters, are of brief hand waving/rotating, arm flapping, finger wiggling, duration, and are less complex than stereotypies. body rocking, head nodding) and may be initially 2. Complex motor tics are quick, rapid movements that misdiagnosed as normal mannerisms, habits, or mere involve either a cluster of simple motor tics or a more nervousness. Suggested definitions are broadly descrip- coordinated sequence of movements. Complex tics tive and visualization of the movements is essential for have several features in common with stereotypies; proper diagnosis. Motor stereotypies should be consid- for example, they are often repetitive, patterned, and ered distinct from the multiple domains of repetitive intermittent and may be precipitated by excitement. behaviors often mentioned with autism, for example, A variety of other characteristics, however, are help- restricted interests and routines, cognitive rigidity ful in distinguishing the two disorders (Table 7-1). symptoms, unusual sensory responses, and social com- Comorbid tics are not uncommon in patients with munication difficulties.7,8 stereotypies.9,10

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TABLE 7-1 Factors Distinguishing Stereotypies from Tics Motor Stereotypies Tics Stereotypies Age at onset 6–7 years <3 years Pattern Variable, wax and wane Fixed, identical, patterned, predictable Movements Blink, grimace, twist, shrug Arms/hands (flap, wave), body rock/head nod O Vocalizations Sniffing, throat clearing Moan, humming with movement 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 With distraction, rare conscious increased “inner tension”) effort Distraction Reduction of tics Stops Family history Frequently positive May be positive Force sensitive Brief, less rhythmic Longer duration: more rhythmic Platform analysis116 qualities Treatment Clonidine, antidopaminergic No established therapy drugs

Adapted from Mahone EM, Bridges D, Prahme C, Singer HS: Repetitive arm and hand movements (complex motor stereotypies) in children, J Pediatr 145(3):391–395, 2004.

3. Compulsions are repetitive behaviors or men- 5. Masturbation, or self-stimulation of the genitalia, is tal acts that are performed to prevent or reduce a normal part of human sexual behavior that occurs distress or some dreaded event or situation, and in both males and females. In some infants and are driven by an obsessive thought or by intrinsic young children such self-gratifying behavior can rules that must be applied rigidly. The compul- manifest as patterned, coordinated, repetitive move- sion is either (a) unrealistically connected to dis- ments, usually consisting of crossing and extending tress reduction or contingency prevention or (b) of legs or repetitive pelvic movements that may be clearly excessive.11 Compulsions are often asso- classified as a stereotypy.12,13 Observation of move- ciated with obsessive thoughts that intrude into ments on a video can often clarify the diagnosis consciousness and are typically experienced as and eliminate the need for unnecessary diagnostic senseless or alien. tests.14 The most challenging aspect of this form 4. Paroxysmal dyskinesias are generally shorter in dura- of stereotypy is to help the parents understand the tion and usually occur as dystonic or choreoathe- benign and self-remitting nature of this behavior. toid movements that are precipitated by voluntary movement (paroxysmal kinesigenic dyskinesias), Pathophysiology exertion of exercise (paroxysmal exertional dyskinesia), or are less predictable, arising from normal The underlying pathophysiologic mechanism for stereo- background activity (paroxysmal nonkinesigenic typies is unknown, with hypotheses ranging from psy- dyskinesias) (see Chapter 8). chologic concerns to neurobiologic abnormalities.15–22

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In the former, the observation of a higher frequency Several methodologic approaches have suggested an of stereotyped behaviors in situations characterized abnormality of dopamine neurotransmission in animal by tedium or an altered state of arousal has led some models of, and patients with, motor stereotypies. In investigators to suggest that these movements act to rodent models, stereotypic behaviors can be induced maintain an optimal state of arousal.23 Proponents in response to both directly and indirectly acting dop- of a psychogenic mechanism tend to suggest several amine receptor agonists and may require a combina- possibilities: (1) a form of self stimulation designed tion of both D1 and D2 receptors.29,38–43 Punding in to compensate for a deficit of external arousal (e.g., humans, that is, stereotyped behaviors characterized by congenital blindness, caging, autism, or mental retar- a fascination with repetitive, meaningless movements, dation); (2) an attempt to use up excess attention have been linked to stimulation of dopamine receptors capacity or to reduce external distractions by channel- with levodopa, dopamine agonists, and, rarely, dop- ing thoughts and actions into movements;24 (3) a rela- amine receptor blockers.44,45 In adults with high rates tionship to obsessive-compulsive disorder (OCD),25 of body rocking, measurements of plasma concentra- a general anxiety disorder,26 and perfectionism or tions of the dopamine metabolite homovanillic acid impulse dyscontrol;27 and (4) in autistic spectrum were reduced.46 Using eye-blinking rate as a nonin- disorders repetitive behaviors take the place of imagi- vasive indicator of dopamine function, the mean eye native activities.28 Psychogenic basis of stereotypies is blink rate was lower in adults with stereotypic behav- also suggested by the observation that when animals iors studied in a state mental facility.47 are taken from their natural (wild) habitat into a con- A pattern of mendelian inheritance, perhaps auto- strained environtment, such as the zoo or a cage, they somal dominant, has been suggested in typically often develop repetitive motor behaviors, such as shift- developing children based on a family history of ing weights, orofacial chewing movements, and other motor stereotypies present in 25% of first-degree rela- stereotypies. The study of habits and rituals of animals tives.9 Results of genetic studies in this population are may provide insights into the pathogenesis of human pending. stereotypies.29 A neurologic basis for stereotypies is supported by Classification of Motor Stereotypies its association with disorders of the central nervous system, such as autism and mental retardation, its Repetitive motor stereotypic behaviors are common in onset after brain insults, and its pharmacologic induc- children with autism, mental retardation, or sensory tion in animal models and in humans. In fact, the best deprivation, as well as typically developing children. example of adult-onset stereotypy is tardive dyskine- A favored classification subdivides by etiology into sia. The precise neuroanatomic localization for motor primary and secondary categories, dependent on the stereotypies is unknown. Neurodiagnostic evaluations existence of other behavioral or neurologic findings including routine electroencephalogram (EEG) and (Table 7-2). Whereas some investigators have sug- magnetic resonance imaging MRI scans in typically gested that a particular movement or its duration may developing children with stereotypies are unremark- be more indicative of a secondary type, others have able. Several investigations have suggested abnormal- emphasized that there is considerable overlap between ities located within cortico-striatal-thalamocortical the two subdivisions. pathways, the proposed localization of multiple move- Primary ment disorders. Volumetric reductions in frontal white matter have been identified in a small group of non- This category implies that there is no specific cause autistic boys with stereotypies.30,31 Stereotypic move- for the stereotypy as it occurs in an otherwise normal ments have spontaneously appeared in a patient after individual; mild delays in either language or motor meningoencephalitis with bilateral frontoparietal cor- development may be present.3,9,48 Primary stereotyp- tical lesions,32 and in association with strokes involv- ies can be readily classified into three groups: common ing the right putamen,33 right lenticular nucleus,34 and behaviors (e.g., rocking, head banging, finger drum- bilateral paramedian thalamic and midbrain regions.35 ming, pencil tapping, hair twisting) and two forms In patients with Down syndrome, cerebellar white that contain atypical or complex behaviors, that is, matter volumes positively correlated with the severity head nodding, or those with complex motor movements of stereotypic behaviors.36 In autistic children, how- (e.g., hand and arm flapping/waving). Precise esti- ever, stereotyped behaviors negatively correlated with mates of the prevalence of stereotypic movements in the size of the cerebellar vermal lobules VI and VII, and the typically developing child are unknown, especially positively correlated with frontal lobe volumes.37 since some investigators have included activities such

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TABLE 7-2 Classification of Stereotypies were often accompanied by general distress, anxiety, Based on Etiology obsessive-compulsive symptoms, and impulsive aggressive traits, some investigators have suggested that com- I. Primary mon stereotypies may lie on a spectrum with other Common type neuropsychiatric disorders, especially obsessive-compulsive phenomena.25,26,60 Whether body rocking Head nodding should be considered as a separate entity, based on a Complex motor high frequency in first-degree relatives with similar II. Secondary (in the Presence of Other Pathology) movements and without evidence of mental retardation or autism,25,26 is controversial. Autism: Infantile autism, Asperger’s syndrome, pervasive developmental disability, Rett syndrome Head-Nodding Stereotypies Mental retardation Rhythmic regular head movements (either a side-to-side, Sensory deprivation: congenital blindness/deafness, “no” movement; an up-and-down, “yes” movement; or caging, constraints a shoulder-to-shoulder movement) with a frequency of 1 to 2 per second, that can be stopped voluntarily, have Inborn errors of metabolism: Lesch-Nyhan been reported in normal children as a form of stereo- syndrome typy.9,61 Up-gaze eye deviations or movements of the Genetic: Neuroacanthocytosis hands or feet occasionally accompany the head shaking. Drug-induced: psychostimulants, tardive dyskinesia Several different etiologies may be involved, since many of the children in the Hottinger-Blanc group had hypo- Infection: encephalitis tonia, delayed motor and language development, and Tumor: bobble-headed doll syndrome ataxia. In a study following eight children with typical development and head nodding, three stopped entirely, Trauma suggesting that outcome may differ in this category as Psychiatric: OCD, schizophrenia, catatonia, functional compared to children with complex motor stereotypies.9 Pathophysiologic etiologies for head movements have ranged from a congenital-brainstem-cerebellar abnor- as thumb and hand sucking, nail biting, and foot tap- mality to perpetuation of a “normal” motor program. ping.49,50 The outcome of stereotypies in this group has The differential diagnosis in this group of patients been controversial. Some investigators have suggested includes such entities as Sandifer’s syndrome, spasmus that they increase by 3 years of age and decline after nutans, bobble-head doll syndrome, congenital nystag- age 4,51 whereas others have suggested that the majority mus, oculomotor apraxia, and jactatio capitis nocturna of complex motor behaviors persist.9,48 (rhythmic movement disorder/nocturnal head banging). The Bobble head doll syndrome is characterized by Common Stereotypies stereotypic antero-posterior (rarely side to side) head Behaviors such as thumb sucking, nail/lip biting, hair movements at a frequency of 2-3 Hz.18,22 The move- twirling, body rocking, self-biting, and head bang- ments tend to increase with activity and excitement ing, sometimes called habits, are relatively common and decrease with concentration.18,22 This phenomenon in childhood and generally most regress.50–54 In some is usually associated with lesions of the third ventricle children stereotypic behaviors evolve with thumb and but has been reported in association with aqueductal hand sucking in the younger child replaced by body stenosis, Dandy-Walker Syndrome,117 and large supra- rocking and head banging, and later by nail biting, sellar arachnoid cysts.118 The precise pathophysiologi- finger tapping, and foot tapping.55 It has been esti- cal mechanism is unknown. Surgical treatment of the mated that about 20% of healthy children exhibit underlying lesion typically results in complete resolu- stereotypies.56 Investigation of stereotypies in col- tion of the abnormal head movement. lege students has identified a variety of common movements (touch face; play with hair, pens, or jew- Complex Hand and Arm Movement Stereotypies elry; shake leg, tap fingers, scratch head, etc.), but Movements in this group include hand shaking, pos- most were not time-consuming or disruptive.57 The turing, flapping or waving, opening and closing of the prevalence of body rocking has varied between 3% hands, finger writhing, arm flapping, and flexion and and 25% depending on the identifying methodol- extension of the wrists. Additional movement pat- ogy.58 In the college population, since stereotypies terns may occur in conjunction (e.g., body rocking, leg

[email protected] 66485438-66485457 60 Section 3 pAroxysmal Movement Disorders shaking or kicking, facial grimacing, mouth open- severity of illness,66,67 cognitive deficiency,63,68 impairing, neck extension, and involuntary noises), but the ment of adaptive functioning,5,69 and symbolic play.70 hand/arm movements are dominant.9,48 Although sev- In neurodevelopmentally delayed populations, the dif- eral small studies have attempted to compare and con- ferentiation of stereotypies, tics, repetitive behaviors, trast stereotypic movements of children in the general and compulsions has been variable and often depend- population to those in autistic children,6,51 most inves- ing on the bias of the evaluator.71,72 Based on scoring of tigators suggest that the complex stereotypies seen in motor stereotypies observed on videos of standardized typical children can be prolonged, include complex play sessions, children with autism or those with a low motor patterns, and resemble those in the autistic nonverbal IQ had a greater number and variety of tics population. than controls.72a These authors further suggested that Two chart review/telephone follow-up studies have the stereotypy of gazing atypically at fingers or objects evaluated typical children with complex motor stereotyp- was almost entirely found in cognitively impaired autis- ies and found similar results.9,48 In the larger study, involv- tic children. Other investigators have suggested that ing 90 children (58 boys, 32 girls) with complex motor “hands to ears” (abducting and externally rotating the stereotypies, onset of movements occurred on or before arms with the hands close to the ears) was more com- age 2 years in 80%, and in all by 37 months.9 Movements mon in children with autistic spectrum disorder than lasted for less than 10 seconds in 37%, 11 to 60 seconds controls,73 whereas visual fixation/staring at objects was in 27%, and more than a minute in 37%. Complex ste- more common in children with developmental delay reotypies occurred more than once a day in about 80%. than autism.74 Nevertheless, despite these individ- Triggers included excitement/happy (86%), being focused/ ual suggestions of a possible behavioral marker, most engrossed (34%), anxiety/stress (27%), and tired/fatigued researchers emphasize the considerable overlap in rep- (21%); more than one trigger was commonly identified. ertoire of stereotypic movements among autistic, men- If distracted, in all but one case, the movement ceased. tally retarded, and typically developing children. In subjects 7 years of age and older, that is, beyond the Studies into the genetics of autistic disorders may expected age for symptom appearance, 30% had ADHD provide insights into the mechanisms of neurologic and 18% had tics. Obsessive-compulsive behaviors were deficits, including stereotypies, associated with this also common in this population. Consistent with a prior increasingly recognized childhood neurologic disorder. report,48 an extended longitudinal follow-up confirmed One potential candidate gene involved in autisms is the that most motor stereotypies were persistent, that is, only CNTNAP2 gene on chromosome 7q35 that codes for 3% stopped, 28% were better, 61% remained stable, and Contactin Associated Protein-Like 2, a neurexin family 11% worsened.9 Hence, suggestions to parents that com- member involved in myelination of axons.75,76 plex motor stereotypies are brief and transient appear to be erroneous. Rett Syndrome Classic Rett syndrome (RS) occurs in young girls who Secondary have had a normal prenatal and perinatal history, normal head circumference, and normal psychomotor develop- Associated with Autism and Mental Retardation ment through the first 6 to 12 months of life.77 The Repetitive behaviors are a major diagnostic feature course is then one of developmental arrest or regression, of autistic disorder, that is, “restricted repetitive and with deterioration of communicative skills, social with- stereotyped patterns of behavior, interests, and activi- drawal, and loss of fine finger function. The RS child ties.”11 Some authors have attempted to divide repetitive continues to deteriorate over the next few years, resulting and stereotyped behaviors of autism into narrow sub- in a loss of language, poor motor function (truncal and groups (e.g., repetitive movements, motor sequencing, gait apraxia/ataxia), and a deceleration of head growth. sensory behaviors, inflexibility, and complex repetitive Bilateral hand washing movements are a hallmark of behaviors),60,63 whereas others have devised less com- this syndrome, but have been identified in a group of plex systems. Stereotypic motor behaviors are common children without the MeCP2 gene mutation.78 In addi- in the vast majority of autistic children and in many tion to the hand movements, individuals with RS also are complex in nature.64 Attempts, however, to identify have a variety of other rhythmic movements.79–83 Hair specific behavioral markers that can assist in the iden- pulling, bruxism, and cervical retropulsion have been tification of a neurodevelopmental origin have been found to occur more frequently in mutation-positive unsuccessful. Children with autism have more stereotyp- individuals.78 Stereotypic movements may begin before ies than do equally retarded children without autism,65 or after the loss of purposeful hand movements or the and their severity and frequency positively relate to onset of developmental regression.84,85

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Associated with Sensory Deprivation tions99–101 and various pharmacotherapies have been used Stereotypic motor behaviors occur frequently in vision- with variable success. In a small number of nonautistic impaired children, for example, eye rubbing, press- children, the combination of two behavior-modifying ing, or poking (“oculodigital phenomena”).86–88 In this techniques, habit reversal and differential reinforcement group it has been suggested that voluntary stimulation of other behaviors, was beneficial in reducing motor ste- of the optic nerve evokes sensations of light at the cor- reotypies.102 In the autistic or retarded population, many tical level, termed phosphenes.89 Other interpretations with associated self-injurious behaviors, the response of for these behaviors include a desire to produce certain stereotypic movements to medications is generally incon- insensitivity to pain. Blind children also have a variety of sistent. Recommendations, often based on noncon- additional stereotypies including, in descending order of trolled therapeutic trials, have included benzodiazepines frequency, body rocking, repetitive handling of objects, (clonazepam), alpha-adrenergic agonists (clonidine), hand and finger movements, lying face down, and jump- opiate antagonists (naltrexone),62,103,104 beta-blockers,105 ing.90 These activities have been variably attributed to a antiepileptic medications (valproate, carbamazepine),106 lack of stimulation or as a means of reducing tension. antipsychotics (risperidone, olanzapine, haloperidol, or Deaf children frequently have rocking behaviors, but thioridazine),107,108 monoamine depletors such as tet- fewer self-injurious behaviors.91 Stereotypies also occur rabenazine,109 selective serotonin reuptake inhibitors in association with imprisonment in close quarters.92 (fluoxetine, fluvoxamine, paroxetine),110,111 and others (clomipramine, propranolol).112–114 Isolated case reports Associated with Inborn Errors of Metabolism/Genetic have reported some improvement with clonazepam and Lesch-Nyhan disease is characterized by hyperuricemia, clonidine.3,115 The use of dopamine receptor blocking self-injurious behaviors, and neurologic problems. In drugs (neuroleptics), such as haloperidol, thioridazine, these patients, common stereotypic movements include and risperidone, is strongly discouraged because of the self-biting, head banging, eye poking, and arm flinging. risk of tardive dyskinesia. Neuroacanthocytosis is characterized by the presence of acanthocytes, orofacial dyskinesias, extrapyramidal movements, and tics. Affected individuals often have REFERENCES stereotypic movements and self-injurious behaviors. Drug-Induced 1. Jankovic J: Stereotypies. In Marsden CD, Fahn S, editors: Movement disorders, 3rd ed. Oxford, 1994, Butterworth- The classic features of tardive dyskinesia (repetitive oro- Heinemann. lingual and facial movements) have been considered by 2. Kurlan R, O’Brien C: Spontaneous movement disorders 93 some to be classic examples of stereotypies. For exam- in psychiatric patients. 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9. Harris K, Mahone EM, Singer H: Nonautistic motor 27. Niehaus DJ, Emsley RA, Brink P, Stein DJ: Stereotypies: stereotypies: clinical features and longitudinal follow-up, prevalence and association with compulsive and impul- Pediatr Neurol 38:267–272, 2000. sive symptoms in college students, Psychopathology 10. Ringman JM, Jankovic J: Occurrence of tics in Asperger’s 33(1):31–35, 2000. syndrome and autistic disorder, J Child Neurol 15:394– 28. Wing L, Gould J: Severe impairments of social interac- 400, 2000. tion and associated abnormalities in children: epidemiology 11. American Psychiatric Association: Diagnostic and statisti- and classification, J Autism Dev Disord 9(1):11–29, 1979. cal manual of mental disorders, fourth edition, text revision, 29. Graybiel AM: Habits, rituals, and the evaluative brain, Washington, DC, 2000, American Psychiatric Association. Annu Rev Neurosci 31:359–387, 2008. 12. Mink JW, Neil JJ: Masturbation mimicking paroxys- 30. 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44. Evans AH, Katzenschlager R, Paviour D, et al: Punding 61. Hottinger-Blanc PM, Ziegler AL, Deonna T: A special in Parkinson’s disease: its relation to the dopamine dys- type of head stereotypies in children with developmental regulation syndrome, Mov Disord 19(4):397–405, 2004. (?cerebellar) disorder: description of 8 cases and litera- 45. Miwa H, Morita S, Nakanishi I, Kondo T: Stereotyped ture review, Eur J Paediatr Neurol 6(3):143–152, 2002. behaviors or punding after quetiapine administra- 62. Willemsen-Swinkels SH, Buitelaar JK, van Berckelaer- tion in Parkinson’s disease, Parkinsonism Relat Disord Onnes IA, van Engeland H: Brief report: six months 10(3):177–180, 2004. continuation treatment in naltrexone-responsive chil- 46. 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76. Arking DE, Cutler DJ, Brune CW, et al: A common dyskinesias in autistic children, J Clin Psychopharmacol genetic variant in the neurexin superfamily member 9(3):207–209, 1989. CNTNAP2 increases familial risk of autism, Am J Hum 95. Burke RE, Kang UJ, Jankovic J, et al: Tardive akath- Genet 82:160–164, 2008. isia: an analysis of clinical features and response to open 77. Singer HS, Naidu S: Rett syndrome: “We’ll keep the therapeutic trials, Mov Disord 4(2):157–175, 1989. genes on for you,” Neurology 56(5):582–584, 2001. 96. Ellinwood EH Jr, Sudilovsky A, Grabowy R: Olfactory 78. Temudo T, Oliveira P, Santos M, et al: Stereotypies in forebrain seizures induced by methamphetamine and Rett syndrome: analysis of 83 patients with and without disulfiram, Biol Psychiatry 7(2):89–99, 1973. detected MECP2 mutations, Neurology 68(15):1183– 97. Fernandez HH, Friedman JH: Punding on L-dopa, 1187, 2007. Mov Disord 14(5):836–838, 1999. 79. Wales L, Charman T, Mount RH: An analogue assess- 98. 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112. Brasic JR, Barnett JY, Kaplan D, et al: Clomipramine 115. Trinidad KS, Wang D, Kurlan R: Paroxysmal stereo- ameliorates adventitious movements and compul- typic dyskinesias in children, Mov Disord 8:417, 1993. sions in prepubertal boys with autistic disorder and 116. Crosland KA, Zarcone JR, Schroeder S, et al Use of severe mental retardation, Neurology 44(7):1309–1312, an antecedent analysis and a force sensitive platform to 1994. compare stereotyped movements and motortics. Am J 113. Gordon CT, State RC, Nelson JE, et al: A double- Ment Retard 110:181–192, 2005. blind comparison of clomipramine, desipramine, and 117. de Brito Henriques JG, Henriques KS, Filho GP, placebo in the treatment of autistic disorder, Arch Gen et al, Bobble-head doll syndrome associated with Psychiatry 50(6):441–447, 1993. Dandy-Walker syndrome. Case report. J Neurosurg 107 114. Garber HJ, McGonigle JJ, Slomka GT, Monteverde E: (3 Suppl):248–250, 2007. Clomipramine treatment of stereotypic behaviors and 118. Navigated laser-assisted endoscopic fenestration of a self-injury in patients with developmental disabilities, suprasellar arachnoid cyst in a 2-year-old child with J Am Acad Child Adolesc Psychiatry 31(6):1157–1160, bobble-head doll syndrome. Case report. J Neurosurg 1992. 104 (5 Suppl):348–351, 2006.

[email protected] 66485438-66485457 8 Paroxysmal Dyskinesias O Introduction the condition paroxysmal kinesigenic choreoathetosis, suggesting that it was a specific entity within the paroxys Paroxysmal dyskinesias comprise a subset of hyperki mal choreoathetosis syndrome. A striking feature of the netic movement disorders that typically begin in child kinesigenic form was the brief (seconds to minutes) hood. They are defined by their episodic nature, usually duration of the episode, whereas the episodes described arising out of a background of normal movement and by Mount and Reback were longer lasting (minutes behavior. The specific type of dyskinesia can be dys to hours). To better distinguish these forms, Richards tonia, chorea, or a combination. Many movement and Barnett3 coined the term paroxysmal dystonic chore- disorders in childhood are paroxysmal, but the disor oathetosis of Mount and Reback to help delineate it from ders falling in the category of paroxysmal dyskinesias paroxysmal kinesigenic choreoathetosis. A third form are limited and specific. Other paroxysmal movement of paroxysmal dyskinesia was reported by Lance4 in a disorders are considered in other chapters, includ family with intermediate-duration attacks that were ing episodic ataxia (see Chapter 13), hyperekplexia precipitated by prolonged exercise. These attacks were O(see Chapter 11), tics (see Chapter 6), stereotypies differentiated from paroxysmal dystonic choreoathetosis (see Chapter 7), and a variety of transient disorders and paroxysmal kinesigenic choreoathetosis. that are related to specific periods during development (see Chapter 5). Clinical Characteristics Paroxysmal dyskinesias may be classified as primary (most likely genetic) or secondary (caused by identifi The clinical manifestations of paroxysmal dyskinesias able disorders). The terminology used to describe and can be complex. The movements may be dystonic, classify paroxysmal dyskinesia has varied over the years choreic, athetotic, or a combination. The duration of and has led to confusion about whether there were attacks may be highly variable. Although the histori multiple entities, each with characteristic presentation, cal distinction between paroxysmal kinesigenic choreo or few entities, each with wide phenotypic variability. athetosis and paroxysmal dystonic choreoathetosis Recent genetic advances, aided by a concise descrip included differences in attack duration, this was not tive classification scheme, have provided important a reliable differentiating factor. Further, “paroxysmal insights into the mechanisms underlying these disor dystonic choreoathetosis” was not always “dystonic,” ders and have resulted in better diagnostic and treat and neither form always included “choreoathetosis.” ment strategies. In 1995, Demirkiran and Jankovic5 proposed a descrip The term paroxysmal choreoathetosis first appeared in tive classification scheme that was based primarily on a report by Mount and Reback1 of a family in which the the precipitating event, arguing that the precipitant proband had infantile onset of periodic but prolonged was the best predictor of clinical course and response to dyskinesia that could be induced by alcohol and other specific medications (Table 8-1). This empirical classifi agents. The episodes were characterized by an aura of a cation scheme helped objectify the identification of dif tight sensation in the neck and abdomen and a sense of ferent forms of paroxysmal dyskinesia. They proposed fatigue followed by involuntary flexion of the arms and four categories based on precipitating factors: (1) kine extension of the legs (dystonia). Spells typically pro sigenic, (2) nonkinesigenic, (3) exertion induced, and gressed to involuntary choreoathetosis and dysarthria (4) hypnogenic (also known as paroxysmal nocturnal with preservation of consciousness. Mount and Reback dystonia of sleep). After the precipitant is identified, called the condition familial paroxysmal choreoatheto- secondary categorization is based on duration: less than sis. Subsequently, Kertesz2 described a group of patients or equal to 5 minutes (short) or greater than 5 minutes who had childhood onset of paroxysmal choreoatheto (long). Tertiary classification is based on presumed sis that was precipitated by sudden movement. Kertesz etiology: primary (familial versus sporadic) or secondary. highlighted the kinesigenic component and called This descriptive scheme is helpful in making clinical 66 [email protected] 66485438-66485457 Chapter 8 Paroxysmal Dyskinesias 67

Most patients have dystonia, but some have a combina Table 8-1 Classification Hierarchy tion of chorea and dystonia. The attacks may be limited for Paroxysmal Dyskinesias to one side of the body or even to one limb. The attacks I. Precipitant decrease in frequency during adulthood.2 The patients a. Kinesigenic b. Nonkinesigenic typically respond well to anticonvulsants. The attacks c. Exertion-Induced occur frequently—up to 100 per day. The duration is d. Hypnogenic short, usually a few seconds to a few minutes. However, 5 II. Duration longer-lasting attacks may occur rarely. a. Short (< 5 minutes) A study of 121 individuals referred for a genetic study O b. Long (> 5 minutes) of PKD has helped to clarify the features of this disorder.8 Ninety-five of the 121 subjects had “classic” PKD. III. Presumed Etiology a. Primary Sixty-four of the 95 had a family history of PKD. Nearly i. Familial 100% of familial cases and 79% of the total sample had ii. Sporadic a homogeneous phenotype that included the following: b. Secondary (1) identified trigger for the attacks, (2) short duration i. Demyelinating of attacks, (3) no loss of consciousness or pain dur ii. Hypoxic-Ischemic iii. Traumatic/Vascular ing attacks, (4) clinical response to antiepileptic drugs, iv. Metabolic/Endocrine and (5) age at onset between 1 and 20 years (Fig. 8-1). 1. Thyroid The typical trigger was sudden movement. Most epi 2. Parathyroid sodes lasted less than 1 minute. Dystonia was the most 3. Hypoglycemic common form of dyskinesia, occurring in 57%, with 4. Hypernatremic v. Drug-Induced chorea occurring in 6%, and a combination of different 1. Antipsychotics forms of dyskinesia in 33%. Attacks were unilateral in 2. Phenytoin 36%, bilateral in 35%, and variable in the remainder. vi. Others In those subjects with a family history of PKD, the male:female ratio was approximately 1:1, but in spo Modified from Demirkiran M, Jankovic J: Paroxysmal dyskinesias: clinical features and classification, Ann Neurol radic cases, the male:female ratio was greater than 2:1. 38:571–579, 1995. This is consistent with, but less pronounced than, what has been reported previously.6 Infantile convulsions were reported in 48% of kindreds with familial PKD and in 10% of kindreds with sporadic PKD. The authors also distinctions, and has also proved useful in identifying described two sets of outliers: 12 subjects with onset phenotypes for genetic association studies. All forms before 1 year of age and 14 subjects with onset after can be sporadic, have a genetic basis, or be symptom 1 year of age but with atypical features.8 One of the atic, see Tables 8-1. The typical features of kinesigenic, 12 infants had onset at 10 months of age of hemidystonia nonkinesigenic, and exertion induced paroxysmal induced by walking, with a response to carbamazepine dyskinesias are listed in and Table 8-2. and a family history of PKD. The other 11 almost cer tainly had other paroxysmal events that were distinct Specific Disorders from PKD. Two of the 14 outliers with onset after 1 year of age were atypical because of age at onset greater Paroxysmal Kinesigenic Dyskinesia than 20 years.8 The others were later determined to have Paroxysmal kinesigenic dyskinesia (PKD) is often inher paroxysmal nonkinesigenic dyskinesia, paroxysmal exer ited in an autosomal dominant manner, but a quarter tional dyskinesia, or psychogenic disorders. of the cases are sporadic. Males are affected more often then females (male:female = 4:1).6,7 The age at onset is in Etiology the first or second decade of life in familial cases but may Most cases of PKD are idiopathic and the cause is pre be variable in sporadic cases. The attacks are typically sumed to be genetic. Substantial progress has been made precipitated by the individual being startled or making in genomic mapping of several of the paroxysmal dys a sudden movement after a period of rest. There is often kinesias. Three types of paroxysmal kinesigenic dys a refractory period after an attack during which sudden kinesia have been linked to chromosome 16. The first movement will not provoke another attack. Patients may is the syndrome of familial infantile convulsions and only have an abnormal sensation in the limbs involved, paroxysmal choreoathetosis, which has been linked or the sensation may precede motor manifestation. to the pericentromeric region of chromosome 16.9,10

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TABLE 8-2 Distinguishing Features of Kinesigenic, Nonkinesigenic, and Exertion Induced Paroxysmal Dyskinesias Feature PKD PNKD PED Trigger Movement ETOH, caffeine Prolonged exercise, hyperventilation Lateralization Unilateral or bilateral Unilateral or bilateral Unilateral or bilateral Duration Seconds to minutes Minutes to hours 5 minutes to 2 hours Male:female 4:1 1.4:1 1:1 Onset age <1 year to 40 years <1 year to 30 years 2-30 years Effective medication Carbamazepine, Benzodiazepines Acetazolamide, phenytoin benzodiazepines Frequency Up to hundreds per day Up to a few per day One per day Aura Sometimes Sometimes Improvement with age Yes Yes unknown

20 16p, within the pericentromeric region identified for par 18 oxysmal kinesigenic dyskinesia with or without infantile 16 convulsions.15 It appears that individuals homozygous 14 12 for the disease haplotype at chromosome 16p12-q12 10 may have earlier age at of onset and higher frequency of 8 attacks than heterozygous family members.16 6 PKD can also occur in association with other iden 4 tifiable disorders.17 Secondary PKD should be consid Number of patients (N) 2 ered in all atypical cases, such as onset before 1 year of 0 <1 510152025304050 age, prolonged duration of attacks, and when there are associated interictal neurologic deficits. In secondary Age (y) PKD episodes are kinesigenic, but they usually differ Figure 8-1. Age of onset of first attack in 121 individuals from typical PKD in some way. referred with PKD. Children with onset at less than 1 year of age are most likely to have another disorder. (From Bruno Demyelinating Disease MK, Hallett M, Gwinn-Hardy K, et al: Clinical evaluation The most common cause of secondary PKD in adults of idiopathic paroxysmal kinesigenic dyskinesia: new is demyelinating disease; there are no such reports in diagnostic criteria, Neurology 63(12):2280-2287, 2004.) children. Paroxysmal hemidystonia may be the initial manifestation of multiple sclerosis or may occur in established disease.18 The attacks may be kinesigenic but Despite the strong linkage to chromosome 16p11-q21, are most consistently precipitated by hyperventilation no specific gene has yet been identified.11 A syndrome and can be extremely painful. Attacks typically involve of paroxysmal kinesigenic dyskinesia without infantile one side of the body with or without the face but may convulsions has also been linked to the pericentromeric occur bilaterally. Each attack lasts from a few seconds to region of chromosome 16 that overlaps with the region a few minutes, and multiple attacks may occur during for infantile convulsions and paroxysmal choreoatheto the day. The attacks tend to subside spontaneously over sis.12 A family with paroxysmal kinesigenic dyskinesia has many weeks in spite of continuing disease activity. been described with linkage to 16q and with no overlap with the pericentromeric region reported for the other Cerebral Palsy families.13,14 A family with autosomal recessive paroxys PKD has been described as a delayed manifestation mal exertional dystonia, rolandic epilepsy, and writer’s after perinatal hypoxic encephalopathy.19 The age at cramp has been shown to have linkage to chromosome onset was 12 years and the attacks were precipitated

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by being bumped from behind rather than by a sudden remarkable responsiveness to anticonvulsants, nor voluntary movement. These were short lasting (5 to 30 malization of neurologic examination between seconds) and occurred 5 to 20 times a day. events, and familial association.25 As noted, some families contain individuals with infantile convul Metabolic and Toxic Disorders sions alone or who had infantile convulsions before PKD has been reported with hypoparathyroidism20 development of PKD. Some patients have abnormal and with pseudohypoparathyroidism.21,22 Basal ganglia baseline EEGs.6 calcifications may be seen in these cases. In addition, Several reports support the idea of basal ganglia PKD has been reported in association with severe global dysfunction in PKD. In five patients with PKD, proton mental retardation and thyroid hormone abnormali magnetic resonance spectroscopy revealed decreased ties as an X-linked condition due to mutations in the basal ganglia levels of choline in two patients and decrea thyroid hormone transporter gene MCT8.23 PKD has sed myoinositol in one patient.26 In one case of PKD, also been reported in association with methylphenidate ictal single-photon emission computed tomography therapy.24 It is likely, however, that the PKD in that (SPECT) revealed increased perfusion of the basal patient was idiopathic because it persisted even after ganglia.27 A study of 16 patients with idiopathic PKD discontinuation of methylphenidate and it responded and 18 controls demonstrated significant interictal to carbamazepine. hypoperfusion in the posterior regions of the caudate 28 Differential Diagnosis and Evaluation nuclei bilaterally. PKD must be distinguished from nonparoxysmal Treatment and Outcome action dystonia, seizures, pseudoseizures, and tics. PKD responds best to anticonvulsants, including phe Many individuals with dystonia have little or no invol nytoin, carbamazepine, phenobarbital,6 levetiracetam,29 untary movement when at rest and the dystonia is only gabapentin,30 oxcarbazepine,31 lamotrigine,32 and topi present with action. Sometimes the dystonia is associ ramate.33 PKD is exquisitely sensitive to phenytoin and ated with specific actions (see Chapter 10). However, carbamazepine at doses that are usually much less than action dystonia is present with specific movements and the dosages used to treat epilepsy.34,35 Treatment with is not precipitated by sudden movements. In addition, levodopa has also been reported to be successful in rare action dystonia persists as long as the action is being patients.36 performed, but PKD typically resolves quickly. Reflex Outcome is good for patients with typical PKD. epilepsies may resemble PKD superficially, although The great majority have excellent response to treat sudden movement is a rare precipitant of seizures. Tics ment. In addition, many patients report marked spon are commonly preceded by an “urge,” although they are taneous improvement (25%) or complete remission rarely precipitated by sudden movement. They are also (27%) in adulthood;37 most patients remit during their rarely seen in isolation without other tics, and rarely twenties. involve dystonia or chorea of multiple body parts (see Chapters 6 and 10). Paroxysmal Nonkinesigenic Dyskinesia A detailed history and videotape documentation are Paroxysmal nonkinesigenic dyskinesia (PNKD) is also most important in the differential diagnosis of parox usually inherited as an autosomal dominant trait. The ysmal dyskinesias. A detailed family history should be attacks occur more often in males (male:female = 2:1). obtained. In children with typical features of PKD and The age at onset can be in early childhood, but attacks with a family history of PKD, no further evaluation may not start until the early twenties. The frequency may be necessary. In children with atypical features varies from three per day to two per year. The usual but with no other neurologic signs or symptoms, an precipitating factors are fatigue, alcohol, caffeine, and electroencephalogram (EEG), serum glucose, serum emotional excitement. The attack may start with invol electrolytes, and serum calcium testing are recommended. untary movements of one limb but may spread to In those with atypical features and an abnormal involve all extremities and the face. The usual dura interictal examination or abnormal development, tion is minutes to 3 to 4 hours. During the attack the further evaluation is warranted as determined by the patient may be unable to communicate, but the patient coexisting features. remains conscious and continues to breathe normally. Pathophysiology Some families exhibit predominant dystonia,38 whereas Paroxysmal dyskinesia has some features in common others exhibit predominant choreoathetosis.1 The with epilepsy, including presence of an aura for attacks are relieved by sleep and in some cases respond many patients, the paroxysmal nature of events, to pharmacologic intervention.

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Identification of an association of PNKD with over four generations. Of 13 individuals for whom mutation in the myofibrillogenesis regulator 1 (MR-1) detailed clinical information was reported, 12 had gene on chromosome 239 has provided more precise PNKD either alone (n = 7) or in combination with specification of the phenotype associated with this seizures (n = 5). One affected individual had seizures mutation.37 In a study of 49 patients with PNKD who alone. The characteristics of the PNKD are not fully were positive for an MR-1 mutation and 22 patients described in this family. It is not known if the epi with PNKD who did not have MR-1 mutation, several sodes were precipitated by caffeine or alcohol. At least common features were found in the MR-1 mutation two family members benefited from benzodiazepines. positive subjects. Patients with MR-1 mutations had Most seizures in this family were absence in type and the following: (1) onset in infancy or early child when EEG abnormalities were present, there were hood, typically in the first decade of life, with 33% 3 to 3.5 Hz generalized spike-wave discharges. This having onset in the first year of life; (2) a mixture of BK mutation is associated with increased neuronal chorea and dystonia in the limbs, face, and trunk; excitability by causing rapid repolarization of action 88% had a mixture of chorea and dystonia, 12% had potentials.45 Thus this form of PNKD is due to a dystonia alone; (3) typical attack duration between channelopathy. 10 minutes and 1 hour, but could be as long as 12 As described for PKD, PNKD can also occur sec hours; (4) precipitation by caffeine, alcohol, or emo ondary to other disorders.17 Similar to PKD, the most tional stress; and (5) favorable response to benzodiaz common cause of secondary PNKD is demyelinating, epines. Families without MR-1 mutations had more multiple sclerosis. Most disorders causing PKD have variable age at onset, precipitants, clinical features, also been associated with PNKD, and in some reports and response to medications. Forty-one percent of it is unclear whether the patient had PKD, PNKD, or those with MR-1 mutation had a premonitory sen both. However, PNKD has been reported specifically sation localized to a limb (80%) or a sense of anxi in a child with maple syrup urine disease46 and in one ety (20%). Alcohol and caffeine precipitated spells child with GLUT1 deficiency.47 PNKD is more likely in 98% of subjects with an MR-1 mutation. Unlike to be a presentation of a conversion disorder than is PKD, there was no benefit from typical antiepileptic PKD.5,37 medications, but there was moderate benefit from Differential Diagnosis and Evaluation diazepam or clonazepam.37 It is more difficult to separate PNKD from other epi Although PNKD is typically mono-symptomatic it sodic movement disorders than is PKD because of the has also been reported in a patient with familial ataxia.40 lack of a temporally clear precipitant. PNKD must be In one family PNKD was accompanied by myo differentiated from dopa-responsive dystonia, seizures, kymia.41 Some families also have exertional cramp pseudoseizures, and tics. Dopa-responsive dystonia ing, which may be a forme fruste of PNKD,42 or it usually manifests in childhood and may have marked may represent paroxysmal exertion-induced dyskinesia diurnal fluctuations, with the patient improving with (see below). rest and worsening with exercise.48 However, discrete Etiology paroxysms do not occur. Other differential diagnostic considerations are discussed in the section on PKD ear Before association of PNKD with mutations in MR-1, lier in this chapter. it was thought that PNKD was most likely due to In children with typical features of PNKD and channelopathy. The function of MR-1 is not known, with a family history of PNKD, no further evalu but it is not an ion channel protein. It has substan ation may be necessary. In children with atypical tial homology with hydroxyacylglutathione hydrolase features but with no other neurologic signs or symp (HAGH).43 HAGH catalyzes the final step in the con toms, an EEG, serum glucose, serum electrolytes, and version of methylglyoxal to lactic acid and reduced glu serum calcium testing are recommended. In those tathione. Interestingly, methylglyoxal is found in coffee with atypical features and an abnormal interictal and in alcoholic beverages,44 both of which reliably pre examination or abnormal development, further eval cipitate attacks of PNKD.37 uation is warranted as determined by the coexisting An autosomal dominant syndrome of generalized features. epilepsy and PNKD has been described in a single large family in association with mutation on chro Pathophysiology mosome 10q22 in the alpha subunit of the large Several reports implicate the basal ganglia in PNKD. conductance calcium-sensitive potassium (BK) chan Positron emission tomography (PET) scanning nel.45 The family included 16 affected individuals revealed abnormalities in the basal ganglia metabolism

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of a patient with post-traumatic PNKD.49 One patient family has been described with PED and migraine that with PNKD showed decreased [18]FDOPA uptake was not linked to the PNKD locus on chromosome and increased [11]C raclopride binding in the stria 2, the PKD locus on chromosome 16, or the famil tum, but no metabolic abnormalities with [18]FDG ial hemiplegic migraine locus on chromosome 19.62 PET. 50 Invasive electrophysiology showed no corti Another family with autosomal dominant PED, gen cal discharges associated with the episodes of PNKD, eralized epilepsy, developmental delay, and migraines but showed an abnormal discharge in the caudate has been described in which linkage to chromosomes nucleus. 2 and 16 were excluded.63 Thus it appears that at least Treatment and Outcome three phenotypic forms of PED exist with possibly as many genetic bases. Avoidance of precipitating factors such as alcohol, caf Secondary causes of PED have been reported only feine, and stress is important. Several drugs have been occasionally. Families with PED accompanied by epi used, none with consistent success. These have included lepsy and mild developmental delay have been reported clonazepam,4 lorazepam,51 haloperidol,52 levetiracetam,53 54 52 with mutations in the SLC2A1 gene encoding glucose alternate-day oxazepam, valproate, and anticholin 47,64,65 55 transport 1 (GLUT1). One family also had hemo ergics. Benzodiazepines, especially clonazepam, appear lytic anemia with echinocytosis and altered erythrocyte to be most consistently effective.37 Anticonvulsants are ion concentrations. In other cases of secondary PED, ineffective in most cases. Deep brain stimulation of thal the cause was trauma.5,66 amus56 and globus pallidus internal segment57 has been reported to be effective in single adult cases. Pathophysiology Outcome is variable, but there is a tendency toward In 2 patients with PED, SPECT scanning revealed decreased attacks with age.37 Complete remission is decreased ictal perfusion of the frontal cortex during uncommon. the motor attacks. In contrast, increased cerebellar per fusion was observed. The perfusion of the basal ganglia Paroxysmal Exertion-induced Dyskinesia also decreased.67 No cortical hyperperfusion indicative of an epileptic nature was seen. Cerebellar hyperactiv Paroxysmal exertion-induced dyskinesia (PED) is usually ity in connection with prominent frontal hypoactivity inherited in an autosomal dominant fashion although has also been described in both the idiopathic and the sporadic cases have been described.58,59 The attacks are symptomatic forms of PED. triggered by prolonged exercise,4 in contrast to the sud den movement that triggers PKD. The frequency varies Treatment and Outcome from one per day to two per month. The usual duration Avoidance of prolonged exercise may help diminish is 5 to 30 minutes. The clinical features may be indistin the frequency of attacks. Drug therapy is often ineffec guishable from PNKD of long-lasting type, but the legs tive, but there are isolated reports of improvement with are usually more affected. However, exercise limited to levodopa5 and acetazolamide.59 the upper extremity may provoke an attack in the upper Outcome appears to be variable, but has not been extremity alone.58 Of note, 68% of the MR-1–negative studied systematically. PNKD patients described by Bruno and colleagues37 had attacks of dyskinesia provoked by exercise. Another Paroxysmal Hypnogenic Dyskinesia form of exercise-induced dyskinesia is the so-called run Paroxysmal hypnogenic dyskinesia (PHD) or noctur ner’s dystonia, seen in long-distance runners and mani nal paroxysmal dystonia (NPD) is characterized by fested by usually unilateral leg dystonia precipitated by attacks of dystonia, chorea, or ballism during non- prolonged (several miles) running.60 Thus there may be REM sleep.68,69 The frequency may be from five times some phenotypic overlap between different conditions per year to five times per night. These attacks may be manifested by exertion-induced dystonia. associated with EEG signs of arousal, and the patient usually falls asleep after the attack. The usual duration Etiology of the attacks is 30 to 45 seconds but may be longer. PED is less common than PKD and PNKD, so there Sometimes the patients may have daytime attacks of has been less systematic study of this condition. dyskinesia. PHD may be a heterogeneous condition Autosomal dominant paroxysmal choreoathetosis/spas comprising attacks of different durations and clinical ticity, an exercise-induced dyskinesia frequently includ features. Although the longer-lasting attacks may repre ing spastic paraplegia during the episode, has been sent a movement disorder, typical short-lasting attacks mapped to a 12 cM region on chromosome 1p in the are more likely to represent a frontal lobe seizure.70,71 vicinity of a potassium channel gene cluster.61 Another However, it appears that the great majority of cases of

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PHD represent frontal lobe epilepsy.72 Indeed, some 14. Spacey SD, Valente EM, Wali GM, et al: Genetic and patients have PHD attacks preceding tonic-clonic clinical heterogeneity in paroxysmal kinesigenic dyskine seizures. sia: evidence for a third EKD gene, Mov Disord 17:717– 725, 2002. Etiology 15. Guerrini R, Bonanni P, Nardocci N, et al: Autosomal recessive rolandic epilepsy with paroxysmal exercise- As already stated, PHD represents a form of frontal induced dystonia and writer’s cramp: delineation of the lobe epilepsy in most cases. syndrome and gene mapping to chromosome 16p12-11.2, Treatment and Outcome Ann Neurol 45:334–352, 1999. Treatment is with antiepileptic therapies. 16. Demir E, Prud’homme JF, Topcu M: Infantile convul sions and paroxysmal choreoathetosis in a consanguine ous family, Pediatr Neurol 30:349–353, 2004. REFERENCES 17. Blakeley J, Jankovic J: Secondary paroxysmal dyskine sias, Mov Disord 17:726–734, 2002. 1. 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Dure LS, Mussell HG: Paroxysmal dyskinesia in a features and classification, Ann Neurol 38:571–579, patient with pseudohypoparathyroidism, Mov Disord 1995. 13:746–748, 1998. 6. Goodenough DJ, Fariello RG, Annis BL, Chun RW: 22. Mahmud FH, Linglart A, Bastepe M, et al: Molecular Familial and acquired paroxysmal dyskinesias. A pro diagnosis of pseudohypoparathyroidism type Ib in a posed classification with delineation of clinical features, family with presumed paroxysmal dyskinesia, Pediatrics Arch Neurol 35:827–831, 1978. 115(2):e242–e244, 2005. 7. Lotze T, Jankovic J: Paroxysmal kinesigenic dyskinesias, 23. Brockmann K, Dumitrescu A, Best T, et al: X-linked par Semin Pediatr Neurol 10:68–79, 2003. oxysmal dyskinesia and severe global retardation caused 8. Bruno MK, Hallett M, Gwinn-Hardy K, et al: Clinical by defective MCT8 gene, J Neurol 252:663–666, 2005. evaluation of idiopathic paroxysmal kinesigenic dyski 24. Gay CT, Ryan SG: Paroxysmal kinesigenic dystonia nesia: new diagnostic criteria, Neurology 63(12):2280– after methylphenidate administration, J Child Neurol 2287, 2004. 9:45–46, 1994. 9. Szepetowski P, Rochette J, Berquin P, et al: Familial 25. Schlaggar BL, Mink JW: A 16-year-old with episodic infantile convulsions and paroxysmal choreoathetosis: hemisdystonia, Semin Pediatr Neurol 6(3):210–215, 1999. a new neurological syndrome linked to the pericentro 26. Kim MO, Im JH, Choi DG, Lee MC: Proton MR spec meric region of human chromosome 16, Am J Hum troscopic findings in paroxysmal kinesigenic dyskinesia, Genet 61:889–898, 1997. Mov Disord 13:570–575, 1998. 10. Swoboda KJ, Soong B-W, McKenna C, et al: Paroxysmal 27. Koh C, Kong C, Ngai W, Ma K: Ictal (99m)Tc ECD kinesigenic dyskinesia and infantile convulsions: Clinical SPECT in paroxysmal kinesigenic choreoathetosis, and linkage studies, Neurology 55:224–230, 2000. Pediatr Neurol 24:225–227, 2001. 11. Kikuchi T, Nomura ��M, Tomita H, et al: Paroxysmal kine 28. Joo E, Hong S, Tae W, et al: Perfusion abnormality of the sigenic choreoathetosis (PKC): confirmation of linkage caudate nucleus in patients with paroxysmal kinesigenic to 16p11-q21, but unsuccessful detection of mutations choreoathetosis, Eur J Nucl Med Mol Imaging 32:1205– among 157 genes at the PKC-critical region in seven 1209, 2005. PKC families, J Hum Genet 52(4):334–341, 2007. 29. Chatterjee A, Louis ED, Frucht S: Levetiracetam in the 12. Bennett LB, Roach ES, Bowcock AM: A locus for par treatment of paroxysmal kinesiogenic choreoathetosis, oxysmal kinesigenic dyskinesia maps to human chromo Mov Disord 17:614–615, 2002. some, Neurology 54:125–130, 2000. 30. Chudnow RS, Mimbela RA, Owen DB, Roach ES: 13. Valente EM, Spacey SD, Wali GM, et al: A second paroxys Gabapentin for familial paroxysmal dystonic chore mal kinesigenic choreoathetosis locus (EKD2) mapping oathetosis, Neurology 49(5):1441–1442, 1997. on 16q13-q22.1 indicates a family of genes which give 31. Tsao CY: Effective treatment with oxcarbazepine in rise to paroxysmal disorders on human chromosome 16, paroxysmal kinesigenic choreoathetosis, J Child Neurol Brain 123(pt 10):2040–2045, 2000. 19(4):300–301, 2004.

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32. Uberall MA, Wenzel D: Effectiveness of lamotrigine in 51. Dooley JM, Brna PM: Sublingual lorazepam in the treat- children with paroxysmal kinesigenic choreoathetosis, ment of familial paroxysmal nonkinesigenic dyskinesia, Dev Med Child Neurol 42(10):699–700, 2000. Pediatr Neurol 30(5):365–366, 2004. 33. Huang Y, Chen Y, Du F, et al: Topiramate therapy for 52. Przuntek H, Monninger P: Therapeutic aspects of kine- paroxysmal kinesigenic choreoathetosis, Mov Disord siogenic paroxysmal choreoathetosis and familial parox- 20:75–77, 2005. ysmal choreoathetosis of the Mount and Reback type, 34. Homan R, Vasko M, Blaw M: Phenytoin plasma con- J Neurol 230(3):163–169, 1983. centrations in paroxysmal kinesigenic choreoathetosis, 53. Alemdar M, Iseri P, Selekler M, Komsuoglu SS: Neurology 30:673–676, 1980. Levetiracetam-responding paroxysmal nonkinesigenic 35. Wein T, Andermann F, Silver K, et al: Exquisite sensitiv- dyskinesia, Clin Neuropharmacol 30(4):241–244, ity of paroxysmal kinesigenic choreathetosis to carbam- 2007. azepine, Neurology 47:1104–1106, 1996. 54. Kurlan R, Shoulson I: Familial paroxysmal dystonic 36. Loong SC, Ong YY: Paroxysmal kinesigenic chore- choreoathetosis and response to alternate-day oxazepam oathetosis. Report of a case relieved by L-dopa, J Neurol therapy, Ann Neurol 13(4):456–457, 1983. Neurosurg Psychiatry 36(6):921–924, 1973. 55. Micheli F, Fernandez Pardal M, de Arbelaiz R, et al: 37. Bruno MK, Lee HY, Auburger GWJ, et al: Genotype- Paroxysmal dystonia responsive to anticholinergic drugs, phenotype correlation of paroxysmal nonkinesigenic Clin Neuropharmacol 10:365–369, 1987. dyskinesia, Neurology 68(21):1782–1789, 2007. 56. Loher TJ, Krauss JK, Burgunder JM, et al: Chronic thal- 38. Forssman H: Hereditary disorder characterized by attacks amic stimulation for treatment of dystonic paroxysmal of muscular contraction, induced by alcohol amongst nonkinesigenic dyskinesia, Neurology 56(2):268–270, other factors, Acta Med Scand 170:517–533, 1961. 2001. 39. Rainier S, Thomas D, Tokarz D, et al: Myofibrillogenesis 57. Yamada K, Goto S, Soyama N, et al: Complete sup- regulator 1 gene mutations cause paroxysmal dystonic pression of paroxysmal nonkinesigenic dyskinesia by choreoathetosis, Arch Neurol 61(7):1025–1029, 2004. globus pallidus internus pallidal stimulation, Mov Disord 40. Mayeux R, Fahn S: Paroxysmal dystonic choreoatheto- 21(4):576–579, 2006. sis in a patient with familial ataxia, Neurology 32:1184– 58. Plant GT, Williams AC, Earl CJ, Marsden CD: Familial 1186, 1982. paroxysmal dystonia induced by exercise, J Neurol 41. Byrne E, White O, Cook M: Familial dystonic chore- Neurosurg Psychiatry 47(3):275–279, 1984. oathetosis with myokymia; a sleep responsive disorder, 59. Bhatia KP, Soland VL, Bhatt MH, et al: Paroxysmal J Neurol Neurosurg Psychiatry 54:1090–1092, 1991. exercise-induced dystonia: eight new sporadic cases and 42. Kurlan R, Behr J, Medved L, Shoulson I: Familial par- a review of the literature, Mov Disord 12:1007–1012, oxysmal dystonic choreoathetosis: a family study, Mov 1997. Disord 2:187–192, 1987. 60. Wu LJ, Jankovic J: Runner’s dystonia, J Neurol Sci 43. Lee HY, Xu Y, Huang Y, et al: The gene for paroxysmal 251:73–76, 2006. non-kinesigenic dyskinesia encodes an enzyme in a stress 61. Auburger G, Ratzlaff T, Lunkes A, et al: A gene for auto- response pathway, Hum Mol Genet 13(24):3161–3170, somal dominant paroxysmal choreoathetosis/spasticity 2004. (CSE) maps to the vicinity of a potassium channel gene 44. Hayashi T, Shibamoto T: Analysis of methylglyoxal in cluster on chromosome 1p, probably within 2 cM between foods and beverages, J Agric Food Chem 33:1090–1093, D1S443 and D1S197, Genomics 31:90–94, 1996. 1985. 62. Munchau A, Valente EM, Shahidi GA, et al: A new 45. Du W, Bautista JF, Yang H, et al: Calcium-sensitive family with paroxysmal exercise induced dystonia and potassium channelopathy in human epilepsy and par- migraine: a clinical and genetic study, J Neurol Neurosurg oxysmal movement disorder, Nat Genet 37(7):733–738, Psychiatr 68:609–614, 2000. 2005. 63. Kamm C, Mayer P, Sharma M, et al: New family with 46. Temudo T, Martins E, Pocas F, et al: Maple syrup disease paroxysmal exercise-induced dystonia and epilepsy, Mov presenting as paroxysmal dystonia, Ann Neurol 56:749– Disord 22(6):873–877, 2007. 750, 2004. 64. Weber YG, Storch A, Wuttke TV, et al: GLUT1 muta- 47. Zorzi G, Castellotti B, Zibordi F, et al: Paroxysmal tions are a cause of paroxysmal exertion-induced dyski- movement disorders in GLUT1 deficiency syndrome, nesias and induce hemolytic anemia by a cation leak, Neurology 71(2):146–148, 2008. J Clin Invest 118(6):2157–2168, 2008. 48. Nygaard T: Dopa-responsive dystonia, Curr Opin Neurol 65. Suls A, Dedeken P, Goffin K, et al: Paroxysmal exercise- 8:310–313, 1995. induced dyskinesia and epilepsy is due to mutations in 49. Perlmutter JS, Raichle ME: Pure hemidystonia with basal SLC2A1, encoding the glucose transporter GLUT1, ganglion abnormalities on positron emission tomogra- Brain 131:1831–1844, 2008. phy, Ann Neurol 15(3):228–233, 1984. 66. Lim EC, Wong YS: Post-traumatic paroxysmal 50. Lombroso CT, Fischman A: Paroxysmal non-kinesigenic exercise-induced dystonia: case report and review of dyskinesia: pathophysiological investigations, Epileptic the literature, Parkinsonism Relat Disord 9(6):371–373, Disord 1:187–193, 1999. 2003.

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67. Kluge A, Kettner B, Zschenderlein R, et al: Changes 70. Tinuper P, Cerullo A, Cirignotta F, et al: Nocturnal par in perfusion pattern using ECD-SPECT indicate fron oxysmal dystonia with short-lasting attacks: three cases tal lobe and cerebellar involvement in exercise-induced with evidence for an epileptic frontal lobe origin of paroxysmal dystonia, Mov Disord 13:124–134, 1998. seizures, Epilepsia 31(5):549–556, 1990. 68. Lugaresi E, Cirignotta F: Hypnogenic paroxysmal 71. Meierkord H, Fish DR, Smith SJ, et al: Is nocturnal par dystonia:epileptic seizure or a new syndrome? Sleep 4(2): oxysmal dystonia a form of frontal lobe epilepsy? Mov 129–138, 1981. Disord 7(1):38–42, 1992. 69. Lugaresi E, Cirignotta F, Montagna P: Nocturnal parox 72. Hirsch E, Sellal F, Maton B, et al: Nocturnal paroxysmal ysmal dystonia, J Neurol Neurosurg Psychiatry 49(4):375– dystonia: a clinical form of focal epilepsy, Neurophysiol 380, 1986. Clin 24(3):207–217, 1994.

[email protected] 66485438-66485457 [email protected] 66485438-66485457 9 Chorea, Athetosis, and Ballism O Introduction and Overview Ballism refers to involuntary, high-amplitude, flinging movements typically generated proximally. Chorea, athetosis, and ballism are nonpatterned, hyper- These movements may be brief or continual and kinetic movement disorders which overlap and cannot may occur in conjunction with chorea. Often, one be defined precisely as mutually exclusive phenomena. side of the body is affected, that is, hemiballism. In However, they are characterized by some salient many cases, hemiballism becomes milder and evolves features. Some authors place these hyperkinetic into chorea.1 Severe continuous ballism can cause disorders on a continuum based on amplitude, velocity, rhabdomyolysis. and distribution: ballism → chorea → athetosis. Athetosis is defined as slow, writhing, continu- In practice, many children with hyperkinetic move- ous, involuntary movements. This may be historically ment disorders have a combination of chorea, athetosis, referred to as choreoathetosis. Some view athetosis on or ballism. To complicate matters, dystonia, tics, or the spectrum of chorea. In contrast to dystonia, in Omyoclonus may also be present. Moreover, the relative which there is a sustained, twisting, patterned move- predominance of one type of phenomenology may be ment, athetosis is typically a continual, nonsustained state dependent. For example, athetosis may evolve form of movement. Athetosis sometimes occurs as part into ballism when children are stimulated or excited. of a mixed spastic, hyperkinetic movement disorder in Anatomically, chorea classically results from distur- children with static encephalopathy (cerebral palsy). bances in the striatum but can also have thalamic or Some experts view athetosis as on a spectrum with cortical origin. Ballism often localizes to subthalamic dystonia and chorea. nucleus. Athetosis often accompanies basal ganglia diseases that also produce chorea or dystonia. Thus, Clinical Characteristics— despite phenomenologic distinctions, clinicians may Phenomenology of Chorea, use the presence of any of these dyskinetic movements Athetosis, and Ballism in Children as key factors in directing diagnostic and therapeutic decision making toward the basal ganglia. Chorea History Definitions of Chorea, Athetosis, In childhood, chorea is most often acquired acutely or subacutely, and thus parents can describe the onset and Ballism and the way in which the child’s speech and purpose- Chorea refers to an involuntary, continual, irregular ful movements have changed. Acquired chorea usu- hyperkinetic disorder in which movements or move- ally interferes with purposeful movement, causing ment fragments with variable rate and direction occur functional impairment. In subtle cases, particularly in unpredictably and randomly. Some movements may young children with underdeveloped motor coordina- be flowing or rapid, similar to ballism or myoclonus, tion or speech articulation, a parent’s report that coor- others slower or more jerky. All body parts may be dination or speech has changed must be relied on. involved, with certain distributions being more charac- In contrast, however, when chorea occurs as a late teristic of distinct diseases or disorders. Choreic move- or minor feature of chronic neurologic disease, parents ments usually worsen during attempted voluntary may not accurately report chorea onset or impairment. action. Individuals with chorea may generate so-called In diseases where chorea accompanies a global enceph- parakinesias, semivolitional movements that attempt to alopathy, the impact of the chorea on the child’s qual- mask the involuntary choreic movements or incorpo- ity of life is unclear but is probably limited. However, rate them into seemingly purposeful movements, such diagnostically, the presence of chorea may have some as touching the face. localizing and etiologic value. 76 [email protected] 66485438-66485457 Chapter 9 Chorea, Athetosis, and Ballism 77

Examination Ballism The child with chorea may have generalized or local- In childhood, ballism usually does not occur in ized adventitious movements, but usually the face isolation. Ballismus or ballism refers to involuntary, and upper limbs are involved. There is an appearance high-amplitude, flinging movements typically occur- of restlessness as movements flow irregularly but ring proximally. These movements may be brief or continually around the body. Speech may be slurred continual and may occur in conjunction with chorea. or slow because of involvement of tongue and facial It can occur in children with static encephalopathies or muscles. Involvement of upper limbs is usually bilateral choreoathetoid cerebral palsy. Such children have action- but also usually is asymmetric. Choreic movements can induced choreoathetoid movements at baseline but O occur in both proximal and distal muscles. may develop severe, forceful, flinging, high-amplitude Action and certain postures usually exacerbate or movements during febrile illnesses. In severe cases, these enhance chorea, and therefore chorea usually interferes movements can lead to rhabdomyolysis, renal failure, with coordination of purposeful movements. Careful and death.4–7 Hemiballism is occasionally described as observation in the presence of certain actions or pos- the result of an acute process such as a vascular insult. tures may demonstrate the involvement of areas less Flinging, ballistic movements sometimes occur in SC. affected at rest. The motor function problems in chorea should be Athetosis readily distinguished from ataxia. Close observation The child with athetoid movements has problems demonstrates that the choreic movements are intrud- similar to the child with chorea. If the athetosis is ing on the trajectory of the purposeful movement. Thus symptomatic of a chronic global encephalopathy, the when chorea involves the legs, for example, the child movement alone usually causes little functional diffi- may lurch intermittently when walking, but there is not culty, relative to the encephalopathy. If the athetosis is the consistent broad-based gait seen in ataxia. Similarly, acquired acutely or subacutely, the difficulties related there may be difficulty with finger-to-nose and rapid alternating movement testing, but the problem is much solely to athetosis may be more prominent. more irregular than one sees with cerebellar disease. Children with chorea, particularly Sydenham’s chorea Localization and Pathophysiology (SC) (see later discussion), often have motor imper- Neuroanatomy of Chorea, sistence, described by Gowers in 1888 as “unintended Athetosis, Ballism relaxation.”2 Motor impersistence is the inability to maintain a posture or stable motor command. The Based on many examples of localized metabolic, vascular, appearance is one of intermittent interruption of the and hereditary neurodegenerative diseases, it is reasonable intended, sustained signal from motor cortex to muscle. to conclude that the primary substrate for choreic move- For example, two classic signs in SC are “darting ments is disturbance in structure or function of striatum, tongue” caused by inability to keep the tongue pro- particularly the caudate nucleus and/or pallidum, or their truded and “milkmaid’s grip” caused by inability to inflow or outflow pathways. These neuroanatomic path- maintain a steady grip force. In both cases, in response ways are described in more detail in Chapter 1. The most to the examiner’s command, the cooperative patient common form of acquired chorea in children worldwide reactivates the muscles repeatedly, leading to these back- is poststreptococcal SC.8 A case control study showed sub- and-forth activation/relaxation patterns. Choreic intru- tle increases in size of caudate, putamen, and globus pal- sions, unintended relaxations, or both may contribute lidus but not other areas in children with SC, suggesting to the phenomenon of motor impersistence. The abnor- an inflammatory process.9 Other forms of autoimmune mal movements tend to occur reproducibly during chorea also show preferential involvement of striatum.10 attempts to maintain certain postures. They cannot be In adults, degeneration of the caudate and putamen in entrained, which helps distinguish them from psycho- Huntington’s disease (HD) is associated with chorea. This genic chorea.3 is also true for early-onset HD, which becomes apparent Some degree of hypotonia is also apparent in many in later teenage years; however, childhood-onset HD, the cases. This leads to hyperextensibility across joints. Westphal variant, usually manifests with parkinsonism, Another sign is “hung up” muscle stretch reflexes. This dementia, and seizures rather than chorea.11 In children, is best seen at the knee with the patient sitting and leg lesions in the parietal cortex or thalamus may also be asso- unsupported. Repeated tapping of the quadriceps ten- ciated with chorea. don may elicit a brief period of sustained leg extension Figures 9-1 through 9-5 demonstrate several ana- against gravity. tomic localizations and etiologies of chorea in children.

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Figure 9-1. MRI T2 axial images of two children with Huntington Disease (HD). Both children were symptomatic at the time of genetic testing and both had affected fathers. At left, caudate volume loss and signal change in caudate and putamen in an 11-year-old boy with childhood onset HD (Westphal Variant), with dystonia and parkinsonism, progressive for several years; CAG repeat count 84. By age 17 this boy had progressive myoclonic epilepsy, dementia, and had lost ambulation. Similar imaging findings at right in a 17-year-old girl with early onset HD, mild depression, mild chorea on examination manifested functionally with clumsiness, and CAG copy number 65.

Figure 9-2. Subtle focal areas of signal change with no mass effect seen in MRI axial FLAIR imaging of 10-year-old boy with fever, chorea, and encephalopathy. Chorea lasted for 6 months, responded well to typical neuroleptics, and Figure 9-3. Axial T2 MRI shows one of several small basal full recovery subsequently occurred. A specific etiology was ganglia lesions seen in a 20-year-old woman imaged because not identified, but the monophasic clinical course with of headaches, 6 years after diagnosis of Sydenham’s Chorea. encephalopathy after fever and multiple focal areas of signal This finding was not present not seen on MRI performed change in gray and white matter supported a diagnosis of at the time of chorea presentation but likely represent form of acute disseminated encephalomyelitis (ADEM). encephalomalacia from small vessel ischemic changes.

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Figure 9-4. At left, neuroimaging of 9-year-old boy with precocious puberty, cognitive decline over several months, escalating headaches. Preoperative MRI showed a thalamic pilocytic astrocytoma (arrow). He underwent partial resection and cranial irradiation. Eight months later the patient had acute-onset headache and left-sided hemichorea. Computed tomography (CT) scan at right showed dystrophic calcification and a small focus of radiation necrosis in right thalamus (arrow). Chorea responded to neuroleptics and resolved within several months.

Figure 9-5. Axial MRI of two infants who developed continuous choreiform movements between 6 and 12 months of age. At left, 11-month-old with microcephaly, agenesis of corpus callosum, and elevated lactate consistent with metabolic disorder. At right, infant with acute-onset encephalopathy and severe choreiform movements. Imaging shows multifocal areas of signal change, most prominent in parietal lobe, consistent with a mitochondrial disease. Muscle biopsy testing showed a severe complex IV, electron transport chain deficiency. Treatments targeting mitochondrial dysfunction and suppression of chorea were not beneficial.

Neurophysiology of Chorea, Diseases and Disorders Athetosis, Ballism Etiologic Categories of Diseases Clinically, neither peripheral nor central neurophysio- Producing Chorea, Athetosis, Ballism logic studies are helpful in diagnosis or treatment decisions for chorea, athetosis, or ballism. Electromyography Choreiform, athetoid, or ballistic movements can of muscle shows that muscle activity differs in chorea emerge as a consequence of a vast number of disease pro- versus normal voluntary movement. The normal initial cesses, including genetic and metabolic diseases, endo- agonist burst in a voluntary movement usually lasts less crine abnormalities, infections, autoimmune conditions, than 100 ms. However, in SC, the initial burst duration cerebrovascular disease, neoplasms, neurodegenerative may be longer.12 Routine EEGs show at most nonspe- diseases, toxins, and trauma. This is partly due to the cific abnormalities which are not helpful for diagnosis vulnerability of the basal ganglia to a wide variety of or treatment. pathologies. In many of these diseases, the hyperkinetic

[email protected] 66485438-66485457 80 section 4 hyperkinetic and Hypokinetic Movement Disorders movement disorder is not the sole or predominant neu- Pathophysiology rologic problem. Table 9-1 shows key etiologic categories BHC is caused, in some but not all pedigrees, by a and important diagnoses. Additional detail is provided mutation in the NKX2.1 gene encoding TITF-1.16,22 in the remainder of this section. Whether haplotype insufficiency or some other mech- Physiologic Chorea anism results in subtle changes in corticostriatal circuits is unknown. Magnetic resonance imaging (MRI) Chorea in Infancy is probably normal,19 although in one family abnor- 20 Clinical Features malities in striatum and cerebellum are reported. A postmortem study showed loss of a subset of stri- The decomposed or immature movements of infants 21 may sometimes be described as choreiform. These do not atal interneurons but no gross abnormalities. One generally indicate neurologic disease. In the context of a study that used technetium single-photon emission normally developing child with normal head circumfer- computed tomography (SPECT) for two affected ence and these movements can be monitored clinically. children showed apparent decreased uptake in the striatum and thalamus.18 This finding is difficult to Chorea Minor interpret because the abnormality was unilateral, was Children diagnosed with neurobehavioral disor- not present in all genetically and clinically affected ders such as attention-deficit/hyperactivity disorder individuals, and did not clearly correlate with disease (ADHD) are significantly more likely to manifest some severity. subtle difficulties with motor control, including motor Homozygous knockout of the NKX2 gene in mice overflow and mild choreiform movements.13 results in a very severe phenotype. Prenatally, mice develop Primary Choreas severe lung and pituitary deficits, with abnormal development of the striatum, basal forebrain, and cerebral The main primary chorea is benign hereditary cho- cortical GABAergic neurons, which are incompatible rea (BHC). The term primary is applied here because with extrauterine life.23,24 The heterozygous mice, the disease is genetic and chorea is the predominant which would be the model for the human disease, do neurologic symptom. not have readily apparent neurologic deficits.

Benign Hereditary Chorea Diagnostic Approach Clinical Features BHC should be considered in children with relatively BHC, described by Haerer and colleagues in 1967, is isolated chorea in the first 5 years of life and an auto- a rare, autosomal dominant, childhood-onset, nonpro- somal dominant family history. Features supporting gressive, hyperkinetic movement disorder character- this diagnosis include the presence of broadly normal ized by early onset, before age 5, of chorea.14 In 2000, intellectual development with no regression or loss of a detailed review of 42 families with BHC, showed cognitive skills, absence of other significant neuro- nearly all had affected individuals with “atypical” clini- logic problems such as epilepsy, normal general exam- cal features. The authors concluded that many of the ination with no dysmorphic features, and, with the affected individuals had other neurologic diseases, exception of chorea, a normal neurologic examination. including myoclonus dystonia, and suggested that As is often true in movement disorders, it is important BHC should be considered a syndrome rather than a to examine other family members in addition to taking distinct disease.15 a multigeneration history. The presence of mild symp- Subsequently, a multicountry collaboration resulted toms in a parent would support the presence of auto- in identification, in four BHC pedigrees from Europe somal dominant inheritance in BHC. Neuroimaging and North America, of mutations in the NKX2.1 gene should usually be obtained, and this should generally encoding thyroid transcription factor 1 (TITF-1).16 be normal in BHC. Other diagnoses to consider in This provided an etiology and biologic marker that a child under age 5 with chorea include ataxia telan allowed for a more consistent identification of a dis- giectasia (AT),25 which is autosomal recessive (see ease phenotype. In these families, as well as others sub- Chapter 13), dyskinetic cerebral palsy (see Chapter 17), sequently identified, mutations have been found at a and metabolic disorders (see Chapter 15). variety of loci. The severity of the chorea varies substantially within and between families.17,18 Onset of Treatment chorea occurs consistently between ages 1 and 5 years, No symptomatic treatment has been shown to be bene- with a fairly stable course thereafter and some symp- ficial in genetically confirmed BHC. Interestingly, there tom improvement in adulthood. is a report of improvement with levodopa treatment.26

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TABLE 9-1 etiologic Categories Physiologic Chorea Infancy Choreiform movements in neurobehavioral disorders

Primary Choreas Benign hereditary chorea (including syndrome of choreoathetosis, hypothyroidism, neonatal respiratory distress) Symptomatic, Secondary Choreas Autoimmune Poststreptococcal, Sydenham’s chorea (SC) (Figure 9-3) Chorea secondary to systemic lupus erythematosus (SLE) Chorea secondary to antiphospholipid antibody syndrome (APS) Acute disseminated encephalomyelitis (ADEM) (Figure 9-2) Other infections and encephalitides: Lyme, human immunodeficiency virus, mycoplasma Vascular/hypoxic ischemic Stroke (Figure 9-4) Third trimester/perinatal hypoxic ischemic injuries leading to choreoathetoid cerebral palsy Post–cardiac transplant—“postpump chorea” Toxin induced Carbon dioxide Methyl alcohol Manganese Toluene Iatrogenic chorea/dyskinesia Psychostimulants, dopamine agonists Dopamine receptor blocking agents/neuroleptics/antipsychotics Selective serotonin reuptake inhibitors Psychiatric polypharmacy Anticonvulsants: carbamazepine, phenytoin, tiagabine Choreas in Neurodegenerative Diseases and Severe Encephalopathies Biopterin-dependent hyperphenylalaninemia (type VI) Gangliosidosis Mitochondrial encephalopathies/Leigh’s disease (Figure 9-5) Glutaric aciduria Lesch-Nyhan disease Phenylketonuria Wilson’s disease Neuroacanthocytosis Early (adolescent, not childhood onset) Huntington’s disease (Figure 9-1)

Diseases with Chorea as a Minor or Late Feature Alternating hemiplegia of childhood Bilateral striatal necrosis Ceroid lipofuscinosis Neurodegeneration with brain iron accumulation Rasmussen’s encephalitis Succinate semialdehyde dehydrogenase deficiency Cerebral creatine deficiency secondary to guanidineoacetate methyltransferase (GAMT) deficiency Hypoparathyroidism

Chorea in Ataxias Friedreich’s ataxia Ataxia telangiectasia Ataxia with oculomotor apraxia 1 and 2 Dentatorubropallidoluysian atrophy Spinocerebeller Ataxias (SCAs) 1, 2, 3, 6 (adult onset more common)

Paroxysmal Choreas (see Chapter 8) Paroxysmal nonkinesigenic dyskinesia 1 (PNKD) Paroxysmal kinesigenic dyskinesia (PKD) Psychogenic Chorea (see Chapter 19)

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Choreoathetosis, Hypothyroidism, Neonatal SC is rare in the United States. In three regions Respiratory Distress—Allelic to Benign Hereditary with relatively higher prevalence, Utah,2 Western Chorea Pennsylvania,8 and Southwest Ohio,30 academic Mutations or deletions in the NKX2.1 gene encoding centers report evaluating just 3 to 10 children with TITF-1 can also cause a broader constellation of symp- this diagnosis per year. The presence of markers of toms, including congenital hypothyroidism, neonatal GABHS infection is nonspecific. Therefore in ambig- respiratory distress, and persistent choreoathetosis.27 uous cases or those with only chorea, the possibility of SLE and APS should be considered, as discussed Secondary (Acquired) Choreas later in this chapter. Consultation with rheumatology The majority of childhood-onset diseases where chorea may be considered in cases involving joints or mul- is the predominant movement disorder are acquired, tiple body systems, or when antibody testing results with acute/subacute onset. Sydenham’s chorea is the do not confirm SC. most common acquired chorea in children ages 5 to Chorea in SC develops over hours to days. Parents 15 years, and chorea associated with systemic lupus and children can often identify the day or week and erythematosus (SLE) and antiphospholipid antibody sometimes may remember the hour of onset. Symptom syndrome (APS) manifest similarly. The majority of severity varies widely. Difficulty with activities of daily acquired chorea in childhood is self-limited. living and fine motor tasks such as dressing or writing is common. Patients may describe that they are clumsy or Choreas Occurring in Immunologic/Autoimmune weak, often dropping items in their hands. Abnormal Disease movements decrease or stop during sleep. Sydenham’s Chorea In addition to changes in motor function that are Clinical Features due directly to chorea, parents often report personality changes with nearly the same time of onset. These Sydenham’s chorea (SC) is considered a manifesta- include inattention, anxiety, obsessive compulsiveness, tion of rheumatic disease, a group of sequelae of group paranoia, and reluctance to speak.30–34 Interestingly, A -hemolytic streptococci (GABHS) infections. β children with rheumatic fever not only commonly GABHS are gram-positive bacteria that colonize or develop obsessive-compulsive symptoms, they also invade the upper respiratory tract. Surface M proteins have a higher than expected prevalence of these symp- are important for virulence and have different sub- toms in first-degree relatives.35 types with varying levels of immunogenicity. Cytolytic On examination, affected children appear rest- toxins, including streptolysin O, induce antibody less or fidgety while sitting. There may be a paucity of responses. Elevated measurements of both antistrep- speech36 and facial movements, combined with inap- tolysin O (ASO) and anti-DNAse B (ADB) titers in propriate adventitious facial expressions or facial tics. blood are markers of prior infections. Speech articulation may be slurred. Coordination is The relationship of GABHS to SC is supported by often poor with erratic performance of finger-to-nose epidemiologic observations, including the reduction in testing and intermittent lurching while walking. Falls cases in the post-antibiotic era and common co-occur- are not common. Delirium is rare. rence of chorea and other manifestations of rheumatic There are four classic neurologic signs. These are disease, particularly carditis and arthritis.8 The chorea nonspecific and may be present in chorea due to other appears the same whether or not carditis and arthri- causes, but they nearly always occur together and sup- tis occur. In the proper setting, chorea only following port the diagnosis of SC: GABHS is also classified as rheumatic disease. That is, children manifest with subacute chorea, with or with- 1. Spooning sign. The examiner asks the child to out carditis or arthritis/arthralgia, weeks or months extend both arms straight forward, horizontally after GABHS infections, and meet the Jones Criteria from the shoulders, with hands pronated (palms for Rheumatic Disease.28 GABHS is the etiologic agent down) and fingers spread wide. Children with SC of “strep throat,” a highly prevalent bacterial infec- tend to hyperextend at the metacarpophalangeal tion that occurs one or more times in many children. (MCP) joint. This “spooning” is dystonic Most infections are uncomplicated, responding readily posturing. This maneuver also tends to induce more to penicillin or other appropriate antibiotics with few chorea in proximal and distal arm muscles. Often, sequelae, and many infections are self-limited, resolving the movements are asymmetric. These movements without antibiotics. Infections may also be minor, so may worsen further if an additional task is added, that affected individuals do not seek medical attention. such as protruding the tongue.

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2. Touchdown (or three-point shot) sign. The exam- infections does not “treat” or reduce the chorea or iner asks the child to extend both arms up ver- psychiatric symptoms in SC. tically from the shoulders with palms facing 2. There is no correlation between the titer of any anti- each other. This induces choreiform move- streptococcal antibodies and chorea severity in SC. ments and results in hand pronation and elbow In SC as well as in APS, antibody titers may remain flexion, again often asymmetric. elevated long after chorea resolves.10 This suggests 3. Milkmaid’s grip. The examiner offers her or his index that other factors, such as blood-brain barrier perme- and middle fingers together, both hands, for the ability or host brain susceptibility, may play a role. In child to squeeze. The child attempts to squeeze both addition, it also suggests that antibody titers cannot hands and typically is unable to persist in squeezing. and should not be used to monitor the course of the This is motor impersistence. The cooperative child, chorea. Again, with regard to PANDAS, one would each time the grip releases, tries to squeeze again. As not expect tic or OCD severity to correlate with this happens repeatedly, this resembles “milking” the antibody titers. Recent prospective data in a 2-year examiner’s fingers. Even in cases where hand and arm study of a cohort of children diagnosed clinically signs 1 and 2 are asymmetric, in SC there is usually with PANDAS did not show a correlation between some degree of grip impersistence in both hands. antibody titers and symptom exacerbations.40 4. Darting tongue. The examiner asks the child to stick Long-term prognosis of SC is generally good, with out his or her tongue. The child attempts to cooper- resolution of symptoms in most cases in less than ate but the tongue protrusion cannot be maintained, 41,42 resulting in a “darting tongue.” 1 year. However, chorea, OCD, depression, and other behavioral symptoms may persist for years or 43 Because SC is a form of rheumatic disease, it is critical decades. to assess the child carefully for the presence of a systolic Pathophysiology heart murmur, or of arthritis or arthralgia.8 The presence of a systolic murmur in this setting, particularly if the Although the clinical phenomenology of SC has been parents believe a murmur was not previously reported recognized for centuries, a causal relationship with 44 to them by their primary physician, is virtually pathog- GABHS infection was not established until the 1950s. nomonic for rheumatic chorea. Antibodies to the caudate and subthalamic nucleus 45 The high prevalence of psychiatric symptoms, as have been identified in children with SC. It is impor- well as tics, in SC has led to a great deal of research tant to point out that these same antibodies were found devoted to determining whether there is a parallel but elevated in HD and Parkinson’s disease, as well as in 46 distinct acquired condition with these neuropsychiatric lower proportions of healthy people, so these findings symptoms but no chorea. This entity has been called are not specific and may in some cases be epiphe- pediatric autoimmune neuropsychiatric disorders associ- nomena or effects, rather than causes. In addition, ated with streptococcal infections (PANDAS) and based some studies find high titers of antibrain antibodies in 47 on the most recent prospective studies is, at best, of healthy control groups. This suggests that circulating questionable validity as a discrete diagnostic entity.120 antibodies may not always have sufficient access to the This is addressed in greater detail in Chapter 6. The brain required to produce symptoms. The identifica- terms PANDAS and SC should not be used inter- tion of M proteins on streptococci that can evoke anti- 48 changeably. However, two clinical points bear mention bodies that cross-react with human brain suggested that relate to the similarities of PANDAS to SC. that molecular mimicry may play a role. The relative rarity of SC and other rheumatic complications sug- 1. One result of the PANDAS concept is that many gests that some important bacterial or host factors or clinicians in practice have come to believe that susceptibility may be required. they can treat tics, obsessive-compulsive disorder Another recent series of studies found elevated (OCD), or other psychiatric symptoms with anti- immunoglobulin G (IgG) antibodies to neuronal tubu- biotics.37,38 This is not evidence based3 (although lin in blood and cerebrospinal fluid (CSF) in SC. These certain hypotheses in this regard are worth inves- antibodies cross-react to GABHS. In vitro, binding to tigating). SC is an autoimmune disease triggered caudate and putamen brain sections was blocked by by GABHS, not caused by an active GABHS infec- both lysoganglioside GM1 and by an antitubulin anti- tion. If PANDAS is similar, antibiotics should not body. Functionally, in a neuronal cell line, the acute reduce symptoms. Moreover, the use of antibiotics chorea sera induced calcium/calmodulin-dependent (see below) for secondary prevention of GABHS protein kinase II activity in human neuronal cells.33

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Diagnostic Approach these anti-streptococcal antibodies are both negative, or The differential diagnosis of chorea is large. Fortunately, in cases where the natural history or other findings sup- only a few categories of disease need to be considered port an alternative diagnosis. in a school-age, previously healthy child when chorea Chorea caused by other infections, such as Lyme develops over a period of hours to days. Most such chil- disease, human immunodeficiency virus, mycoplasma dren will have SC. Diagnostic evaluation will therefore pneumonia, or Legionnaire’s disease, may be consid- focus on GABHS and rheumatic disease. ered, in the appropriate clinical setting, if no history Drug-induced chorea may be considered, particu- or clinical evidence of GABHS infection, SLE, or APS larly in toddlers. Chorea caused by endocrine disor- can be identified. ders such as hyperthyroidism, hyperparathyroidism, Neuroimaging Obtaining a brain MRI scan to rule and hyperglycemia may also be considered and ruled out brain structural causes should be considered as out with laboratory testing. Hyperthyroidism can part of the evaluation of any child with subacute cho- cause chorea, but usually tachycardia, diarrhea, and rea. A number of studies have reported subtle signal skin changes should also be present.49 Vascular diseases change or volume increase in basal ganglia nuclei.8,9,54 are unlikely in childhood to produce solely chorea However, in most cases where the clinical diagnosis because of the low prevalence of small vessel intra-cra- is SC, neuroimaging does not guide further manage- nial disease. Vascular causes may be considered in cases ment.8 MRI findings would also point toward diagno- of acute, thunderclap onset of unilateral chorea or bal- ses of mitochondrial/metabolic diseases, degenerative, lism, or when careful neurologic examination suggests neoplastic, and other inflammatory diseases targeting a constellation of symptoms in a distribution support- the basal ganglia. However, experienced clinicians, ing vascular disease (see Figure 9-4). Mitochondrial in the presence of a classic, unambiguous case of SC, diseases may selectively affect basal ganglia and pro- may elect not to obtain neuroimaging, because of the duce chorea (see Figure 9-5).50 These should be accom- expense, the common need for sedation to allow for panied by characteristic findings of signal change on high-quality images in the presence of hyperkinetic MRI or basal ganglia lactate elevation on magnetic chorea, and the low clinical utility. Subsequently, if the resonance spectroscopy. Psychogenic movement disor- patient’s clinical course diverges from what is expected ders may have a choreic phenomenology.3,51 for SC, neuroimaging can be reconsidered and, after Laboratory Testing Chorea with a subacute course, the acute period, some striatal changes may be pres- with gradual evolution of symptoms over minutes to ent (Figure 9-3). SPECT scans show striatal hyperper- 55–57 hours or days, is typical of an inflammatory disease and fusion, and positron emission tomography (PET) 58 thus these should be the focus of laboratory investiga- scans show hypermetabolism in basal ganglia during tion. GABHS is the most common postinfectious eti- the acute phase of the illness. Volumetric MRI scans ology, and therefore obtaining a history of infection show increased basal ganglia size of statistical but not 9 during the prior 6 months with headache, fever, and clinical significance. Although informative regarding sore throat is important. Documenting a prior posi- pathophysiology, these findings are not specific and do tive throat culture is helpful. If there is no known prior not guide clinical management. infection or the history is vague, blood testing for ele- Other Testing and Specialty Consultation Echo vations in both streptococcal antibodies—antistrep- cardiography or cardiology consultation is recom- tolysin O (ASO) and anti-DNAse B (ADB)—should mended in the presence of a new murmur. If no murmur be obtained. It is important that these studies be run in is heard, an echocardiogram need not be obtained at the an experienced laboratory and compared against child- time of chorea presentation because identification of a hood normative levels for that laboratory. Interpreting trivial murmur will not change management. However, these results requires some caution, because GABHS careful surveillance with a thorough cardiac examina- infections are nearly ubiquitous and therefore antibody tion should be emphasized at follow-up visits. elevations are nonspecific. Moreover, in some develop- Treatment ing countries, the background rate of elevated antibody There are three treatment issues to be considered: sec- titers is higher,52 reducing the specificity of this testing ondary prevention, chorea symptom suppression, and in the setting of chorea. However, two studies in the immune modulation. United States, 40 years apart, found the sensitivity when both antibodies were tested was 87%53 and 90%.30 As Secondary Prevention of GABHS Infections The these are most likely true positives in this setting, it is standard of care for all children diagnosed with probably cost effective to test for SLE or APS only when SC, even in cases of isolated chorea, is secondary

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prevention with penicillin.28 The purpose is to intravenous immune globulin, or plasmapheresis is also reduce the risk of recurrences of chorea but espe- worth investigation in severe cases. cially to reduce the likelihood that future GABHS A number of case reports, series, and small trials infections could cause carditis and permanent val- report benefit with immune-modulating treatment. vular damage.59 An appropriate alternative may These are summarized in Table 9-2. The most compel- be selected for children with penicillin allergies. ling evidence for benefit from steroids comes from a Current recommendations in the United States are randomized, blinded, placebo-controlled study by Paz for treatment until age 21 years with either monthly and colleagues.42 Relative to placebo, a 4-week 2 mg/kg intramuscular (IM) penicillin or daily oral penicil- daily oral dose of prednisone, followed by a taper, lin. Some physicians favor monthly IM penicillin reduced duration of chorea and accelerated the reduc- to ascertain compliance. Infectious disease consul- tion in symptoms. Weight gain was substantial by the tation may be considered if GABHS recurs despite end of 2 months, and long-term results including recur- prophylaxis, which is rare, or if there is concern that rence rates were similar in both groups. More support- the individual or family members are asymptomatic ive evidence comes from a clinical trial by Garvey and GABHS carriers. Some otolaryngologists will oper- colleagues,64 comparing a lower dose of prednisone ate to remove adenoids and tonsils in children with to intravenous immunoglobulin (IVIG) and plasma- SC who have moderate or large tonsils, but this has pheresis. This study was not blinded, and the 4-week not been systematically studied. response to prednisone appeared to be less robust. Chorea Symptom Suppression Additional suggestive evidence comes from a large retrospective observational study. Treatment allocation A more general discussion of pharmacologic treatment was nonrandom, and follow-up was nonstandardized of chorea appears at the end of this chapter in the treat- and nonblinded.29 The estimate of treatment effects is ment section. Symptom-suppressing medication is not likely imprecise because of low follow-up ascertainment. needed in mild cases. However, treatment is reason- In addition, because there were substantially fewer able for children for whom important daily activities untreated patients who were followed up, bias due to are impaired by chorea. As is the case for many move- case mix (untreated patients with persistent chorea were ment disorders, there are many small, uncontrolled more likely to be followed up) makes interpretation of case series reporting benefit of many medications. treatment versus no-treatment effects difficult. These include benzodiazepines and several anticonvulsants, most commonly valproic acid.60,61 Because Chorea in Primary Antiphospholipid Antibody chorea in SC is self-limited, it is difficult to interpret Syndrome and Systemic Lupus Erythematosus these positive reports. Many experts consider dop- Clinical Features amine receptor blocking agents, typical neuroleptics, and the dopamine depleting agent, tetrabenazine, to The clinical features of APS and SLE manifesting with be the most effective chorea-suppressing agents.30,62,63 chorea overlap with those of SC. There is no evidence Although parents and some physicians may be under- that these diagnoses, when they manifest with chorea, standably reluctant to use these medications because of can be clinically distinguished from SC. APS can manifest with other neurologic signs and symptoms, such as concerns about side effects, it is helpful to emphasize epilepsy, which are rare in SC. Cerebrovascular disease, that the expected course of treatment will be brief, usually less than 1 year, and that often low doses are suf- cognitive impairment, and transverse myelopathy can ficient. These factors reduce the risk of neurologic side also be symptoms of APS, and SLE may have multi- effects of dopamine receptor blockers. organ disease. Anticholinergic agents such as benztropine or tri- Pathophysiology hexyphenidyl should not be used. These agents, As for SC, the pathophysiology of APS is believed to although helpful in some primary, lesional, and neuro- be the generation of antibodies, although the trigger leptic-induced dystonias, can make chorea worse. is unknown. These are believed to enter the brain, Immune Modulation Based on the pathophysiol- cross-reacting with striatal epitopes due to a process of ogy of SC, it is reasonable to consider immune-mod- molecular mimicry, resulting in altered striatal func- ulating therapies to shorten the course of illness. By tion. A biologically relevant animal model has been analogy with other subacute neurologic and medical developed. In this model, mice are immunized with conditions, including acute inflammatory demyelinat- β2-glycoprotein I, which induces both persistent high ing polyneuropathy, Kawasaki’s disease, and idiopathic levels of antiphospholipid antibodies and motoric thrombocytopenic purpura, treatment with steroids, (hyperactive) and adverse cognitive changes.65

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Citation N umber 29 64 42

n = 6): 29%; n = 22): 54 days IVIG ( n = 4): 72%; PEX ( n = 8): 50% (85% reduction at 4 weeks); PLACEBO ( n = 15): 120 days (33% reduction at 4 weeks) one half of cases. PRED ( n = 32): 4 weeks; NO PRED ( n = 17): 9 weeks. R esult No data available for PRED ( PRED (

at 4 weeks

chorea resolution severity reduction resolution (mean chorea scale reduction severity) O utcome R eported Median time to Mean chorea scale Mean time to chorea

dardized blinded and nonstan at 1 month, 12 months controlled, double blinded, standardized longitudinal assessments active comparator, no active comparator, placebo, standardized but nonblinded assessment treatment allocation, non- follow-up S tudy D esign Retrospective, nonrandom Randomized controlled, Randomized, placebo

ydenham’s Chorea reatment for S ydenham’s over 9 years over 3 years over 18 years S ample ize 102 SC cases 18 SC cases 37 SC cases

d , i mmune M odulating T reatment D etails treatment; PRE NO PRED 10 days, day taper; IVIG 2 g/kg; PEX 5–6 courses (max 60 mg) for 4 weeks, then 3-week taper; PLACEBO B LE 9-2 TA T No protocol for PRED PO 1 mg/kg PRED PO 2 mg/kg chorea. IVIG, intravenous immune globulin; PEX, plasmapheresis; PO, by mouth; PRED, prednisone; SC, Sydenham’s

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Diagnostic Approach Treatment SC is a much more prevalent cause of acute/subacute The best treatment is prevention and, fortunately, with chorea in childhood, but both APS and SLE can mani- careful attention to the clinical features of this compli- fest initially with isolated chorea and associated neurop- cation and improvement of surgical technique, there sychiatric symptoms, particularly in children.66 Because are far fewer cases. Only anecdotal descriptions of of the long-term implications of these diagnoses, and treatment are available with little success.70,72 differences in management, it is important to carefully Dyskinetic/Choreoathetoid Cerebral Palsy consider the possibility of APS and SLE in children with new chorea.67 If there is clinical or laboratory evi- The basal ganglia appear to be selectively vulnerable to dence of prior GABHS infection and if the chorea is hypoxic/ischemic or metabolic injury in term infants, classic for SC, as described previously, the likelihood of possibly because of developmental features of neu- SLE or APS is very low. Some authors advocate obtain- rophysiologic activity and neurotransmitter expres- 73,74 75 ing testing for lupus anticoagulant and/or anticardio- sion. This can result in athetoid cerebral palsy, lipin antibodies in all children in this clinical setting.67 as discussed in Chapter 17. A small number of cases However, as discussed previously, it may be reasonable of patients with dyskinetic cerebral palsy, some idio- to consider these diagnoses in some previously healthy, pathic, have been described where movements worsen school-age children with acute/subacute chorea in the markedly to the point of severe, life-threatening bal- 4–6,76 presence of negative antistreptococcal antibody tests or lism with rhabdomyolysis, during febrile illnesses. of positive supporting symptoms. Several caveats regarding laboratory testing are Kernicterus/Chronic Bilirubin Encephalopathy needed. First, because of the high prevalence of GABHS Clinical Features infections, elevated antistreptococcal antibody titers The three classic neurologic sequelae in children are common, and these may persist for months or years with chronic bilirubin encephalopathy are hearing in some children. Second, elevated anticardiolipin anti- loss, hyperkinetic movement disorder, and impaired 54 77,78 bodies can rarely occur in SC, and β2-microglobulin upgaze. Dystonia, athetosis, or choreic movements antibodies can also occur in SC. may be prominent in severe cases in both term and preterm infants,79 with higher total bilirubin levels over- Treatment all.80 Symptoms are chronic. Cognitive impairment Treatment of SLE lies outside the scope of this chapter. is variable. Brain MRI may appear normal in the first However, in general, immune-suppressive therapies will year or may have subtle T1 signal hyperintensity in the reduce chorea associated with SLE or APS. Prednisone globus pallidus interna (GPI).81 Subsequently, scarring has been reported to reduce chorea in a case where in the GPI is more obvious, with increased T2 signal. neuroleptic medication was not helpful.10 Pathophysiology Vascular/Hypoxic Ischemic Damage to selective brain cell populations occurs in the “Postpump Chorea”—Chorea after Neonatal and neonatal period. Unconjugated bilirubin elevations occur Infant Cardiac Surgery as part of physiologic jaundice in healthy newborns. Clinical Features Excessive bilirubin elevations may occur because of other factors, including hemolytic diseases of the newborn and Chorea has long been described as a neurologic com- excessive bruising during delivery. In most cases, there is a plication of cardiac surgery in neonates and infants.68 history of markedly elevated serum unconjugated biliru- Dyskinetic movements may be very dramatic, and may bin in the early postnatal period. However, in some sick be transient or prolonged. Long-term outcomes in infants, chronic sequelae have occurred in the absence of these children include persistent chorea in some cases marked hyperbilirubinemia.79,81 Parameters for neonatal and significant cognitive problems in all cases.69,70 The intervention with phototherapy and exchange transfu- incidence of this problem has markedly diminished in sion have traditionally been based on total bilirubin lev- the past two decades. els, postconceptual age, and illness in the child. A more Pathophysiology relevant laboratory finding may be the molar ratio of This occurs because of injury to striatum, likely selec- bilirubin to albumin (bound bilirubin remains in the tively vulnerable at this age. Postmortem studies in blood). Ratios exceeding 0.5 may be a more reliable two children showed reactive gliosis, neuronal loss, and indicator of risk, as recent case series have empha- degeneration of myelinated fibers, relatively selectively sized.79,81 Postmortem studies show bilirubin staining localized to the external globus pallidus.71 and neuronal damage in globus pallidus, subthalamic

[email protected] 66485438-66485457 88 section 4 hyperkinetic and Hypokinetic Movement Disorders nucleus, hippocampus, substantia nigra pars reticulate, Huntington’s Disease in Late Teens 78,82 and brainstem and cerebellar nuclei. Clinical Features Hyperglycemia/Diabetes–Associated Subacute Huntington’s disease (HD) (see Figure 9-1) is a neu- Hemichorea or Hemiballism rodegenerative disease that produces chorea, cognitive Clinical Features decline, and psychiatric disturbances in adults. Juvenile, childhood-onset HD produces parkinsonism and dys- Subacute-onset chorea, hemiballism, or hemichorea have tonia. This clinical presentation, as well as pathophys- been described in adults, typically elderly adults with iology, is discussed in greater detail in Chapter 14. chronic hyperglycemia. Women and Asians are more Onset of HD in adolescence may yield motor symp- commonly affected, and patients usually present with toms more similar to adult cases, including chorea, chorea during an episode of non ketotic hyperglycemia. clumsiness, and speech and gait difficulties, as well as The chorea is usually transient, although symptoms can cognitive and emotional disturbances. persist or relapse. CT scans show bright signal in contralateral putamen. MRI shows increased signal in putamen Diagnostic Approach on T1 imaging.83–85 This has been described in diabetic The diagnosis of HD is based on characteristic clin- adolescent twins with similar neuroimaging findings ical features, autosomal dominant family history, with a polymerase gamma I (POLG1) mutation.86 and detection in the HD gene of an expansion to 36 or more CAG trinucleotide repeats. For a variety Pathophysiology of psychologic and economic reasons, as well as to A spectrum of focal striatal pathology may be responsi- respect the autonomy of the individual in adulthood, ble, as there are reports of focal microhemorrhage and of presymptomatic testing in children is strongly discour- striatal gliosis.87,88 Acute/subacute disruption of function aged (Huntington’s Disease Society of America, www. of fronto-striatal pallido-thalamic circuits, particularly hdsa.org). Neurologists familiar with HD in children because of putamenal pathology, appears to be likely. should be consulted, and, in the presence of character- Diagnostic Approach istic symptoms and family history, confirmatory testing Laboratory testing should include basic serum chemis- may be performed at an HD center or clinic where psy- tries, thyroid studies, lactate, and pyruvate for metabolic chologic and genetic counseling services are available. disorders. In the case of known or suspected diabetes, Treatment appropriate studies including hemoglobin A1c are indi- At present, there is no therapy available to prevent neu- cated. Tests for chronic neurodegenerative disorders such rodegeneration in persons genetically at risk for HD. If as Wilson’s disease or pantothenate kinase–associated future treatments are shown to slow the progression of neurodegeneration would typically not be appropriate HD, these recommendations may change. Candidates in this setting. Neuroimaging should be obtained in include coenzyme Q (ubiquinone), a component of the cases of acute and subacute hemichorea or hemiballism, electron transport chain in mitochondria and an antioxi- particularly if there is no history supportive of SC. dant, which is being tested for several neurodegenerative Treatment diseases. In addition, both lithium92 and the mammalian Acute treatment of hyperglycemia may improve the target of rapamycin (mTOR) inhibitors93 have shown chorea. In some cases, symptomatic treatment with dop- promise in animal models of HD as they may reduce amine receptor blocking or dopamine depleting agents the toxicity of protein aggregates in HD by upregulating (e.g., tetrabenazine) is needed.89–91 autophagy. In 2008 tetrabenazine was approved by the Food and Drug Administration as treatment for chorea Multisystem and Genetic Diseases associated with HD.89,94 This treatment is symptomatic Where Chorea is Prominent only and does not slow disease progression. In most diseases in which heredodegenerative or symptom- Infantile Bilateral Striatal Necrosis atic chorea occurs, encephalopathy dominates. Choreas Choreoathetosis, along with developmental regression, that occur as part of the ataxias are discussed in Chapter mental retardation, pendular nystagmus, optic atro- 13. A vast number of genetic diseases and acquired brain phy, dysphagia, dystonia, spasticity, and severe bilat- insults can preferentially affect the basal ganglia and may eral striatal atrophy, is a feature of familial infantile result in chorea, athetosis, or ballism. These include bilateral striatal necrosis (IBSN). IBSN, an extremely hypoxic ischemic injury, viral encephalitides, metabolic rare autosomal recessive neurodegenerative disease, is insults, hypoxia/anoxic insults, and exposure to heavy associated with mutation of nup62 on chromosome metals and other toxins that can produce chorea. 19q13.32-13.41.95 Biotin may slow disease progression.96 [email protected] 66485438-66485457 Chapter 9 Chorea, Athetosis, and Ballism 89

(Continued)

children, mainly in adults adolescence onset cases associated with greater repeat length, paternal inheritance

A ge of onset infants early childhood childhood or adolescence childhood or adolescence neonatal infancy or childhood has been described in a few mode is 30–40’s, childhood/ mode is 30–40’s,

rigid symptoms, dystonia, and psychiatric problems choreiform movement, later ataxia, dementia spasticity, as predominantly chorea between ages 18 months and 5 years. gradually progressive hypothyroidism abnormalities, cataracts and microcornea, progressive neuropathy, hypomyelination, developmental cognitive impairment, hearing loss, mild chorea disorder with chorea, tics, dementia, seizures progressive, normal to slightly subnormal intelligence Movement disorder precedes skin findings juvenile HD presents with hypokinetic/ Clinical Features early onset optic atrophy and initial movement disorder may present childhood onset chorea or dystonia, non progressive or minimally hypotonia, choreoathetosis, multisystem disease with skeletal multisystem neurodegenerative

AD I nheritance AR AR AR AD AD AR AD

degenerative D isease Category degenerative degenerative degenerative primary primary degenerative degenerative

with partially preserved function encoding thyroid transcription factor TITF1 in some patients c-terminal domain of the phosphatase of RNA polymerase II (CTDP1) CAG repeat in the gene encoding atrophin-1 CAG repeat in the Huntingtin gene

expanded trinucleotide Gene gene mutation in the OPA3 gene mutations in the ATM gene Mutations in the ATM mutations in the gene Allelic to BHC mutation in the expanded trinucleotide

100

106 99,

104 98

Genetic Causes of Chorea 101

103

105 102, a b le 9-3

Variant hypothyroidism, neonatal respiratory distress facial dysmorphism, and neuropathy pallidoluysian atrophy aciduria type III Chorea BHC

(Figure 9-1) Chorea/Disease HD T D isease 3-methylglutaconic Ataxia telangiectasia Ataxia telangiectasia, Benign Hereditary Choreoathetosis, Congenital Cataracts, Dentatorubral- Huntington’s Huntington’s

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(Continued)

children, mainly in adults

infancy or childhood A ge of onset childhood infancy infancy or childhood has been described in a few neonatal

dystonic movement lasting minutes to hours, usually several times per week, precipitated by stress, caffeine, alcohol disorder with dystonia, chorea, ataxia, dementia, seizures chorea, basal ganglia / cerebral cerebellar/ spinal cord lesions, lactic acidemia, respiratory failure profound cognitive myoclonic epilepsy, impairment disorder with chorea, tics, dementia, seizures severe cognitive impairment, with basal ganglia calcification, early death microcephaly, episodic, with choreoathetoid or Clinical Features multisystem neurodegenerative infantile onset tetraplegia, chorea, multisystem disease with hypotonia, multisystem neurodegenerative neonatal classic: hypotonia, severe

(adult form)

AD I nheritance AR AR or AD X-linked AR AR

paroxysmal D isease Category degenerative degenerative metabolic degenerative metabolic

in myofibrillogenesis regulator-1 gene 4p15.3 polypeptide-1 of the pyruvate dehydrogenase complex 1 gene VPS13A encoding chorein have been described for ‘P’, ‘T’, and ‘H’ proteins in mitochondrial glycine cleavage syndrome

can be caused by mutation Gene linked to chromosome unknown mutation in the E1 alpha mutations in the gene mutations in several genes

113 111

112,

107 114 110

108 109,

ganglia calcification (IBGC), childhood onset, aka bilateral striopallidodentate calcinosis X-linked hyperglycinemia (aka Glycine Encephalopathy) Like - 3 HDL3

Nonkinesigenic Dyskinesia 1 D isease Disease Huntington’s Idiopathic basal Leigh Syndrome, Neuroacanthocytosis Nonketotic Paroxysmal

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have been reported

infancy childhood childhood early adults, adolescents with psychiatric symptoms, nystagmus, ataxia, seizures, cerebral and cerebellar dementia. Dystonia, chorea atrophy, occasionally present impairment, seizures, poor feeding, severe choreiform dyskinesias, brainstem and cerebellar hypoplasia, early death with progressive ataxia, mild cognitive impairment, dysarthria, dystonia, ophthalmoplegia, spasticity, chorea progressive ataxia, dysarthria, retinal degeneration, optic atrophy, dystonia, ophthalmoplegia, spasticity, chorea multisystem neurodegenerative disorder microcephaly, severe cognitive microcephaly, neurodegenerative disease neurodegenerative disease with

AD AR AD AD

degenerative degenerative degenerative degenerative

repeat in the TATA-Box repeat in the TATA-Box binding protein (TBP)

repeat in gene encoding ataxin 1 repeat in gene encoding ataxin 7 unknown expanded trinucleotide expanded trinucleotide expanded trinucleotide CAG

115

Genetic Causes of Chorea—Cont’d

116 117 119

118, hypoplasia type II

ataxia 1 ataxia 7

17 B LE 9-3 TA Pontocerebellar Spinocerebellar Spinocerebellar Spinocerebellar ataxia

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A summary of other genetic causes of chorea is shown REFERENCES in Table 9-3. 1. Wijemanne S, Jankovic J: Hemidystonia-hemiatrophy Summary of Diagnostic and syndrome, Mov Disord Mar 15 24(4):583–589, 2009. 2. Gowers WR: General and functional diseases of the Therapeutic Approach nervous system: chorea. A manual of diseases of the nervous Chorea is rare in children. In otherwise healthy chil- system, Philadelphia, 1888, Blakiston. dren who acquire chorea, poststreptococcal SC is 3. Ferrara J, Jankovic J: Psychogenic movement disorders in children, Mov Disord 23:1875–1881, 2008. most common, but chorea associated with SLE, APS, 4. Harbord MG, Kobayashi JS: Fever producing ballismus hyperthyroidism, toxins, and acute metabolic and vas- in patients with choreoathetosis, J Child Neurol 6:49–52, cular injuries may need to be considered. In chronic 1991. encephalopathies, chorea may also occur. The presence 5. Kakinuma H, Hori A, Itoh M, et al: An inherited of acute or chronic chorea suggests disordered neural disorder characterized by repeated episodes of bilateral transmission or structural pathology in the basal gan- ballism: a case report, Mov Disord 22:2110–2112, 2007. glia or occasionally in other structures. Athetosis and 6. Okun MS, Jummani RR, Carney PR: Antiphospholipid- ballism have similar etiologies. Athetosis is more likely associated recurrent chorea and ballism in a child with to occur in chronic neurologic conditions, and ballism cerebral palsy, Pediatr Neurol 23:62–63, 2000. may occur in SC or as hemiballism in acute basal gan- 7. PeBenito R, Talamayan RC: Fever-induced protracted glia injury. ballismus in choreoathetoid cerebral palsy, Clin Pediatr 40:49–51, 2001. Therapeutics 8. Zomorrodi A, Wald ER: Sydenham’s chorea in western Pennsylvania, Pediatrics 117:e675–e679, 2006. Etiology-specific treatment is the goal, but is not avail- 9. Giedd JN, Rapoport JL, Kruesi MJ, et al: Sydenham’s able in most cases. For autoimmune-mediated forms of chorea: magnetic resonance imaging of the basal ganglia, chorea, prednisone or other immune-modulating treat- Neurology 45:2199–2202, 1995. ments may be helpful. 10. Wu SW, Graham B, Gelfand MJ, et al: Clinical and positron emission tomography findings of chorea associated It is helpful in considering pharmacologic, symptom- with primary antiphospholipid antibody syndrome, Mov suppressing treatment for chorea to consider the Disord 22:1813–1815, 2007. following possible alterations in neurotransmission: 11. Foroud T, Gray J, Ivashina J, Conneally PM: Differences (1) relatively increased transmission of dopamine into in duration of Huntington’s disease based on age at onset, striatum, particularly into the indirect pathway (see J Neurol Neurosurg Psychiatry 66:52–56, 1999. Chapter 1); (2) relatively decreased GABAergic pro- 12. Hallett M, Kaufman C: Physiological observations jection from striatum, particularly to the globus palli- in Sydenham’s chorea, J Neurol Neurosurg Psychiatry dus externa; and (3) relative preservation of cholinergic 44:829–832, 1981. transmission within striatum. 13. Cole WR, Mostofsky SH, Larson JCG, et al: Age-related On this basis, chorea suppression with typical, changes in motor subtle signs among girls and boys with high-potency dopamine receptor blocking agents ADHD, Neurology 71:1514–1520, 2008. 14. Haerer AF, Currier RD, Jackson JF: Hereditary nonpro- has been used for many years and is reasonable in gressive chorea of early onset, N Engl J Med 276:1220– cases where chorea causes significant functional 1224, 1967. interference and where the disease process is likely 15. Schrag A, Quinn NP, Bhatia KP, Marsden CD: Benign to be self-limited. Anticonvulsants such as valproic hereditary chorea—entity or syndrome? Mov Disord acid, perhaps through increasing striatal gamma- 15:280–288, 2000. aminobutyric acid (GABA), may also be helpful. 16. Breedveld GJ, van Dongen JW, Danesino C, et al: Anticholinergics should not be used. Similarly, dop- Mutations in TITF-1 are associated with benign heredi- aminergic agents—psychostimulants, levodopa-car- tary chorea, Hum Mol Genet 11:971–979, 2002. bidopa, or dopamine agonists—should not be used 17. Kleiner-Fisman G, Rogaeva E, Halliday W, et al: Benign or should be used with caution. Tetrabenazine, a hereditary chorea: clinical, genetic, and pathological monoamine depleting and dopamine receptor block- findings, Ann Neurol 54:244–247, 2003. 18. Mahajnah M, Inbar D, Steinmetz A, et al: Benign hered- ing medication, was recently approved in the United itary chorea: clinical, neuroimaging, and genetic find- States for treatment of chorea in HD. It has been ings, J Child Neurol 22:1231–1234, 2007. used for years in a variety of hyperkinetic movement 19. Hageman G, Ippel PF, van Hout MS, Rozeboom AR: 90,97 disorders. To date there is little specific informa- A Dutch family with benign hereditary chorea of early tion about its use in children with SC or other dis- onset: differentiation from Huntington’s disease, Clin eases causing chorea. Neurol Neurosurg 98:165–170, 1996.

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20. do Carmo Costa M, Costa C, Silva AP, et al: Nonsense 36. Bye AM, Cunningham CA, Chee KY, Flanagan D: Outcome mutation in TITF1 in a Portuguese family with benign of neonates with electrographically identified seizures, or at hereditary chorea, Neurogenetics 6:209–215, 2005. risk of seizures, Pediatr Neurol 16:225–231, 1997. 21. Kleiner-Fisman G, Calingasan NY, Putt M, et al: 37. Gabbay V, Coffey BJ, Babb JS, et al: Pediatric autoim- Alterations of striatal neurons in benign hereditary mune neuropsychiatric disorders associated with strep- chorea, Mov Disord 20:1353–1357, 2005. tococcus: comparison of diagnosis and treatment in the 22. Shimohata T, Hara K, Sanpei K, et al: Novel locus for community and at a specialty clinic, Pediatrics 122:273– benign hereditary chorea with adult onset maps to chro- 278, 2008. mosome 8q21.3 q23.3, Brain 130:2302–2309, 2007. 38. Scolnick B: Pediatric Autoimmune neuropsychiatric dis- 23. Kimura S, Hara Y, Pineau T, et al: The T/ebp null mouse: orders associated with streptococcus, Pediatrics 123:e171, thyroid-specific enhancer-binding protein is essential for 2009. the organogenesis of the thyroid, lung, ventral forebrain, 39. Gilbert D, Gerber MA: Regarding “Antibiotic prophy- and pituitary, Genes Dev 10:60–69, 1996. laxis with azithromycin or penicillin for childhood-onset 24. Sussel L, Marin O, Kimura S, Rubenstein JL: Loss of neuropsychiatric disorders” [comment], Biol Psychiatry Nkx2.1 homeobox gene function results in a ventral 58:916, 2005. to dorsal molecular respecification within the basal tel- 40. Singer HS, Gause C, Morris C, Lopez P: Serial immune encephalon: evidence for a transformation of the pal- markers do not correlate with clinical exacerbations in lidum into the striatum, Development 126:3359–3370, pediatric autoimmune neuropsychiatric disorders associ- 1999. ated with streptococcal infections, Pediatrics 121:1198– 25. Lavin MF, Gueven N, Bottle S, Gatti RA: Current 1205, 2008. and potential therapeutic strategies for the treatment 41. Aron AM, Freeman JM, Carter S: The natural history of ataxia-telangiectasia, Br Med Bull 81–82:129–147, of Sydenham’s chorea. Review of the literature and long- 2007. term evaluation with emphasis on cardiac sequelae, Am J 26. Asmus F, Horber V, Pohlenz J, et al: A novel TITF-1 Med 38:83–95, 1965. mutation causes benign hereditary chorea with response 42. Paz JA, Silva CA, Marques-Dias MJ: Randomized dou- to levodopa, Neurology 64:1952–1954, 2005. ble-blind study with prednisone in Sydenham’s chorea, 27. Doyle DA, Gonzalez I, Thomas B, Scavina M: Autosomal Pediatr Neurol 34:264–269, 2006. dominant transmission of congenital hypothyroidism, 43. Cardoso F, Vargas AP, Oliveira LD, et al: Persistent neonatal respiratory distress, and ataxia caused by a Sydenham’s chorea, Mov Disord 14:805–807, 1999. mutation of NKX2-1, J Pediatr 145:190–193, 2004. 44. Taranta A, Stollerman GH: The relationship of 28. American Academy of Pediatrics: Group A streptococcal Sydenham’s chorea to infection with group A strepto- infections. In Pickering LK, et al: Red book: 2006 report cocci, Am J Med 20:170–175, 1956. of the Committee on Infectious Diseases, Elk Grove, IL, 45. Husby G, van dr, Zabriskie JB, et al: Antibodies react- 2006, American Academy of Pediatrics. ing with cytoplasm of subthalamic and caudate nuclei 29. Walker AR, Tani LY, Thompson JA, et al: Rheumatic cho- neurons in chorea and acute rheumatic fever, J Exp Med rea: relationship to systemic manifestations and response 144:1094–1110, 1976. to corticosteroids, J Pediatr 151:679–683, 2007. 46. Husby G, Li L, Davis LE, et al: Antibodies to human 30. Ridel KR, Lipps TD, Gilbert DL: The prevalence of caudate nucleus neurons in Huntington’s chorea, J Clin neuropsychiatric disorder in children diagnosed with Invest 59:922–932, 1977. Sydenham’s chorea: a long-term follow-up of a clinic 47. Singer HS, Hong JJ, Yoon DY, Williams PN: Serum based sample. Pediatric Neurology 2009 (in press). autoantibodies do not differentiate PANDAS and 31. Asbahr FR, Garvey MA, Snider LA, et al: Obsessive- Tourette syndrome from controls, Neurology 2005 compulsive symptoms among patients with Sydenham 01.wnl.0000183223.69946.f1. chorea, Biol Psychiatry 57:1073–1076, 2005. 48. Bronze MS, Dale JB: Epitopes of streptococcal M pro- 32. Freeman JM, Aron AM, Collard JE, Mackay MC: The teins that evoke antibodies that cross-react with human emotional correlates of Sydenham’s chorea, Pediatrics brain, J Immunol 151:2820–2828, 1993. 35:42–49, 1965. 49. Seeherunvong T, Diamantopoulos S, Berkovitz GD: A 33. Kirvan CA, Cox CJ, Swedo SE, Cunningham MW: nine year old girl with thyrotoxicosis, ataxia, and cho- Tubulin is a neuronal target of autoantibodies in rea, Brain Dev 29:660–661, 2007. Sydenham’s chorea, J Immunol 178:7412–7421, 2007. 50. Wong LJ, Naviaux RK, Brunetti-Pierri N, et al: 34. Maia DP, Teixeira AL Jr, Quintao Cunningham MC, Molecular and clinical genetics of mitochondrial dis- Cardoso F: Obsessive compulsive behavior, hyperactiv- eases due to POLG mutations, Hum Mutat Jun 10 ity, and attention deficit disorder in Sydenham chorea, 29(9):E150–E172, 2008. Neurology 64:1799–1801, 2005. 51. Isaacs KM, Kao E, Johnson MD, Gilbert DL: Precipitating 35. Hounie AG, Pauls DL, do Rosario-Campos MC, et al: events and significant life stressors of pediatric patients diag- Obsessive-compulsive spectrum disorders and rheu- nosed with a psychogenic movement disorder. 37th Annual matic fever: a family study, Biol Psychiatry 61:266– Meeting of the International Neuropsychological Society. 272, 2007. Atlanta, GA, 2009.

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52. Ayoub EM, Nelson B, Shulman ST, et al: Group A 68. Brunberg JA: Hyperintense basal ganglia on T1-weighted streptococcal antibodies in subjects with or without MR in a patient with Langerhans cell histiocytosis [com- rheumatic fever in areas with high or low incidences of ment], AJNR Am J Neuroradiol 17:1193–1194, 1996. rheumatic fever, Clin Diagn Lab Immunol 10:886–890, 69. du Plessis AJ, Kaufmann WE, Kupsky WJ: Intrauterine- 2003. onset myoclonic encephalopathy associated with cerebral 53. Ayoub EM, Wannamaker LW: Streptococcal antibody cortical dysgenesis, J Child Neurol 8:164–170, 1993. titers in Sydenham’s chorea, Pediatrics 38:946–956, 70. Medlock MD, Cruse RS, Winek SJ, et al: A 10-year 1966. experience with postpump chorea, Ann Neurol 34: 54. Faustino PC, Terreri MT, da Rocha AJ, et al: Clinical, 820–826, 1993. laboratory, psychiatric and magnetic resonance find- 71. Kupsky WJ, Drozd MA, Barlow CF: Selective injury of ings in patients with Sydenham chorea, Neuroradiology the globus pallidus in children with post-cardiac surgery 45:456–462, 2003. choreic syndrome, Dev Med Child Neurol 37:135–144, 55. Barsottini OG, Ferraz HB, Seviliano MM, Barbieri A: 1995. Brain SPECT imaging in Sydenham’s chorea, Braz J Med 72. Strauss KA, Puffenberger EG, Robinson DL, Morton Biol Res 35:431–436, 2002. DH: Type I glutaric aciduria, part 1: natural history 56. Kabakus N, Balci TA, Kurt A, Kurt AN: Cerebral blood of 77 patients, Am J Med Genet C Semin Med Genet flow abnormalities in children with Sydenham’s chorea: 121:38–52, 2003. a SPECT study [see comment], Indian Pediatr 43:241– 73. Calabresi P, Centonze D, Bernardi G: Cellular factors 246, 2006. controlling neuronal vulnerability in the brain: a lesson 57. Lee PH, Nam HS, Lee KY, et al: Serial brain SPECT from the striatum, Neurology 55:1249–1255, 2000. images in a case of Sydenham chorea, Arch Neurol 74. Johnston MV, Hoon AH Jr: Possible mechanisms in 56:237–240, 1999. infants for selective basal ganglia damage from asphyxia, 58. Aron AM: Sydenham’s chorea: positron emission tomo- kernicterus, or mitochondrial encephalopathies, J Child graphic (PET) scan studies, J Child Neurol 20:832–833, Neurol 15:588–591, 2000. 2005. 75. Morris JG, Grattan-Smith P, Jankelowitz SK, et al: 59. Panamonta M, Chaikitpinyo A, Auvichayapat N, et al: Athetosis II: the syndrome of mild athetoid cerebral Evolution of valve damage in Sydenham’s chorea during palsy, Mov Disord 17:1281–1287, 2002. recurrence of rheumatic fever, Int J Cardiol 119:73–79, 76. Beran-Koehn MA, Zupanc ML, Patterson MC, et al: 2007. Violent recurrent ballism associated with infections in 60. Daoud AS, Zaki M, Shakir R, al-Saleh Q: Effectiveness two children with static encephalopathy, Mov Disord of sodium valproate in the treatment of Sydenham’s 15:570–574, 2000. chorea, Neurology 40:1140–1141, 1990. 77. Connolly AM, Volpe JJ: Clinical features of bilirubin 61. Kulkarni ML: Sodium valproate controls choreoathe- encephalopathy, Clin Perinatol 17:371–379, 1990. toid movements of kernicterus, Indian Pediatr 29: 78. Volpe JJ: Bilirubin and brain injury. In Neurology of the 1029–1030, 1992. newborn, Philadelphia, 2001, Saunders. 62. Diaz-Grez F, Lay-Son L, del Barrio-Guerrero E, Vidal- 79. Merhar SL, Gilbert DL: Clinical (video) findings and Gonzalez P: Sydenham’s chorea. A clinical analysis of cerebrospinal fluid neurotransmitters in 2 children with 55 patients with a prolonged follow-up, Rev Neurol 39: severe chronic bilirubin encephalopathy, including a 810–815, 2004. former preterm infant without marked hyperbilirubine- 63. Fahn S, Jankovic J: Chorea, ballism, athethosis: phenom- mia, Pediatrics 116:1226–1230, 2005. enology and etiology. Principles and practice of movement 80. Powers KM, Miller SJ, Shapiro SM: Exposure to exces- disorders, Philadelphia, 2007, Churchill Livingstone sive hyperbilirubinemia earlier in neurodevelopment Elsevier. is associated with auditory-predominant kernicterus 64. Garvey MA, Snider LA, Leitman SF, et al: Treatment subtype, Ann Neurol 64:S105, 2008. of Sydenham’s chorea with intravenous immunoglobu- 81. Govaert P, Lequin M, Swarte R, et al: Changes in glo- lin, plasma exchange, or prednisone, J Child Neurol 20: bus pallidus with (pre)term kernicterus, Pediatrics 112: 424–429, 2005. 1256–1263, 2003. 65. Katzav A, Chapman J, Shoenfeld Y: CNS dysfunction 82. Ahdab-Barmada M, Moossy J: The neuropathology of in the antiphospholipid syndrome, Lupus 12:903–907, kernicterus in the premature neonate: diagnostic prob- 2003. lems, J Neuropathol Exp Neurol 43:45–56, 1984. 66. Cervera R, Piette JC, Font J, et al: Antiphospholipid 83. Ahlskog JE, Nishino H, Evidente VG, et al: Persistent syndrome: clinical and immunologic manifestations chorea triggered by hyperglycemic crisis in diabetics, and patterns of disease expression in a cohort of 1,000 Mov Disord 16:890–898, 2001. patients, Arthritis Rheum 46:1019–1027, 2002. 84. Lai PH, Tien RD, Chang MH, et al: Chorea-ballismus 67. Kiechl-Kohlendorfer U, Ellemunter H, Kiechl S: Chorea with nonketotic hyperglycemia in primary diabetes melas the presenting clinical feature of primary antiphos- litus, AJNR Am J Neuroradiol 17:1057–1064, 1996. pholipid syndrome in childhood [see comment], 85. Oh SH, Lee KY, Im JH, Lee MS: Chorea associated Neuropediatrics 30:96–98, 1999. with non-ketotic hyperglycemia and hyperintensity basal

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ganglia lesion on T1-weighted brain MRI study: a 102. Devriendt K, Vanhole C, Matthijs G, de Zegher F: meta-analysis of 53 cases including four present cases, J Deletion of thyroid transcription factor-1 gene in an Neurol Sci 200:57–62, 2002. infant with neonatal thyroid dysfunction and respi- 86. Hopkins SE, Somoza A, Gilbert DL: Rare autosomal ratory failure, N. Engl. J. Med 338(18):1317–1318, dominant POLG1 mutation in a family with meta- 1998. bolic strokes, posterior column spinal degeneration, and 103. Krude H, Schutz B, Biebermann H, et al: Choreoathe multi-endocrine disease, J Child Neurol EPUB, 2009. tosis, hypothyroidism, and pulmonary alterations due 87. Mestre TA, Ferreira JJ, Pimentel J: Putaminal petechial to human NKX2-1 haploinsufficiency.[see comment], haemorrhage as the cause of non-ketotic hyperglycaemic J. Clin. Invest 109(4):475–480, 2002. chorea: a neuropathological case correlated with MRI find- 104. Varon R, Gooding R, Steglich C, et al: Partial defi- ings, J Neurol Neurosurg Psychiatry 78:549–550, 2007. ciency of the C-terminal-domain phosphatase of RNA 88. Ohara S, Nakagawa S, Tabata K, Hashimoto T: polymerase II is associated with congenital cataracts Hemiballism with hyperglycemia and striatal T1-MRI facial dysmorphism neuropathy syndrome, Nat. Genet hyperintensity: an autopsy report, Mov Disord 16:521– 35(2):185–189, 2003. 525, 2001. 105. Burke JR, Wingfield MS, Lewis KE, et al: The Haw 89. Kenney C, Hunter C, Davidson A, Jankovic J: Short- River syndrome: dentatorubropallidoluysian atrophy term effects of tetrabenazine on chorea associated with (DRPLA) in an African-American family, Nat. Genet Huntington’s disease, Mov Disord 22:10–13, 2007. 7(4):521–524, 1994. 90. Kenney C, Hunter C, Jankovic J: Long-term tolerabil- 106. MacMillan JC, Morrison PJ, Nevin NC, et al: ity of tetrabenazine in the treatment of hyperkinetic Identification of an expanded CAG repeat in the movement disorders, Mov Disord 22:193–197, 2007. Huntington’s disease gene (IT15) in a family reported 91. Kenney C, Jankovic J: Tetrabenazine in the treatment of to have benign hereditary chorea, J. Med. Genet hyperkinetic movement disorders, Expert Rev Neurother 30(12):1012–1013, 1993. 6:7–17, 2006. 107. Kambouris M, Bohlega S, Al-Tahan A, Meyer BF: 92. Sarkar S, Floto RA, Berger Z, et al: Lithium induces Localization of the gene for a novel autosomal reces- autophagy by inhibiting inositol monophosphatase, sive neurodegenerative Huntington-like disorder to J Cell Biol 170:1101–1111, 2005. 4p15.3.[see comment], Am. J. Hum. Genet 66(2): 93. Ravikumar B, Vacher C, Berger Z, et al: Inhibition 445–452, 2000. of mTOR induces autophagy and reduces toxicity of 108. 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Straussberg R, Shorer Z, Weitz R, et al: Familial infantile analysis of an X-linked case of Leigh syndrome asso- bilateral striatal necrosis: clinical features and response ciated with thiamin-responsive pyruvate dehydroge- to biotin treatment, Neurology 59:983–989, 2002. nase deficiency, J. Inherit. Metab. Dis 20(4):539–548, 97. Jankovic J, Beach J: Long-term effects of tetrabenazine 1997. in hyperkinetic movement disorders, Neurology 48:358– 111. Hardie RJ, Pullon HW, Harding AE, et al: Neuroa 362, 1997. canthocytosis. A clinical, haematological and patho- 98. Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O: Type III logical study of 19 cases, Brain 114(Pt 1A):13–49, 3-methylglutaconic aciduria (optic atrophy plus syn- 1991. drome, or Costeff optic atrophy syndrome): identifica- 112. Branca D, Gervasio O, Le Piane E, Russo C, Aguglia U: tion of the OPA3 gene and its founder mutation in Iraqi Chorea induced by non-ketotic hyperglycaemia: a case Jews, Am. J. Hum. 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Genet 11(8):971–979, 2002. syndrome of autosomal recessive pontocerebellar

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hypoplasia, microcephaly, and extrapyramidal dyskinesia 118. Koide R, Kobayashi S, Shimohata T, et al: A neurological (pontocerebellar hypoplasia type 2): compiled data disease caused by an expanded CAG trinucleotide repeat from 10 pedigrees, Neurology 45(2):311–317, 1995. in the TATA-binding protein gene: a new polyglutamine 116. Banfi S, Servadio A, Chung MY, et al: Identification disease?, Hum. Mol. Genet 8(11):2047–2053, 1999. and characterization of the gene causing type 1 spi- 119. Nakamura K, Jeong SY, Uchihara T, et al: SCA17, nocerebellar ataxia, Nature Genetics 7(4):513–520, a novel autosomal dominant cerebellar ataxia caused by 1994. an expanded polyglutamine in TATA-binding protein, 117. David G, Abbas N, Stevanin G, et al: Cloning of the Hum. Mol. Genet 10(14):1441–1448, 2001. SCA7 gene reveals a highly unstable CAG repeat expan- 120. Gilbert DL, Kurlan R: PANDAS: Horse or Zebra? sion, Nature Genetics 17(1):65–70, 1997. Neurology 73:1252–1253, 2009.

[email protected] 66485438-66485457 Dystonia O 10 O Introduction and Definition identified and as the phenotypes of primary dystonias are further clarified and reveal comorbid neurologic and Dystonia is a syndrome of sustained or repetitive invol- psychiatric manifestations, division into primary and untary muscle contractions that produce abnormal but secondary categories is not simple. However, it remains patterned postures and movements of different parts useful for bringing order and guiding diagnostic of the body.1 Oppenheim2 coined the term dystonia approach to the many forms of dystonia. musculorum deformans in 1911 to name a progressive Additional classification schemes have been based childhood-onset syndrome characterized by twisted on age of onset and distribution of affected body parts postures, muscle spasms, bizarre walking with bend- (Table 10-1). It should be noted that these classifica- O ing and twisting of the trunk, and eventually fixed pos- tion schemes are interdependent. For example, a patient tural deformities. Subsequently, the term dystonia came with onset in childhood of dystonia involving the entire to be used to refer to the neurologic sign of abnormal body because of a mutation at the DYT1 locus is clas- sustained twisting postures characteristic of those seen sified as having “childhood-onset primary generalized in dystonia musculorum deformans (DMD), regard- dystonia.” A patient with onset in adulthood of writer’s less of cause. Alternatively, it has been used to refer to a cramp with no other neurologic signs or symptoms is syndrome characterized by abnormal sustained twisting classified as having “adult-onset primary focal dystonia.” postures. Wilson3 argued against use of the term dysto- Focal dystonia may affect almost any part of the body, nia, because he viewed the disorder as one of movement for example, involuntary eyelid squeezing associated and not of tone. Denny-Brown4 used dystonia to refer with excessive blinking (called blepharospasm). This to any abnormal posture that resists displacement such focal dystonia is frequently associated with lower facial that a displaced body part tends to return to its initial involvement, including such movements as involuntary posture. In an effort to be more uniform and specific, grimacing. Others have selective involvement of the jaw the Scientific Advisory Board of the Dystonia Medical with involuntary opening or closing, and some may Research Foundation (www.dystonia-foundation.org) have only dystonic movements of the tongue. Cervical has adopted the following definition: “Dystonia is a dystonia may manifest as twisting of the neck (torticol- syndrome of sustained muscle contractions, frequently lis), drawing of the head with neck extension (retrocol- causing twisting and repetitive movements or abnor- lis), pulling of the head forward (anterocollis), tilting of mal postures.” the head to one side (laterocollis), or any combination The etiologies of dystonia in childhood are numer- of these movements and postures. The upper extremities ous. In many disorders, dystonia exists as just one neuro- can have selected involvement in task-specific activities logic sign or symptom among others. In other disorders, such as writer’s cramp or typist’s cramp with involuntary dystonia is the main or the only manifestation. To aid contractions and peculiar posturing when trying to write in classification of disorders characterized by dystonia, or perform other highly skilled, fine motor tasks such disorders are often divided into primary (idiopathic) as typing or playing the piano. The lower extremities and secondary etiologies. Primary dystonias lack other also can be affected with twisting of a foot while walking neurologic deficits and are distinguished further from that may eventually progress to a sustained contraction secondary dystonias by lack of an identifiable etiology during all waking hours. such as birth injury, stroke, or drug reaction.5 Another classification scheme considers “primary dystonias” to Clinical Characteristics of Dystonia be disorders that consist of only dystonia or of dystonia plus tremor. Disorders consisting of dystonia and Many characteristic clinical features of dystonia are other movement disorders are referred to as “dystonia- present regardless of age, etiology, or affected body plus.”6,7 As additional specific genetic etiologies become parts. Some of these features are seen in several types of

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Table 10-1 classifications of Dystonia* the dysfunctional motor control is at a level higher than the final output for selected muscle contraction. Age of Onset Body Part Affected Many people with dystonia find that lightly touch- Childhood onset Focal ing a part of the body may relieve dystonic spasms in Adult onset Segmental that or adjacent body parts. This phenomenon, called Multifocal a geste antagoniste, has been described best in primary Etiology dystonia, but can occur in certain secondary dystonias, too. Examples of geste antagoniste include the following: Primary (idiopathic) Hemi touching near the lateral canthus may relieve the eyelid Secondary Generalized squeezing of blepharospasm; a straw in the mouth may *Note: schemes are overlapping. reduce jaw-closing dystonia; touching the side of the chin may decrease cervical dystonia; and rubbing the back of the hand may diminish writer’s cramp. Even in general- movement disorders, but others are relatively specific ized dystonia, light touch to the neck or an affected limb to dystonia. These features can aid in the diagnosis of may transiently reduce dystonic contractions. dystonia and in distinguishing organic dystonias from psychogenic causes (see Chapter 19). As with many Localization and Pathophysiology movement disorders, stress exacerbates most forms of dystonia. Conversely, the involuntary muscle contrac- Dystonia has been associated with a number of diseases, tions of dystonia nearly completely abate with sleep. but there is often no discrete, identifiable pathologic Dystonic contractions cannot be suppressed volun- abnormality in the brain. Abnormalities at many lev- tarily. Indeed, the biggest problem in dystonia appears els of cellular function have been described in genetic to be the inability to relax unwanted muscle activity. forms of dystonia.8 However, the basal ganglia play a Dystonia may be absent when the patient is at rest, central role in many forms of dystonia. When dystonia but appears with mental activity or attempted volun- is seen after stroke the most common lesion locations tary movement of the affected or distant body parts. are the putamen (most common), globus pallidus, or Dystonia may fluctuate in presence and severity over thalamus.9,10 Furthermore, metabolic disorders that time. Three important characteristic features of dysto- have dystonia as a prominent feature are often associ- nia are patterned, predictable contractions of the same ated with basal ganglia involvement. Lesions of basal muscles; task specificity; and the so-called geste antago- ganglia structures in primates can cause abnormal niste, or sensory trick. These features are typically not postures that are characteristic of human dystonia.11 seen in other hyperkinetic movement disorders and Dopamine D2 receptor binding is reduced in the puta- may be important clues to understanding the underly- men of patients with primary focal dystonia and in an ing pathophysiology of dystonia. animal model of transient dystonia.12,13 These obser- Task specificity has been most frequently described vations and other data suggest that dystonia is due to in focal dystonias, but patients with segmental and abnormal basal ganglia function, which in turn causes generalized dystonia often have exacerbation of their altered regulation of cortical, spinal, and probably brain- dystonia when performing a skilled movement. Task stem sensorimotor mechanisms. The result is abnormal specificity manifests as dystonic posturing occur- muscular co-contraction and overflow of activity to ring only with selected movements and paradoxically muscle adjacent to the prime movers or to the contral- not with others that may use the same muscles. For ateral body part, the so-called mirror dystonia.14,15 example, a patient with writer’s cramp may have dys- There is a large body of evidence implicating dystonia only while writing, but not while knitting, typ- function of the nigrostriatal dopamine system in the ing, or using a screwdriver. In cranial dystonia, lower pathophysiology of dystonia. Although much of the evi- facial grimacing may occur only when talking and not dence is circumstantial, impaired dopamine neurotrans- when eating. The strained, strangled speech of adduc- mission appears to be the common theme: (1) Drugs tor laryngeal dystonia may only affect talking, but not that block dopamine receptors can produce acute dys- singing, whispering or breathing. Walking forward tonic reactions.16 (2) In the syndrome of dopa-responsive may elicit severe lower extremity and truncal twisting, dystonia (DRD), there is a remarkable symptomatic yet walking backward, running, or swimming may be response to levodopa.17 In DRD, there is decreased completely normal in someone with generalized dysto- production of dopamine, despite no loss of nigrostriatal nia. Some people with generalized dystonia can dance, neurons. (3) Patients with idiopathic focal dystonia but cannot walk. All of these observations suggest that have reduced dopamine D2 receptor binding in the

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putamen.18 (4) Dystonia is an early manifestation of to be idiopathic. In the future, classification of pri- Parkinson’s disease in 20% to 40% of patients.19 (5) mary dystonias may rely on identification of genetic The expression of messenger ribonucleic acid (mRNA) defects that either cause the disease or provide a pre- that encodes torsinA, which is the protein product of disposition to the development of dystonia after certain the gene (DYT1) that is responsible for childhood- environmental exposures. Some genetic forms of dys- onset idiopathic generalized torsion dystonia, is particu- tonia have assigned genetic loci identified as DYTx larly concentrated in nigrostriatal dopamine neurons.20 (Table 10-2). However, there is a much longer list of (6) Dystonia associated with “spastic cerebral palsy” genetic disorders in which dystonia is an important fea- may respond to treatment with the dopamine precur- ture (Table 10-3). In some of these disorders dystonia is sor levodopa.21 Although this does not mean that there the primary feature, but in others it is just one of several is dopamine deficiency in spastic cerebral palsy, it does neurologic signs or symptoms. Dystonia can also be a support the notion that dopamine mechanisms may play prominent feature in disorders without a genetic basis an important role in the pathophysiology of dystonia. (Box 10-1). In the following sections, specific etiologies Most studies of dystonia have revealed abnormal of nonparoxysmal childhood-onset dystonia will be dis- co-contraction of agonist and antagonist muscles at cussed. Paroxysmal dystonias are covered in Chapter 8. rest that is often exacerbated by movement14,22–24; how- Management and treatment of dystonia will be ever, one study in children with primary and second- discussed after presentation of the specific etiologies. ary dystonia failed to confirm co-contraction as a basis Early-Onset Primary (Generalized) for dystonia.25 At rest, the abnormal contractions can be sustained or intermittent. The intermittent contrac- Torsion Dystonia (DYT1) tions usually last 1 to 2 seconds, although some are as Clinical Features and Natural History short as 100 ms. During voluntary movement, exces- Early-onset primary torsion dystonia, formerly known sive voluntary contractions are seen in muscles that as dystonia musculorum deformans or Oppenheim would not normally be active in the task. In addition to dystonia, is an autosomal dominant condition with the excessive activity of nearby muscles, agonist muscle incomplete (30% to 40%) penetrance.33 Genetic stud- 26 activity is prolonged, and movement-related corti- ies have found that a GAG deletion in the TOR1A 27 cal potentials are reduced just before movement. The (DYT1) gene at 9q34 produces most autosomal domi- combination of slight reduction in agonist activity and nant, early-onset primary generalized dystonias affect- excessive activity in antagonist muscles causes move- ing Ashkenazi Jewish patients (90%)34 and non-Jews ment to be slow. Movement sequences are relatively (50% to 60%).35 In DYT1 dystonia, symptoms usually 28 more impaired than are the individual components. begin in a limb with a mean onset age of 12.5 years.36 In dystonia, the monosynaptic and long-latency Approximately equal numbers have onset in an arm stretch reflexes are normal at rapid rates of stretch, but (48%) or a leg (49%), but the arm is more likely to be with slower stretches the long-latency reflex is prolonged involved first in Ashkenazi Jews (60%) and the leg is 29 compared with normal. Stretch of one muscle group more likely to be involved first in non-Jews (60%).37 often results in “overflow” activation of other muscle Cervical or laryngeal onset is uncommon. Onset is typ- 24 groups, and it has been suggested that people with dys- ically after 5 and before 26 years of age.7,37 Symptoms tonia have impaired reciprocal inhibition on a supraspinal typically become generalized within 5 years,36 but may 30,31 basis. People with dystonia often have a paradoxical remain multifocal (10%), segmental (12%), or focal activation of a passively shortened muscle (the so-called (21%).37 Diagnosis is made by genetic testing for the 24 shortening reaction). Thus a variety of mechanisms disease causing GAG deletion in TOR1A. may contribute to the abnormal muscle activity seen in dystonia. What these mechanisms appear to have in Genetics and Pathophysiology common is an inability to inhibit unwanted reflex activ- The product of the TOR1A gene is torsinA. TorsinA is a ity in response to stretch.11 This view is supported by evi- member of a family of ATPases with a variety of cellular dence that focal dystonia can be decreased by blocking activities (AAA+), and bears substantial homology to γ-motor neuron drive to spindles with lidocaine.32 heat-shock proteins. TorsinA has been implicated in the regulation of the organization of nuclear envelope and endoplasmic reticulum compartments with respect Etiologies to the cytoskeleton,38,39 and also in the processing of The tremendous advance in molecular and genetic diag- proteins through the secretory pathway.8 To date, the only nostic tools has led to the diagnosis of specific etiolo- known disease-causing mutation in DYT1 dystonia is a gies of some disorders that were previously considered GAG deletion causing the loss of one of a pair of glutamic

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Table 10-2 Genetic Causes of Dystonia (DYT scheme)

Designation Dystonia Type Inheritance Gene Locus Protein DYT1 Early-onset generalized Autosomal 9q34 TorsinA torsion dystonia (dystonia dominant musculorum deformans, Oppenheim dystonia)

DYT2 Autosomal recessive torsion Autosomal Unknown Unknown dystonia recessive DYT3 Dystonia-parkinsonism X-linked Xq13.1 TATA-binding (“lubag”) recessive protein- associated factor-1 (TAF1)

DYT4 Non-DYT1 dystonia Autosomal Unknown Unknown (whispering dysphonia) dominant DYT5 Dopa-responsive dystonia Autosomal 14q22.1-2 GTP (DRD) dominant cyclohydrolase 1 DYT6 Adolescent-onset dystonia of Autosomal 8p21-22 THAP1 mixed type dominant DYT7 Adult-onset focal dystonia Autosomal 18p Unknown dominant

DYT8 Paroxysmal nonkinesigenic Autosomal 2q33-35 Myofibrillogenesis dyskinesia dominant regulator 1 DYT9 Paroxysmal choreoathetosis Autosomal 1p21 Unknown with episodic ataxia and dominant spasticity

DYT10 Paroxysmal kinesigenic Autosomal 16p-q Unknown dyskinesia dominant

DYT11 Myoclonus dystonia Autosomal 7q21 ε-Sarcoglycan dominant (maternal imprinting)

DYT12 Rapid-onset dystonia- Autosomal 19q Na+/K+ ATPase α3 parkinsonism dominant subunit DYT13 Multifocal/segmental Autosomal 1p Unknown dystonia dominant DYT15 Myoclonus dystonia Autosomal 18p Unknown dominant

DYT16 Early-onset dystonia- Autosomal 2q31.3 PRKRA parkinsonism recessive DYT17 Focal torsion dystonia Autosomal 20p11.22-q13.12 Unknown recessive

DYT18 Paroxysmal exertion-induced Autosomal 1p35-31.3 GLUT1 dystonia dominant DYT19 Paroxysmal kinesigenic Autosomal 16q13-q22.1 Unknown dyskinesia 2 dominant DYT20 Paroxysmal kinesigenic Autosomal 2q31 Unknown dyskinesia 2 dominant

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TABLE 10-3 Genetic Causes of Secondary increased in GAG deletion carriers who do not mani- Dystonia in Childhood fest dystonia and is decreased in GAG deletion carriers who do manifest dystonia compared to controls.42,43 Autosomal Autosomal Interestingly, the protective effect of the D216H poly- Recessive Dominant Mitochondrial morphism is only seen when present on the allele AADC deficiency DRPLA Leber disease without the GAG deletion (trans allele). Although Ataxia Hereditary Leigh the protective effect of the D216H polymorphism is telangiectasia spastic syndrome important, it only partially accounts for the incomplete Gangliosidoses paraparesis MERRF Glutaric aciduria with dystonia MELAS penetrance of the DYT1 mutation. Hartnup Huntington’s There are no consistent neuropathologic abnormal- disease disease ities in DYT1 dystonia. Although perinuclear inclu- Homocystinuria Spinocerebellar sions and other neurodegenerative changes have been Juvenile ataxias (SCAs) reported in some cases,44 this initial observation awaits Parkinson’s X-linked disease Dystonia- confirmation from other postmortem studies. TorsinA Metachromatic deafness is expressed in several brain regions, including the sub- leukodystrophy Lesch-Nyhan stantia nigra, striatum, hippocampus, and cerebellum.20 Methylmalonic Pelizaeus It is especially highly expressed in nigral dopamine neu- aciduria Merzbacher rons. TorsinA is expressed in neurons and not in glia.45 Niemann-Pick Rett syndrome type C In transgenic mouse models of DYT1 dystonia, there is PKAN evidence for impaired dopamine neurotranmission.46,47 (Hallervorden- There is also evidence for decreased inhibitory output Spatz) from the basal ganglia in transgenic mice.48 Decreased TH deficiency inhibitory basal ganglia output is consistent with models TPI deficiency 14,49,50 Tyrosinemia of human dystonia. Vitamin E Positron emission tomography (PET) studies of deficiency cerebral glucose metabolism have shown abnormal pat- Wilson’s terns in individuals with DYT1 dystonia.51 Although disease the DYT1 dystonia is only 30% to 40% penetrant, nonexpressing carriers of the deletion have abnormalities on PET imaging that are identical to expressing individuals.51 This suggests that the DYT1 mutation Box 10-1 nongenetic Causes of Secondary conveys a vulnerability to a “second hit” that deter- Dystonia mines whether dystonia manifests or not. An interest- Autoimmune ing rodent model of cranial dystonia suggests that mild Cerebral palsy striatal dopamine deficiency may be a permissive factor Drugs that allows a relatively modest weakening of the lid- Infection closing orbicularis muscle to produce bilateral forceful Kernicterus blinking of the eyelids resembling blepharospasm.52 Psychogenic Stroke Management and Treatment Toxins Trauma Management and treatment of DTY1 dystonia are discussed at the end of this chapter under general discussion of dystonia treatments. acids in the C-terminal region.35 Other rare mutations Other Early-Onset Primary Dystonias in TOR1A have been reported in individuals with dystonia, but a causal role has not been established.40,41 (DYT2; DYT4) The basis for the incomplete penetrance is not A recessive form of early-onset primary dystonia known, but one disease-modifying mutation has been (DYT2) has been postulated based on observation of identified. A single nucleotide polymorphism is pres- an apparent recessive inheritance pattern in several ent in the coding sequence for amino acid residue 216 families.53,54 However, some of the reported individ- in torsinA. In 88% of the population, this amino acid ual cases had atypical features and evidence for this is aspartic acid (D), but in 12% of the population it entity is considered weak.55 No reports of presumed is histidine (H). The frequency of the 216H allele is recessively inherited early-onset primary dystonia

[email protected] 66485438-66485457 102 Section 4 Hyperkinetic and Hypokinetic Movement Disorders have been published since identification of the DYT1 spastic paraparesis.65 Patients with DRD commonly gene. Thus it is unclear whether DYT2 is a true have brisk reflexes and spontaneously upgoing (striatal) specific entity.7 toes, but do not have true spasticity. An autosomal dominant form of early-onset dystonia has been described in a large Australian pedigree in Pathophysiology which linkage studies excluded the DYT1 locus.56 The GTP-cyclohydrolase-1 (GTPCH-1) is the initial, and age at onset of symptoms ranged from 13 to 37 years. rate-limiting, enzyme involved in the biosynthesis of

Most individuals developed dysphonia as the initial tetrahydrobiopterin (BH4) from guanidine triphos- 66 manifestation. This entity has also been referred to as phate (GTP). BH4 is a cofactor for tyrosine hydrox- “Australian whispering dysphonia.” As for DYT2, the ylase (TH), the rate-limiting enzyme in dopamine locus was proposed on clinical grounds and there is no synthesis. Deficiency of BH4 leads to decreased efficacy definitive evidence that DYT4 represents an identifi- of TH and thus to decreased production of dopamine, able genetic form of dystonia.7 but without loss of nigrostriatal dopamine terminals.67

BH4 is also a cofactor for phenylalanine hydroxy- Dopa-Responsive Dystonia (DYT5) lase (PAH) and tryptophan hydroxylase, but typical DRD does not have symptoms related to decreased Clinical Features and Natural History function of those enzymes. However, the decreased Dopa-responsive dystonia (DRD; Segawa disease) is function of PAH allows the use of a phenylalanine probably the most common form of inherited dysto- loading test for diagnostic evaluation of GTPCH-1 nia in childhood. DRD is a syndrome characterized by deficiency.68 However, the phenylalanine loading test childhood-onset progressive dystonia with sustained does not have high sensitivity.69 Cerebrospinal fluid dramatic response to low doses of l-dopa, without (CSF) can be tested for levels of tetrahydrobiopterin, development of complications related to long-term neopterin, and metabolites of catecholamines and treatment.57,58 DRD was first described by Segawa as indolamines.70,71 Genetic testing for GCH1 mutations progressive dystonia with diurnal fluctuations.59 It typ- is cumbersome because a large number of mutations ically manifests with gait disturbance from foot dysto- have been described and thus the entire gene must be nia with the age of onset ranging from 1 to 12 years. sequenced,72 and some families with autosomal domi- If untreated, there is development of diurnal fluctua- nant DRD do not have mutations in the coding region tion with worsening of symptoms toward the end of of the GCH1 gene.73 the day and marked improvement in the morning. DRD caused by TH deficiency is less common In late adolescence or early adulthood, parkinsonian than DRD caused by GTPCH-1 deficiency. There features can develop if DRD remains untreated. Even are a few clinical differences that may help distin- if treatment is instituted late in the course, all features guish TH deficiency from GTPCH-1 deficiency, but typically improve with low-dose levodopa.60 these are neither sensitive nor specific. Parkinsonism There are two major forms of DRD. The autosomal may be more common early in the course with TH dominant form of this disease is associated with a defi- deficiency. Patients with TH deficiency may also have ciency of GTP cyclohydrolase, an enzyme required for signs of norepinephrine deficiency, but this is uncom- biosynthesis of tetrahydrobiopterin, which is a cofactor mon.61,70 DRD caused by TH deficiency can be dis- for tyrosine hydroxylase, the rate-limiting enzyme for tinguished from GTPCH-1 deficiency by measuring dopamine production.17 The autosomal recessive form CSF catecholamines, catecholamine metabolites, and is usually caused by a defect in tyrosine hydroxylase.61 pterins.70,71 However, a rare autosomal recessive form of GTP cyclohydrolase deficiency with a severe phenotype has Management and Treatment also been reported.62 Carbidopa/levodopa is the mainstay of treatment in There can be significant phenotypic variability in the DRD and may be diagnostic if there is complete relief of presentation of DRD. As noted, the typical presenta- symptoms. A starting dose is 1 mg/kg/day of levodopa, tion is onset of dystonia in childhood, usually affecting which can be increased gradually until there is complete gait first, diurnal fluctuation, subsequent development benefit or dose-limiting side effects. Most individuals of parkinsonism, and a dramatic response to levodopa. respond to 4 to 5 mg/kg/day in divided doses, but some However, in some children there is hypotonia in infancy authors have suggested doses up to 10 mg/kg/day. If and delayed attainment of motor developmental mile- there is no response to a dose of 600 mg/day, it is highly stones,63,64 and DRD can be misdiagnosed as cerebral unlikely that DRD is the correct diagnosis. Carbidopa/ palsy. DRD has also been reported to manifest as familial levodopa should be given as 25/100 mg tablets.

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They can be crushed and dissolved in an ascorbic acid a novel mechanism resulting in dystonia. Specific solution or in orange juice and used within 24 hours. treatment for DYT6 dystonia has not been reported. The 10/100 tablets contain insufficient carbidopa to prevent nausea in most patients and should be avoided. Myoclonus Dystonia Syndrome (DYT11) The most common side effects are somnolence, nausea Clinical Features and Natural History and vomiting, decreased appetite, dyskinesia, and Myoclonus dystonia syndrome (MDS) is an autosomal hallucinations. Nausea and vomiting can be reduced by dominant disorder characterized by myoclonus, dys- giving additional carbidopa, available in 25 mg tablets. tonia, or both.76,77 Onset is typically in childhood or Dyskinesia may occur on initiation of treatment or in early adolescence, with a mean onset age of 5 years.78 older individuals who are treated with relatively higher Myoclonus is usually the initial symptom, but dys- doses of levodopa. Dyskinesia can be reduced or elimi- tonia is the first symptom in about 20% of cases.78 nated by reducing the dose of levodopa. If dyskinesia is In rare cases, there is a history of neonatal hypoto- present with the initiation of treatment, reduce the dose. If nia. Myoclonus is usually more severe than the main there is inadequate benefit at the lower dose, it can usually feature and may be the only manifestation in some be increased again slowly without recurrence of dyski- affected individuals.77 The neck and upper limbs are nesia. Motor complications of levodopa therapy that usually more involved than legs and gait. The myo- are seen in Parkinson’s disease do not occur in DRD. clonus often improves with ingestions of ethanol.76,78 In unusual cases of DRD, levodopa is not tolerated. The dystonia is often mild and usually involves the In those cases, trihexyphenidyl is a reasonable alterna- neck or arms. Alcohol abuse and psychiatric symptoms tive. The dosing of trihexyphenidyl for treatment of (obsessive-compulsive disorders, panic attacks) are DRD is not well established. Starting dose should be common among patients with MDS.79 0.5 mg/day in children less than 4 years old and 1 mg/ The rate of progression and severity are highly vari- day in older children. The dose should be increased by able, ranging from mild nonprogressive symptoms to 1 mg every 3 to 7 days in a three-times-daily schedule marked disability in adolescence or early adulthood. until benefit or side effects. In DRD, there is benefit The course of the myoclonus and the dystonia are from relatively low doses compared to those used to often independent. Worsening of myoclonus is not treat other forms of dystonia. Trihexyphenidyl should necessarily accompanied by worsening of dystonia.80 be considered as second-line treatment in DRD because There may be spontaneous improvement of myoclo- it does not reverse the biochemical defect of decreased nus80 or of dystonia.78 Dystonia may resolve completely dopamine synthesis in DRD. Side effects are uncom- in approximately 20% of patients. mon at low doses. Diagnostic criteria for MDS have been proposed.81 In cases of DRD caused by TH deficiency, treatment Criteria for definite MDS include the following: response is often incomplete. In some cases augmentation (1) onset before 20 years of age; (2) myoclonus predomi of l-dopa therapy with a Catechol-O-Methyl Transferase nating in the upper body, either isolated or associated (COMT) inhibitor (entacapone) or monoamine oxidase with dystonia; (3) positive family history with paternal B (MAO-B) (seligiline) inhibitor may be helpful. transmission (paternal transmission is applicable only Adolescent-Onset Mixed-Type for MDS caused by SGCE mutation or deletion—see Dystonia (DYT6) later discussion); (4) exclusion of additional neurologic features, such as cerebellar ataxia, spasticity, and This form of autosomal dominant dystonia was identi- dementia; and (5) normal brain magnetic resonance fied in two large Mennonite families with 15 affected imaging (MRI). Additional suggestive features include 74 individuals. The average age of onset was 19 years, with the following: (1) short myoclonic bursts on EMG onset as young as age 5 years. Some affected individu- (25 to 250 ms) without cortical premyoclonic poten- als had a phenotype indistinguishable from the typical tial, negative C-reflex response, and lack of giant soma- DYT1 phenotype, but approximately 50% of patients tosensory evoked potentials; (2) spontaneous remission had onset in cervical or cranial musculature. Those who of limb dystonia during childhood or adolescence; and started with limb involvement later developed cervical (3) alcohol responsiveness. or cranial symptoms. As noted, cranial involvement is uncommon in DYT1. The gene for DYT6 has been Pathophysiology identified recently.75 Mutations in the THAP1 gene The commonest genetic cause of MDS is mutation of were identified in three Amish-Mennonite families and the SGCE gene, which encodes ε-sarcoglycan protein.81 in a non-Mennonite German family. THAP1 is thought SGCE mutations account for approximately 40% of to have a DNA-binding function, which represents cases of MDS. ε-Sarcoglycan is expressed predominantly

[email protected] 66485438-66485457 104 Section 4 Hyperkinetic and Hypokinetic Movement Disorders in the brain, and is related to the sarcoglycans that are rostrocaudal (face → arm → leg) gradient of involve- mutated in limb girdle muscular dystrophies.82 Most ment; and (3) prominent bulbar findings.89 patients with MDS caused by SGCE mutations inherit RDP is caused by mutations in the Na+/K+-ATPase the disorder from the father. It has been suggested that α3 subunit (ATP1A3 gene).90 The α3 subunit is only this is due to inactivation of the maternal SGCE allele expressed in the brain and heart, perhaps indicating a (“genomic imprinting”), probably by methylation.82 role in electrical excitability. It has been suggested that ε-Sarcoglycan is highly expressed during brain devel- the reported mutations in RDP impair enzyme activ- opment and is highly expressed in dopamine neurons ity or stability.8 in adults.8 SGCE knock-out mice exhibit myoclonus, Patients with RDP do not respond consistently to impaired motor skills, and anxiety-like behaviors. These the usual symptomatic treatments for dystonia, includ- mice have abnormally increased striatal dopamine and ing l-dopa.89 dopamine metabolites.83 Another genetic locus for inherited myoclonus- Early-Onset Multifocal/Segmental dystonia has been identified on chromosome 18p11 Dystonia (DYT13) 84 and listed as DYT15. This was defined in a large This form of dystonia was described in a large Italian Canadian family with 13 affected individuals. The family with early onset of multifocal or segmental dys- inheritance pattern was autosomal dominant and the tonia.91 The average age of onset is 16 years (range 5 to phenotype was similar to what is seen in MDS with 40 years). The upper body is most commonly affected, SGCE mutations. usually involving cranial musculature. Generalization Management and Treatment is uncommon. DYT13 has been linked to chromo- 92 Treatment for MDS is symptomatic and benefit is usually some 1p, but no gene has been identified. incomplete. There are many reports of trials of various Early-Onset Dystonia-Parkinsonism medications.81 Some benefit from anticholinergic medi- (DYT16) cations; clonazepam, sodium oxybate, valproate, levetiracetam, L-5-hydroxytryptophan, and l-dopa have been This entity was initially described in three Brazilian reported.81,85 Botulinum toxin can be used to treat focal families93 and was subsequently reported in a German dystonia in MDS. Deep brain stimulation of the internal boy.94 Affected individuals had a mean onset age of globus pallidus has been reported to provide greater than 9 years (range 2 to 18 years). In most patients, onset 50% improvement of both myoclonus and dystonia in is in a limb with subsequent generalization, although adults with MDS.86,87 Deep brain stimulation has not one patient had onset in cranial musculature.93 Several been reported in children or adolescents with MDS. affected individuals had parkinsonism, pyramidal tract signs, or both. DYT16 is associated with a mutation in Rapid-Onset Dystonia-Parkinsonism the PRKRA gene, which encodes an interferon-induc- (DYT12) ible double-stranded RNA-activator of protein kinase Rapid-onset dystonia-parkinsonism (RDP) is an PKR. This protein is thought to be involved in signal autsomal dominant disorder with variable penetrance transduction, cell differentiation, and apoptosis.7 Little that is characterized by rapid onset of dystonia and paris known of this recently described entity. There have kinsonism.88 RDP typically manifests with abrupt onset been no reports of treatment response for DYT16. and rapid progression over hours to weeks, followed by Secondary Dystonias little further progression.88,89 Onset is usually dramatic and consists of bulbar and limb dystonia with variable There is a long list of secondary dystonias, both features of parkinsonism.89 Occasional vague symptoms with genetic (see Table 10-3) and nongenetic (see preceding the more dramatic onset were reported in Box 10-1) etiologies. Most of the genetic etiologies several patients. Age of onset ranges from 8 to 55 years, are discussed with metabolic diseases causing move- but is before 20 years of age in 47% and between 20 ment disorders in Chapter 15. The great majority and 30 years of age in another 39%. Bulbar symptoms of these diseases have a variety of neurologic signs are typically worse than appendicular symptoms. and symptoms in addition to dystonia. However, Parkinsonism is less prominent than dystonia and usually in a few diseases dystonia can be the presenting fea- consists of bradykinesia, postural instability, and hypo- ture. These include glutaric aciduria, juvenile phonia. Proposed diagnostic criteria consist of the parkinsonism (see Chapter 11), Wilson’s disease, following: (1) abrupt onset of dystonia with features and pantothenate kinase–associated neurodegenera- of parkinsonism over a few minutes to 30 days; (2) tion (PKAN).

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Of nongenetic etiologies, cerebral palsy is the genetic testing may be warranted depending on the most common cause of dystonia. This is discussed in presentation. See earlier in this chapter and Chapter 4 Chapter 17. Other important nongenetic etiologies for specific descriptions of typical manifestations. include drug ingestion (see Chapter 18) and conver- Because of the large number of entities that can cause sion disorder (psychogenic) (see Chapter 19). Stroke is dystonia in childhood, a tiered approach to diagnostic an uncommon cause of dystonia in children, but can testing is advisable, with frequent reevaluation of the manifest with pure dystonia. Dystonia caused by stroke child to assess for progression and development of new usually affects limbs in a “hemi” distribution. The syn- signs or symptoms. drome of hemidystonia-hemiparkinsonism often starts as hemiparesis in the perinatal period or during child- Management and Treatment hood.95 The most common locations of stroke resulting The management of dystonia is unsatisfying in many in dystonia are the putamen, globus pallidus, and cases. Treatment for most forms of dystonia is symp- thalamus.9,10 tomatic and benefit may be incomplete or accompanied by intolerable side effects. The treatment Dystonic Storm (Status Dystonicus) approach is largely the same regardless of etiology. Few This rare complication of dystonia deserves special controlled trials have been performed, and most trials mention. Dystonic storm is a life-threatening com- have included a heterogeneous sample of children with plication of severe dystonia. This is characterized by dystonia from a variety of causes. relentless, sustained, severe dystonic muscle contrac- Carbidopa/Levodopa As discussed earlier in detail tions.96 Etiologies vary, but can include DYT1 dys- for dopa-responsive dystonia, carbidopa/levodopa is tonia,97 medication withdrawal in a variety of forms the mainstay of treatment in DRD. However, other of dystonia,96 PKAN,98 and baclofen pump failure.99 forms of dystonia may respond partially to levodopa. Prompt diagnosis of this condition is essential. Patients Because of its potential for benefit and because with dystonic storm should be managed in an intensive complete response to levodopa can be diagnostic for care unit. They may develop hyperthermia, metabolic DRD, a trial of carbidopa/levodopa is recommended derangements, and rhabdomyolysis with acute renal for all children with dystonia unless there is a family failure. Treatment with intravenous benzodiazepines history of non-DRD dystonia. 98,100 or general anesthetic agents may be required. Trihexyphenidyl Anticholinergic medications are the In extreme intractable cases, intrathecal baclofen or most consistently effective in treatment of primary even deep brain stimulation of the internal globus dystonia,103 although the most dramatic reported 98,101 pallidus may be required. responses may have come from patients with DRD.104 Diagnostic Approach Most available data and experiences are with trihexy General diagnostic considerations are discussed in phenidyl. Children typically tolerate higher doses Chapter 4. However, there are some specific consid- than do adults and may find maximum benefit with doses of 60 mg/day or more. To avoid side effects, erations for dystonia. Specific diagnostic criteria are trihexyphenidyl should be started at 1 mg/day at provided earlier in this chapter for specific genetic bedtime and increased by 1 mg each week until the etiologies of dystonia where they exist. As in all move- desired benefit is obtained or side effects develop. ment disorders, it is of utmost importance to see the The usual maintenance dose varies from 6 mg/day to abnormal movements and to evaluate the patient over 60 mg/day divided three times per day. The most performing a variety of activities. Distribution of common side effects of trihexyphenidyl are sedation, affected body parts, task dependence, and presence dry mouth, decreased concentration and memory, or absence of coexisting neurologic signs and symp- constipation, and blurred vision. Chorea can develop toms are all factors that can help tailor the diagnos- with high doses. Sudden cessation should be avoided tic approach. For most children with dystonia, MRI because it can precipitate mental status changes and/ of the brain is indicated to rule out structural causes or severe dyskinesias. and to look for disease-specific findings. In children with limb-onset dystonia between age 5 years and Baclofen Baclofen is somewhat less effective than adulthood, genetic testing for DYT1 should be per- trihexyphenidyl in most children, but can be helpful formed. A therapeutic (and possibly diagnostic) trial in diminishing pain caused by dystonia. It can of levodopa is warranted in all children with dysto- provide additional benefit when used in combination nia, especially those that begin with leg involvement with trihexyphenidyl. A typical starting dose is 5 mg in the first decade of life. Additional metabolic and at bedtime. The dose should be increased slowly

[email protected] 66485438-66485457 106 Section 4 Hyperkinetic and Hypokinetic Movement Disorders until desired benefit or side effects occur. The usual Physical and occupational therapy can be helpful maintenance dose is 10 to 60 mg/day in three divided in maximizing the function of individuals with pri- doses, but some older children obtain maximum mary generalized dystonia.102 Bracing may be helpful benefit at doses as high as 180 mg/day. The most in some cases. common side effect is sedation. Sudden cessation can precipitate seizures or psychosis and should be Patient and Family Resources avoided. The Dystonia Medical Research Foundation (www. In patients with good benefit from oral baclofen, dystonia-foundation.org) is a voluntary health orga- but who cannot tolerate the effective dose because of nization that provides education and support for side effects, intrathecal baclofen may be an option. Few individuals and families with dystonia. It also funds data are available on the use of intrathecal baclofen in research on dystonia and advocates for development of primary dystonia, and the use of this therapy in pri- new treatments. mary dystonia is controversial.105,106 Botulinum Toxin Botulinum toxin injections are highly effective in focal and segmental dystonias REFERENCES because of the limited number of muscles involved. It 1. Fahn S: Concept and classification of dystonia, Adv plays a smaller role in treatment of generalized dysto- Neurol 50:1–8, 1988. nia because of the large number of involved muscles. 2. Oppenheim H: Uber eine eigenartige Krampfkrankheit However, it can be quite helpful in reducing symp- des kindlichen und jugendlichen Alters (Dysbasia lor- toms when isolated problematic muscle groups are dotica progressiva, Dystonia musculorum deformans), targeted.107,108 Neurol Centrabl 30:1090–1107, 1911. Other Medications Several other medications may be 3. Wilson SAK: Modern problems in neurology, London, 1928, Arnold. effective in a minority of children with primary dysto- 102 4. Denny-Brown D: The basal ganglia and their relation to nia. These include clonazepam, carbamazepine, dop- disorders of movement, London, 1962, Oxford University amine antagonists, and dopamine depletors. Press. 5. Hartmann A, Pogarell O, Oertel W: Secondary dysto- Nonpharmacologic Treatment nias, J Neurol 245:511–518, 1998. Promising neurosurgical treatments of dystonia include 6. Bressman SB: Dystonia genotypes, phenotypes, and clas- thalamotomy, pallidotomy, and deep brain stimula- sification, Adv Neurol 94:101–107, 2004. tion (DBS) of the globus pallidus pars interna.109–112 7. Zorzi G, Zibordi F, Garavaglia B, Nardocci N: Early onset Thalamotomy was the most frequently performed abla- primary dystonia, Eur J Paediatr Neurol EPUB, 2009. tive procedure in the past. However, when performed 8. Breakefield XO, Blood AJ, Li Y, et al: The pathophysi- bilaterally, there is a high incidence of dysarthria and ological basis of dystonias, Nat Rev Neurosci 9:222–234, dysphagia. The benefits of thalamotomy are highly 2008. 9. Bhatia KP, Marsden CD: The behavioural and motor variable. More recently, pallidotomy has been preferred consequences of focal lesions of the basal ganglia in man, to thalamotomy because of the lower morbidity. Direct Brain 117:859–876, 1994. comparison has not been performed, but data suggest 10. Marsden CD, Obeso JA, Zarranz JJ, Lang AE: The that pallidotomy is more effective than thalomot-omy anatomical basis of symptomatic hemidystonia, Brain in DYT1 dystonia. However, the benefits may be tem- 108:463–483, 1985. porary. Thalamotomy may be more effective for sec- 11. Mink JW: The basal ganglia: focused selection and inhi- ondary dystonia. bition of competing motor programs, Prog Neurobiol Most recently, pallidal DBS has been used to treat 50:381–425, 1996. primary dystonia with promising results.109 The effects 12. Perlmutter JS, Tempel LW, Black KJ, et al: MPTP induces of DBS are similar to those of pallidotomy, but DBS is dystonia and parkinsonism. Clues to the pathophysiol- programmable and does not involve a destructive lesion. ogy of dystonia, Neurology 49:1432–1438, 1997. 13. Tabbal SD, Mink JW, Antenor JA, et al: 1-Methyl-4- However, experience in children is limited. The long- phenyl-1,2,3,6-tetrahydropyridine-induced acute tran- term effects of pallidal DBS on dystonia are not yet sient dystonia in monkeys associated with low striatal known. Experience with DBS for secondary dystonia is dopamine, Neuroscience 141:1281–1287, 2006. limited. Although there are reports of benefit in some 14. Berardelli A, Rothwell JC, Hallett M, et al: The disorders,113 one cannot generalize from these to other pathophysiology of primary dystonia, Brain 121:1195– forms of dystonia. 1212, 1998.

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Asmus F, Salih F, Hjermind LE, et al: Myoclonus- tion of dopa-responsive dystonia: generalized hypotonia dystonia due to genomic deletions in the epsilon-sarco- and proximal weakness, Neurology 57:1121–1124, 2001. glycan gene, Ann Neurol 58:792–797, 2005. 65. Furukawa Y, Graf W, Wong H, et al: Dopa-responsive 83. Yokoi F, Dang MT, Li J, Li Y: Myoclonus, motor def- dystonia simulating spastic paraplegia due to tyrosine icits, alterations in emotional responses and monoam- hydroxylase (TH) gene mutations, Neurology 56:260– ine metabolism in epsilon-sarcoglycan deficient mice, 263, 2001. J Biochem 140:141–146, 2006. 66. Furukawa Y, Mizuno Y, Narabayashi H: Early- 84. Grimes DA, Han F, Lang AE, et al: A novel locus for onset parkinsonism with dystonia. Clinical and bio- inherited myoclonus-dystonia on 18p11, Neurology chemical differences from hereditary progressive 59:1183–1186, 2002.

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85. Luciano MS, Ozelius L, Sims K, et al: Responsiveness 99. Alden TD, Lytle RA, Park TS, et al: Intrathecal baclofen to levodopa in epsilon-sarcoglycan deletions, Mov withdrawal: a case report and review of the literature, Disord 24:425–428, 2009. Childs Nerv Syst 18:522–525, 2002. 86. Liu X, Griffin IC, Parkin SG, et al: Involvement of the 100. Manji H, Howard RS, Miller DH, et al: Status dys- medial pallidum in focal myoclonic dystonia: a clinical tonicus: the syndrome and its management, Brain and neurophysiological case study, Mov Disord 17:346– 121:243–252, 1998. 353, 2002. 101. Zorzi G, Marras C, Nardocci N, et al: Stimulation of 87. Magarinos-Ascone CM, Regidor I, Martinez-Castrillo the globus pallidus internus for childhood-onset dysto- JC, et al: Pallidal stimulation relieves myoclonus-dys- nia, Mov Disord 20:1194–1200, 2005. tonia syndrome, J Neurol Neurosurg Psychiatry 76:989– 102. Jankovic J: Treatment of dystonia, Lancet Neurol 5:864– 991, 2005. 872, 2006. 88. Dobyns WB, Ozelius LJ, Kramer PL, et al: Rapid-onset 103. Fahn S: High dosage anticholinergic therapy in dysto- dystonia-parkinsonism, Neurology 43:2596–2602, 1993. nia, Neurology 33:1255–1261, 1983. 89. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al: 104. Jarman P, Bandmann O, Marsden C, Wood N: GTP The phenotypic spectrum of rapid-onset dystonia-par- cyclohydrolase I mutations in patients with dystonia kinsonism (RDP) and mutations in the ATP1A3 gene, responsive to antcholinergic drugs, J Neurol Neurosurg Brain 130:828–835, 2007. Psychiatry 63:304–308, 1997. 90. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al: 105. Hou JG, Ondo W, Jankovic J: Intrathecal baclofen for Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 dystonia, Mov Disord 16:1201–1202, 2001. are associated with rapid-onset dystonia parkinsonism, 106. Walker RH, Danisi FO, Swope DM, et al: Intrathecal Neuron 43:169–175, 2004. baclofen for dystonia: benefits and complications dur- 91. Bentivoglio AR, Del Grosso N, Albanese A, et al: ing six years of experience, Mov Disord 15:1242–1247, Non-DYT1 dystonia in a large Italian family, J Neurol 2000. Neurosurg Psychiatry 62:357–360, 1997. 107. Burlina AP, Zara G, Hoffmann GF, et al: Management 92. Valente EM, Bentivoglio AR, Cassetta E, et al: DYT13, of movement disorders in glutaryl-CoA dehydrogenase a novel primary torsion dystonia locus, maps to chromo- deficiency: anticholinergic drugs and botulinum toxin some 1p36.13-36.32 in an Italian family with cranial- as additional therapeutic options, J Inherit Metab Dis cervical or upper limb onset, Ann Neurol 49:362–366, 27:911–915, 2004. 2001. 108. Sanger TD, Kukke SN, Sherman-Levine S: Botulinum 93. Camargos S, Scholz S, Simon-Sanchez J, et al: DYT16, toxin type B improves the speed of reaching in chil- a novel young-onset dystonia-parkinsonism disorder: dren with cerebral palsy and arm dystonia: an open- identification of a segregating mutation in the stress- label, dose-escalation pilot study, J Child Neurol response protein PRKRA, Lancet Neurol 7:207–215, 22:116–122, 2007. 2008. 109. Kupsch A, Benecke R, Muller J, et al: Pallidal 94. Seibler P, Djarmati A, Langpap B, et al: A heterozygous deep-brain stimulation in primary generalized or frameshift mutation in PRKRA (DYT16) associated segmental dystonia, N Engl J Med 355:1978–1990, with generalised dystonia in a German patient, Lancet 2006. Neurol 7:380–381, 2008. 110. Lozano AM, Kumar R, Gross RE, et al: Globus palli- 95. Wijemanne S, Jankovic J: Hemidystonia-hemiatrophy dus internus pallidotomy for generalized dystonia, Mov syndrome, Mov Disord 24:583–589,2009. Disord 12:865–870, 1997. 96. Manji H, Howard RS, Miller DH, et al: Status dystonicus: 111. Vidailhet M, Vercueil L, Houeto JL, et al: Bilateral the syndrome and its management,Brain 121(pt 2): deep-brain stimulation of the globus pallidus in 243–252, 1998. primary generalized dystonia, N Engl J Med 352:459– 97. Opal P, Tintner R, Jankovic J, et al: Intrafamilial phenotypic 467, 2005. variability of the DYT1 dystonia: from asymptomatic 112. Vitek JL, Zhang J, Evatt M, et al: GPi pallidotomy for TOR1A gene carrier status to dystonic storm, Mov dystonia: clinical outcome and neuronal activity, Adv Disord 17:339–345, 2002. Neurol 78:211–219, 1998. 98. Mariotti P, Fasano A, Contarino MF, et al: Management 113. Castelnau P, Cif L, Valente EM, et al: Pallidal stimula- of status dystonicus: our experience and review of the tion improves pantothenate kinase-associated neurode- literature, Mov Disord 22:963–968, 2007. generation, Ann Neurol 57:738–741, 2005.

[email protected] 66485438-66485457 11 Myoclonus O Introduction and Overview multi-focal, or generalized. Visually, this contraction appears to be lightning quick. Electromyography Myoclonus, like weakness, may result from pathology shows that individual myoclonic jerks usually last 10 in the cerebral cortex, subcortical regions, spinal cord, to 50 milliseconds. The relationship of the jerk to rest, and sometimes peripheral nerves. Both idiopathic disor- voluntary movement, and external triggers is diagnosti- ders and symptomatic conditions can cause myoclonus. cally important, as is neuroanatomic and body location. In children, myoclonus most commonly manifests with Myoclonus may recur or spread to neighboring muscles epilepsy, encephalopathy, or other symptoms. Isolated in predictable or unpredictable ways. Axial myoclonus myoclonus is not a common chief complaint in chil- indicates involvement of the trunk. Multifocal myoclo- dren treated by pediatric neurologists or movement dis- nus refers to randomly appearing jerks in multiple loca- order specialists. Thus clinicians may use the presence of tions. Generalized myoclonus refers to jerking in many myoclonus as one of several key factors in diagnostic and muscles simultaneously. Spontaneous and action denote Otherapeutic decision making. This chapter encompasses the state of the muscle at myoclonus onset, and reflex diseases and disorders resulting in clinical syndromes indicates a preceding sensory input acting as a trigger. that include prominent myoclonus. Repetitive, rhythmic myoclonus is termed by some myoclonic tremor. Myoclonic tremor involves oscillation, Definition of Myoclonus but unlike typical tremor, the alternating movements are fast and then slow. As a result, some movement Myoclonus refers to quick, shock-like movements of disorder experts disagree with using the term tremor one or more muscles. The term is usually applied to to describe the phenomenology. Unilateral rhythmic describe positive myoclonus: sudden, quick, involuntary myoclonus generated by cerebral cortex may be epilep- muscle jerks caused by muscle contraction. In contrast, sia partialis continua. negative myoclonus refers to a sudden, brief interruption of contraction in active postural muscles.1 Asterixis is a form of negative myoclonus. Both negative myoclonus and positive myoclonus occur in children, but throughout the chapter, myoclonus will mainly refer to positive TABLE 11-1 Clinical Features of Myoclonus 2 myoclonus. Startle syndromes will also be discussed. Clinical Features Types Startles are brief, generalized motor responses similar to myoclonus. Muscle action Contraction—positive myoclonus Relaxation—negative Clinical Characteristics— myoclonus Phenomenology of Myoclonus State At rest—spontaneous in Children myoclonus Active—action myoclonus, As with other movement disorders, various forms of postural myoclonus categorization of myoclonus are useful in describ- Stimulated—reflex myoclonus ing the phenomenology and facilitating diagnosis. Location Focal Levels of categorization in wide use are based on clini- Axial 3 cal features, neuroanatomy, and etiology. Table 11-1 Multifocal emphasizes observable clinical characteristics used in Generalized describing forms of myoclonus. Timing Irregular Myoclonus involves synchronous co-contraction of Rhythmic agonist and antagonist muscles which may be focal, 110 [email protected] 66485438-66485457 Chapter 11 Myoclonus 111

Clinical Differentiation of Myoclonus clinically without further diagnostic testing, based on from Other Movement Disorders the key distinguishing features described in Table 11-2. Myoclonus can resemble or co-occur with other move- Localization and Pathophysiology ment disorders, and the distinction can be clinically challenging. The overlap of slow and fast movements The list of the anatomic localizations for myoclonus in mixed movement disorders requires careful, detailed reads like the table of contents of a neuroanatomy text- clinical assessment. Even expert clinicians may be chal- book, and the list of etiologies like that of a clinical lenged, as has been shown for diagnosis of myoclonus- neurology textbook index. Myoclonus can emanate O dystonia versus benign hereditary chorea,4 although from many pathologic derangements in many neuroan- benign hereditary chorea may have infantile onset with atomic locations. Anatomic sources of myoclonus and a more stable course.5 types of observed myoclonus are shown in Table 11-3. involves involuntary, sustained contractions Dystonia Neurophysiology of Myoclonus leading to abnormal posturing. When a dystonic contraction is quick, visual differentiation from myoclonus or By comparison to other movement disorders, myoclo- tics may be difficult. Both symptoms may occur together, nus probably results from a relatively simpler process. as in myoclonus-dystonia. The presence of other more The pathophysiology of myoclonus involves a brief dis- sustained dystonic posturing, irregular dystonic tremor, charge of neurons transmitted, inappropriately, out to or sensory motor tricks may be clues that the movement the body, resulting in brief muscle twitches. Thus, for in question is dystonic rather than myoclonic. example, some pathologic processes that disturb the Chorea involves involuntary, irregular, flowing move- balance of excitation and inhibition within the motor ments. Quick choreic or ballistic movements may also cortex can produce brief abnormal discharges that are be difficult to distinguish from multifocal myoclonus. propagated to muscles, producing myoclonus. A corti- Titubation, truncal ataxia, and limb ataxia may also cal source of the myoclonus can sometimes be recorded result in rapid movements that resemble multifocal using scalp electroencephalography (EEG). The small myoclonus. amplitude of these abnormal discharges means that the Tics, the most common pediatric movement disor- signal does not reliably exceed the background recorded der, resemble myoclonus when the tic movements are electrical activity. Simultaneous electromyography very quick and involve a small number of muscle groups. (EMG) recording of muscle where myoclonus is present It is usually possible to distinguish these movements demonstrates the burst of less than 50 ms duration

TABLE 11-2 Clinical Features of Myoclonus versus Tics vs Chorea Clinical Features Myoclonus Tics Chorea Subjective sense of volition Involuntary Involuntary or Voluntary - may Involuntary be suppressed or postponed but some tics are performed in response to premonitory urges

Relationship to voluntary May occur at onset Rarely occur during purposeful Movement or attempted movement or during purposeful movements; voluntary movement may movements of same movements of same muscles exacerbate muscles usually override tics

Suppressibility Not suppressible Often, at least briefly, Not generally suppressible, leading to suppressible, but increasing urge to perform may be masked by the tic parakinesias, see chapter 9

Premonitory urge None Often present None Co-occurring problems Epilepsy, encephalopathy, Anxiety, obsessive-compulsive Other movement other movement disorder, attention-deficit/ disorders, psychiatric disorders hyperactivity disorder symptoms Age of onset Any Usually between 3 and 10 years Usually after age 1 year

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TABLE 11-3 Type of Myoclonus and in which myoclonus may occur in children appears in Neuroanatomic Location Table 11-6 at the end of this section. Neuroanatomic Substrate Type of Myoclonus Diseases and Disorders Cerebral cortex Focal Physiologic Myoclonus—Myoclonus in Multifocal Certain Settings, in Otherwise Healthy Generalized Reflex/stimulus sensitive Individuals

Thalamus, basal ganglia Focal Physiologic and Benign Forms of Myoclonus Generalized Clinical Features Reflex A common concern for parents is myoclonus related to Brainstem Reticular, generalized their child’s sleep. Myoclonus at sleep onset is usually a Startle, hyperekplexia single, full-body jerk, also known as hypnagogic myoclo- Palatal, myoclonic tremor nus. Myoclonus during sleep is focal or multifocal and Spinal Segmental often occurs during rapid eye movement (REM) sleep. Propriospinal, axial Myoclonus related to sleep, including benign neonatal Peripheral Focal sleep myoclonus, is covered in detail in Chapter 16. In general, these forms of myoclonus do not require Unknown Ballistic movement diagnostic evaluation or treatment. overflow Other forms of physiologic myoclonus include hiccups and exercise- or anxiety-induced myoclonus. electrical activity during the jerk. The relationship Anxiety-induced myoclonus is probably an exaggerated between the premotor EEG discharges and EMG startle response. bursts can be assessed by superimposing and averaging Pathophysiology repeated EEG/EMG tracings to increase the EEG sig- The pathophysiology is unknown. nal-to-noise ratio, bringing out the premotor potential. This method is referred to as back-averaging.6 Diagnostic Approach Back-averaging is a noninvasive method that has been The diagnostic approach is based on history. Brief star- useful in understanding cortical myoclonus. Limitations tles occurring while the child is falling asleep can be of neurophysiology for understanding the pathophysiol- diagnosed clinically, for example. In general, no diag- ogy of myoclonus include lack of specificity, lack of infor- nostic testing or treatment is needed. mation about cellular pathology underlying the cortical Startle Syndromes discharge, and lack of availability in many clinics. In addition, this method is not always sensitive for cortical sources A startle response to an unexpected stimulus is physi- of myoclonus and cannot be used for deeper sources. ologic and adaptive. The startle response to auditory Other neurophysiologic techniques can provide clues stimuli appears in the orbicularis oculi and sterno- about the pathophysiology of myoclonus. For example, cleidomastoid first,19 and usually habituates rapidly. cortical myoclonus may be associated with abnormally The neural substrate of the startle response is in the large amplitude somatosensory evoked potentials6,7 or caudal brainstem. A startle syndrome involves an abnormal changes in motor cortex excitability measured using tendency to exhibit startle reflexes—quick, involuntary transcranial magnetic stimulation over motor cortex.8 jerks in response to a surprising stimulus. Although the Further information about the pathophysiology of duration of a startle response is not as quick as that of myoclonus is available through laboratory, radiologic, myoclonus, many authors include discussions of startle and clinical-pathologic correlations in the case of indi- syndromes in reviews of forms of myoclonus. vidual diseases. In addition to anatomic localization, it Hereditary Hyperekplexias is helpful to consider etiological categories, as shown in Table 11-4, to develop a differential diagnosis for Clinical Features myoclonus. This section is organized into etiological Hyperekplexias may be considered a form of nonepilep- categories and reviews some of the more common or tic, stimulus-induced myoclonus, or disorders of exag- important diseases causing myoclonus in children. gerated startle responses. Tactile, auditory, visual, and The emphasis is on conditions where myoclonus is emotional stimuli provoke an excessive response. The prominent. A more comprehensive table of diseases phenomenology involves head flexion and extension

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Table 11-4 Categories of Disease Producing Myoclonus Etiological Category Clinical Features Physiologic Myoclonus occurs in certain settings in healthy persons. Examples include sleep (hypnic) jerks, hiccoughs, and benign infantile myoclonus with feeding.9 Benign, developmental Myoclonus as a transient symptom during otherwise normal development. Examples include benign neonatal myoclonus and myoclonus of early infancy. See chapter 5.

Startle syndromes Quick, involuntary, stimulus-evoked reflex movements. An exaggerated startle response that may be further subdivided into hereditary, symptomatic, startle epilepsy, and neuropsychiatric startle syndromes (Latah syndrome, jumping Frenchman of Maine, anxiety-induced startle).2

Primary myoclonus Myoclonus occurs as the primary symptom. The cardinal example is essential disorders myoclonus.10, 11 Epileptic A useful category, where myoclonus is associated with clinical seizures and/or epileptiform discharges on EEG, supportive of a cortical origin. Primary epileptic myoclonus Myoclonus as a seizure type or fragment, or myoclonus as a symptom in addition disorders to seizures in an epilepsy syndrome without encephalopathy.12, 13 Progressive myoclonic Myoclonus occurs as part of a multi-symptom, progressive neurologic disease. epilepsies and progressive encephalopathies with myoclonus

Secondary myoclonus Myoclonus occurs secondary to some other identifiable, nongenetic cause or disorders process. Examples include autoimmune diseases, infections/encephalitides, hypoxic ischemic injury (Lance Adams), toxins, metabolic derangements such as uremia, acidosis. Also, secondary to medications, e.g. myoclonus triggered by the use of focal antiepileptic medications in patients with generalized epilepsies.16 – 18 See Chapter 18. Psychogenic Pseudomyoclonus produced as a conversion disorder symptom.14, 15 See Chapter 19.

and abduction of the arms. This category encompasses a Table 11-5, are extremely rare and may be associated number of conditions. When the onset occurs in infancy, with more severe phenotypes, including molybdenum the child may have persistent hypertonia and failure to cofactor deficiency for gephyrin and mental retarda- thrive caused by constant startle and stiffening. This is tion, epilepsy, and early death for collybistin. 2,20 also referred to as the stiff baby syndrome. This stiffness Diagnostic Approach may eventually resolve. Older children may have the clas- Hereditary and sporadic hyperekplexias, with star- sic phenomenology along with other sleep-related symp- tles in the absence of other neurologic signs, may be toms, including periodic limb movements in sleep and diagnosed clinically in the presence of characteris- hypnagogic myoclonus. In some cases, frequent falls may tic history and examination findings, including an occur, leading the child to be fearful of walking in open exaggerated head retraction reflex elicited by tapping spaces. Sporadic and familial cases are described. the tip of the nose.2 Home videos may be helpful. Pathophysiology If the diagnosis appears likely on clinical grounds and symptomatic treatment is effective, genetic confirma- The pathophysiology of startle disorders involves dys- tion is not necessary. In less clear cases, genetic test- function within inhibitory synapses, particularly those ing can be considered based on cost and availability. in reflex circuits. Most familial hyperekplexia results from mutations in the alpha 1 subunit of the glycine Treatment receptor, which acts at the inhibitory chloride receptor. Treatment is nonspecific but can be very helpful. Several other cases caused by mutations in presynaptic Hereditary hyperekplexias in infants can cause failure to sodium- and chloride-dependent glycine transporter 2 thrive due to difficulty feeding. In children, there can have been described. Additional forms, listed in be substantial physical, emotional, and social morbidity.

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Table 11-5 Genetic Hyperekplexias Gene Protein Inheritance ARHGEF992 Collybistin, a rho guanine nucleotide GTP/GDP exchange factor X Linked GLRA193 Glycine Receptor, Alpha-1 subunit AD or AR GLRB94 Glycine Receptor, Beta subunit AR GPHN95 Gephyrin, glycinergic clustering molecule AR SLC6A596 Sodium and Chloride Dependent Glycine Transporter (GlyT2) AR

The treatment of choice initially is clonazepam or other with myoclonic attacks occurring after unexpected tac- benzodiazepines. If these are ineffective, other anticon- tile and auditory stimuli, has been described in oth- vulsant agents such as sodium valproate may be used. erwise normal young children, with good response to treatment with sodium valproate.27,28 Symptomatic Startle Disorders Clinical Features, Pathophysiology Neuropsychiatric Startle Syndromes The phenomenology of the startle is similar, but other Clinical Features features of the clinical presentation are clues to the This diverse but iconic group of movement disorders is diagnosis. Acquired brainstem pathology may result characterized by excessive startle plus behavioral symptoms in exaggerated startle, accompanied by other brain- such as shouting out, echolalia, echopraxia, and jumping. stem findings. Perinatal anoxia may result in spastic The phenomenology of the behaviors may be culturally quadriplegia, profound cognitive impairment, and an mediated. Examples include the jumping Frenchmen of exaggerated startle, which may trigger clonus. Other Maine, or Latah in Southeast Asia, in which the individual global hypoxic ischemic injuries may also cause this mimics involuntarily the quick movements and sounds of form of myoclonus.21 Brainstem inflammatory pro- those nearby. Some include in this category patients with cesses, for example, some viral encephalitides and anxiety disorders or Tourette syndrome who exhibit per- inflammatory lesions in acute disseminated encepha- sistent startles with reduced or impaired habituation. lomyelitis (ADEM) and multiple sclerosis (MS), and Primary Myoclonic Disorders autoanti-bodies to gephyrin22 may result in startle disorders. An exaggerated, nonhabituating startle may The main primary myoclonia is essential myoclonus also occur in neurodegenerative diseases. Diagnostic (EM). The term essential classically designates diseases approach involves history, examination, neuroimag- that have no obvious or known cause and normal neu- ing, and other studies based on the clinical context. roimaging, and indicates that the named symptom dom- Treatment is symptomatic. In cases of diffuse, severe inates the clinical presentation. In this sense essential anoxic injury, treatment of stimulus evoked myoclonus overlaps idiopathic. Some ambiguity about “unknown is not necessary. cause” occurs when idiopathic or essential is applied to diseases with high heritability or linkage identified with high Startle Epilepsies probability, since a cause can then be inferred, and subse- Clinical Features quently when a causative gene is identified. Therefore we Sudden stimuli, usually a loud sound, or photic stimu- will use the term primary as a classification for the neu- lation may provoke a startle response and then a seizure rologic conditions in this section in which myoclonus in children with startle epilepsies. This represents a small dominates and either (1) no proximate cause is known, proportion of pediatric epilepsies. The seizure semiol- or (2) genetic causes are suspected or identified. ogy may suggest involvement of motor or supplemen- Essential Myoclonus tary motor areas.23 Startle epilepsies are probably most common after anoxic or ischemic brain injuries in Clinical Features young children,24 but may occur with occult cerebral The phenomenology of EM is multifocal, arrhythmic lesions in adolescence.23 They have also been described myoclonus. Onset is in the first 20 years, and the long- in children with Down syndrome.25 Many young chil- term course is benign. There should be no epilepsy, dren with startle-provoked epilepsies also have men- dementia, ataxia, or other neurologic defects. Some con- tal retardation.26 Idiopathic, reflex myoclonic epilepsy, sider chin myoclonus to be a form of this disorder.29

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sually 30’s, can sually 30’s, hildhood hildhood hildhood, around hildhood and puberty adolescence childhood occur in childhood

arly to late nfancy Childhood Age of onset c c c c i Infancy Infancy u e Infancy

yoclonus, dyskinesias, seizures, culogyric crises, opisthotonus, dystonia, hin myoclonus/ tremor ilateral myoclonus, tremor, dystonia, ilateral myoclonus, tremor, eizures, ataxia, choreoathetosis, myoclonus, hort stature, cardiomyopathy, seizures, myoclonic seizures GTC seizures abnormal seizures, ataxia, organomegaly, saccades, short stature episodic vomiting neuropathy, and spasticity, organomegaly, respiratory failure organomegaly, torticollis, depression, anxiety, obsessive torticollis, depression, anxiety, compulsive disorder no development, early death epilepsy, myoclonus, hyperreflexia, chorea, irritability dementia spongiform leukoencephalopathy, ataxia, myoclonus, encephalopmyopathy, seizures ailure to thrive, visual loss, startle myoclonus, Clinical Features c b Absence seizures, generalized tonic clonic Morning myoclonic jerks, absence and f o m s Myoclonus, spastic paraparesis, dementia, dementia, pyramidal signs Myoclonic epilepsy, s

AR I nheritance AD AD AD AD AR AR AR AD AR AR

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utations in GABRA1 and GABRD GABA utation in the nuclear encoded ossible linkage to 9q13-q21 DRD2; DYT1 - torsin A; DYT 15 18p11 linkage receptors; CACNB4 Calcium Channels, CLCN2 Chloride Channels succinate CoQ Reductase Deficiency

25 member 15 repeat Gene p gene); DYT 11 - SGCE (epsilon sarcoglycan EFHC2 m sialytransferase-9 SIAT9 AADC dopa-decarboxylase gene PSAP prosaposin DRPLA gene expanded trinucleotide GBA Acid beta-glucosidase SCLC25A15 solute carrier family m 122

121,

44 , 107–109 116 106 100

120

Genetic Causes of Diseases with Prominent Myoclonus in Childhood, by Category 118

117, 34 , 101–102 104–105 115 123 119

able 11-6 111–114 Syndrome Decarboxylase Deficiency Atrophy Hyperammonemia- Homocitrullinuria Syndrome Syndrome deficiency Deficiency

T Disease Primary myoclonus Hereditary Geniospasm Myoclonus Dystonia Epileptic myoclonus without encephalopathy Juvenile Absence Epilepsy Epilepsy Myoclonic Juvenile Myoclonus plus encephalopathy Amish Infantile Epilepsy Aromatic L-Amino Acid Combined Saposin Dentatorubral-pallidoluysian Gaucher Disease IIIA Hyperornithinemia- Mitochondrial complex II 116 sECTion 4 hYPERKINETIC AND HYPOKINETIC MOVEMENT DISORDERS

hildhood or preterm delivery adulthood

arly childhood arly childhood nfancy, usually nfancy, c e Childhood Childhood e Childhood Infancy i

yoclonus, epilepsy, ataxia, spasticity, ataxia, spasticity, yoclonus, epilepsy, yoclonus, neonatal epileptic ataxia, epilepsy, early death ataxia, epilepsy, early death ataxia, epilepsy, weakness, deafness ataxia, early death epilepsy, partial response to encephalopathy, pyridoxine, seizure response to pyridoxal phosphate degeneration of dentate nucleus, globus pallidus, mitochondrial disease findings ataxia, atrophy myoclonus, ataxia, epilepsy, early death myoclonus, ataxia, epilepsy, ailure to thrive, visual loss, myoclonus, m Progressive visual loss, dementia, Progressive visual loss, dementia, myoclonus, Progressive visual loss, dementia, myoclonus, Dementia, myoclonus, epilepsy, GTCs, Myoclonus, ataxia, tremor, f m

Mitochondrial AR AR AR AR AD/ other AR AR

[email protected] 66485438-66485457 thioesterase-1 probably represents a collection of diagnoses, including some that now could have molecular diagnosis polymerase gamma Oxidase Epilepsy variant (Finnish) genes, MTTK, MTTL1, MTTH, MTTS1, MTTS2, MTTF Multiple mitochondrial transfer RNA TPP1 tripeptidyl peptidase 1 CLN3 gene, PPT1 palmitoyl-protein CLN5 gene CLN8 gene, allelic to Northern None- the literature on this syndrome POLG DNA mitochondrial PNPO Pyridoxine Phosphate

130

132

126 127 128 129 Genetic Causes of Diseases with Prominent Myoclonus in Childhood, by Category—Cont’d 131

125

124, able 11-6 with Ragged Red Fibers MERRF Degeneration of Childhood with Liver Disease (Alpers Huttenlocher) Lipofuscinosis 2 Lipofuscinosis 3 Lipofuscinosis 5 Lipofuscinosis 8 Oxidase deficiency

Ramsay Hunt Syndrome

T Myoclonic Epilepsy associated Neuronal Ceroid Neuronal Ceroid Neuronal Ceroid Neuronal Ceroid Progressive Myoclonic Ataxias / Progressive Neuronal Pyridoxine 5-Prime Phosphate Chapter 11 Myoclonus 117

sually adult, some sually adult, some an be early hildhood childhood child infants arly childhood ate teens ate childhood Age of onset Infancy e c u u l l c

oarse c yoclonus, epilepsy, apraxia, dementia, yoclonus, epilepsy, taxia, myoclonus, tremor isual loss, dementia, spasticity, myoclonus, isual loss, dementia, spasticity, brain atrophy ataxia, GTCs, nephropathy/renal failure Dysarthria, mental deterioration visual loss, psychosis

rigidity, death in 2 years rigidity, atrophy, abnormal eye movements atrophy, Clinical Features myoclonus, Severe encephalopathy, v Retardation, a ataxia, Dementia, myoclonus, epilepsy, Progressive action myoclonus, finger tremor, m Myoclonus, ataxia, GTCs, A bsence Seizures,

Inheritance X linked A R A R A D A D A R A R A R

[email protected] 66485438-66485457 lpha-N-acetylgalactosaminidase TXN2 ataxin 2 expanded trinucleotide repeat member 2)

lethal in males Gene MECP2 mutations - X linked, usually a Neuraminidase mutation Linkage 1p21-q23 A Class B, SC A RB2 (Scavenger Receptor, EPM2 A laforin; NHLRC1 malin Cystatin B

1 36 80

137

79, 134 85

133, 110 103 135 Retardation, Coarse facies, short stature, visual loss, macular visceromegaly, cherry-red spot (I) I and II Syndrome and Lundborg type Disease Rett Syndrome in Males Schindler Disease, infantile Storage phenotype — Mental Spinocerebellar ataxia type 19 Spinocerebellar ataxia type 2 Progressive myoclonic epilepsy A ction Myoclonus Renal Failure Myoclonic Epilepsy - Lafora Myoclonic Epilepsy - U nverricht 118 sECTion 4 hYPERKINETIC AND HYPOKINETIC MOVEMENT DISORDERS

Pathophysiology that individual pediatric cases35 and pedigrees with auto- This is unknown, although it appears to be heritable in somal dominant inheritance have been identified that some cases. Linkage has not been identified, but mul- are mutation negative,36 and the majority of individuals tiple pedigrees with familial EM have been described with the phenotype in some series do not have the epsi- in European and Asian populations.30,31 It should be lon sarcoglycan mutation.37,38 Moreover, not all pedi- noted that in medical literature there is overlap between grees support the presence of maternal imprinting.32 EM and myoclonus-dystonia, because in the latter case Diagnostic Approach myoclonus may dominate the clinical picture and there The diagnosis should be suspected in children on clinical were previously no known causative genes. Myoclonus- grounds in the presence of the characteristic features of dystonia is discussed later in this chapter. chronic, action-induced myoclonus. Dystonia should Diagnostic Approach also be apparent during at least some activities, such Family history, phenomenology, and careful distinc- as walking. The phenomenology of proximal, action- tion of myoclonus from tics or rapid dystonic move- induced myoclonus can be diagnostically challenging, ments should suggest a diagnosis of EM. In adolescents because there is overlap with the appearance of fast cho- with predominantly morning myoclonic jerks, a diag- rea in disorders such as benign hereditary chorea. The nosis of juvenile myoclonic epilepsy (JME) should be presence of a pedigree consistent with autosomal domi- considered (see later discussion). nant inheritance with incomplete penetrance is helpful. Affected adults family members may report symptom Treatment improvement with alcohol. A molecular diagnosis of Treatment of EM is symptomatic and often unsatisfac- DYT11 is useful for understanding the disease and rul- tory. Because consciousness is unaffected, impairment ing out other causes. However, some individuals with relates to frequency, as well as social and functional this phenotype may be mutation negative. considerations. Risks and benefits of benzodiazepines Treatment and anticonvulsants such as sodium valproate, levetiracetam, and piracetam should be considered on an indi- There is no specific treatment. General consider- vidual basis. For chin myoclonus, a positive response to ations for treatment of myoclonus and dystonia apply. botulinum toxin injection has been described. Treatment of a severe adult case with deep brain stimulation has been described.39 Myoclonus-Dystonia (DYT11) Benign Myoclonus of Early Infancy Clinical Features Clinical Features Myoclonus-dystonia can have early childhood onset. This disorder is described in this chapter because myoclonus Benign myoclonus of early infancy (BMEI) is a rare 40 may dominate the phenomenology. Myoclonus is action disorder of infancy that may mimic infantile spasms. induced, predominantly in the head, neck, and proximal The phenomenology is myoclonic jerks that may clus- arms. However, adult-onset, distal myoclonus has also been ter and may appear daily. They tend to occur during described, so the phenotype may be variable.32 Alcohol waking. Onset is any time in the first year of life. In ingestion may reduce symptoms. Psychiatric symptoms, contrast to infantile spasms, this condition is benign, including obsessive-compulsive disorder and anxiety, are with no altered consciousness and no encephalopathy. common.33,34 The long-term adult course is stable. Symptoms eventually diminish and resolve, usually in a few months. Long-term developmental outcomes Pathophysiology are usually good. Pathophysiology is unknown. When Myoclonus-dystonia is caused in some individuals by the history and examination are completely reassuring mutations in the epsilon sarcoglycan gene.34 Penetrance, and jerks or shuddering spells are brief without altered the probability that the individual with the gene muta- consciousness, interictal and ictal EEGs during these tion will have the disease, depends on the parent of ori- phenomena are normal.41 Diagnosis is clinical, with gin. This disorder demonstrates maternal imprinting, characteristic features and normal EEG. Treatment is leading to inactivation of the maternal allele. Therefore generally not needed. Additional details are in Chapter 5. if the mutated epsilon sarcoglycan gene is passed on by Epileptic Myoclonus without the mother, the disease is manifest in only approximately Encephalopathy 5% to 10% of cases. However, if the mutated epsilon sarcoglycan gene is passed on by the father, penetrance A complete discussion of epileptic myoclonus lies out- is approximately 90% (because the healthy, maternally side the scope of this text but is reviewed elsewhere.42 inherited allele is inactivated and cannot dominate the However, several key phenomena and conditions, mutated gene). It is important to note also, however, in which myoclonic jerks occur prior to generalized [email protected] 66485438-66485457 Chapter 11 Myoclonus 119

seizures, merit discussion, because these conditions may normal in most cases. Ictal EEG shows generalized poly- present special diagnostic or therapeutic challenges. spikes and waves; interictal EEG is usually normal. Myoclonus is common in a number of forms of Treatment idiopathic and symptomatic epilepsy. If myoclonus Sodium valproate is usually effective.9 is the predominant seizure type or is a prominent phenomenon, the condition is termed myoclonic epilepsy. Myoclonia with Childhood Absence Epilepsies Clinical Features Juvenile Myoclonic Epilepsy Absence epilepsies are forms of childhood general- Clinical Features ized epilepsy that may be accompanied by myoclonus. Adolescents may be seen by neurologists initially with The classic absence seizure semiology is a stare lasting brief myoclonus involving predominantly the arms, a few seconds with interruption of ongoing behavior which usually occurs in the morning and may charac- or speech and loss of awareness with immediate return teristically cause fumbling or dropping hand-held items. to normal consciousness and no postictal confusion. Consciousness is preserved. Eventually, in most cases, one Absence seizures may occur many hundreds of times or more generalized tonic-clonic seizures occur, sometimes per day. Childhood absence epilepsy (ages 3 to 10), triggered by sleep deprivation. Absence seizures may also juvenile absence epilepsy (ages 7 to 20), and juvenile occur. The disorder is believed to persist throughout life. myoclonic epilepsy (ages 7 to 20) are idiopathic gener- Pathophysiology alized epilepsies that occur in children whose cognitive and behavioral phenotype is usually within the normal The myoclonus may be a thalamocortically gener- range, although problems with learning and anxiety are ated myoclonus, or a form of cortical myoclonus.43 reported in some series,48,49 possibly related to reduced The epilepsy is generalized. The pathophysiology is dopamine transporter receptor availability.50 Repetitive genetically heterogeneous, as associations have been movements, or automatisms, such as chewing or lip found with mutations in the gamma-aminobutyric acid smacking, occur during the seizures in some cases. (GABA) receptor GABRA144 and GABRD45 genes, the 46 Myoclonus of the face may also accompany typical calcium channel CACNB4 gene. Linkage studies childhood absence epilepsy.51 Children with the syndrome have identified positive findings at other loci. eyelid myoclonia with absence have brief, generalized absence Diagnostic Approach seizures with prominent bilateral eyelid myoclonus, associ- This is a clinical diagnosis. JME is diagnosed in the setting ated with generalized bursts on EEG and photosensitive of the classic clinical presentation with morning myoclo- EEG bursts.52 There are also children with photosensitive nus plus two or more generalized tonic- clonic seizures generalized epilepsies with brief episodes of eyelid closure (by definition, epilepsy). In the presence of morning and then eyelid flutter at approximately 10 Hz, lasting a myoclonus only, it is helpful to confirm the JME diag- few seconds, with no EEG correlate. These movements nosis with interictal EEG, which may show characteristic may be triggered voluntarily in some cases, increase with 3 to 5 Hz spikes and waves. Many clinicians would then stress, do not respond to antiseizure medication, and may advise treatment on the basis of the EEG and myclonus, continue after the epilepsy remits.53 particularly in individuals who drive. Sleep-deprived Epilepsy with myoclonic absence, ages 3 to 10, is EEG may have higher clinical yield in this clinical set- a more serious syndrome with absence followed by ting. Nonetheless, interictal EEG may be normal. prominent myoclonic jerks that may cause the child to fall and with cognitive impairment.54 Myoclonic Treatment astatic epilepsies are also characterized by myoclonus Myoclonic and generalized tonic-clonic seizures of JME are and absence, but also tonic-clonic and atonic seizures, usually well suppressed by sodium valproate.47 Lamotrigine as well as cognitive deficits. may be preferred for females because of reproductive and Phenomenology endocrine risks; however, the efficacy for myoclonus may Phenomenology is rapid eyelid contraction or flutter with be lower. Other medications effective for generalized epilep- eye deviation or jerk, lasting a few seconds. Eyelids are not sies may also be considered. Treatment should be lifelong. fully closed in childhood absence epilepsy but may fully Benign Familial Myoclonic Epilepsy close during other forms. In epilepsies associated with cog- Clinical Features nitive impairment, massive axial myoclonic jerks may occur. This is a rare form of epilepsy with generalized myo- Pathophysiology clonic seizures occurring in otherwise normal children, The myoclonus accompanying absence epilepsy is likely appearing in the first 2 years of life. Febrile seizures and an epileptic phenomenon, but the source is unclear in reflex myoclonus may be present. Intellectual outcome is those without EEG correlate. [email protected] 66485438-66485457 120 sECTion 4 hYPERKINETIC AND HYPOKINETIC MOVEMENT DISORDERS

Treatment such as no amplification of n-myc.58 In most children Treatment with ethosuximide, sodium valproate, with neuroblastoma, who do not have OMAS, neuro- lamotrigine, or benzodiazepines may suppress eyelid blastoma is diagnosed at a more advanced, malignant myoclonus, as well as the absence seizures. stage. Interestingly, there has also been a case report from Japan of a 10-year-old girl with chronic myoclo- Secondary Myoclonus nus, signal change in thalamus on Fluorodeoxyglucose In most diseases in which symptomatic myoclonus (FDG) positron emission tomography (PET), and occurs, encephalopathy dominates. A vast number of idiopathic antibodies to glutamate receptors.59 genetic diseases and acquired brain insults, including The subacute onset of OMAS and the association with viral encephalitides, metabolic insults, hypoxia/anoxic neural crest tumors support an autoimmune pathophys- insults, and exposure to heavy metals and other tox- iology. The phenomenology suggests that the disease ins, can produce myoclonus. This has been thoroughly targets multiple central nervous system (CNS) sites, reviewed elsewhere.55 In most cases, the proximate including cerebellum and brainstem gaze centers contain- cause is not obscure, because there is evidence by his- ing burst cells that control saccades. Because the disease is tory of exposure, illness, or hypoxia. In this section, we usually not fatal, pathologic confirmation of specific pro- discuss three secondary causes of myclonus. cesses and cell type involvement through autopsy studies is sparse. The relative rarity of the disease, delays in Opsoclonus Myoclonus (Ataxia) Syndrome its diagnosis, and heterogeneity of prodromes and clini- Clinical Features cal features all contribute to difficulties in understanding Opsoclonus myoclonus (ataxia) syndrome (OMAS) typ- this disease. Intensive research into multiple circulating ically begins in early childhood, most often before age autoantibodies including antibodies to Purkinje cell tar- 5 years. Although symptoms of this disease are unusual gets has not, to date, identified any consistently present, and appear in its name, the diagnosis can be difficult. disease-associated antibody. Passive transfer of putative Myoclonus occurs with action, is diffuse, and has small- disease-causing antibodies to animals has not produced amplitude, multifocal mini-myoclonus. Opsoclonus, symptoms or pathology. Thus antibodies found to date rapid bursts of saccadic eye movements in several direc- may be epiphenomena and not pathogenic. The possible tions sequentially, or ocular flutter is pathognomonic role of abnormally recruited or activated lymphocytes has in this setting. The early presence of irritability should been explored with flow cytometry studies of cerebrospi- also be emphasized. A common misdiagnosis is acute nal fluid (CSF).57 These studies have supported involve- cerebellar ataxia (ACA) because both ACA and OMAS ment of abnormal profiles of lymphocytes, including have subacute, progressive disturbances in gait, trun- increased CD19+ B cells and HLA-DR+ (activated) T cal instability, and behavioral irritability. Irritable tod- cells, and reduced CD4+ helper/inducer T cells. dlers are difficult to examine thoroughly, adding to the Diagnostic Approach challenge of discerning the presence of multifocal mini- OMAS is a clinical diagnosis. In the presence of subacute myoclonus and action myoclonus plus ataxia in a toddler irritability, tremor, and ataxia, a diagnosis of OMAS must with OMAS versus titubation, gait, and limb ataxia in be considered, and children diagnosed with acute cerebel- ACA. The presence of end-gaze nystagmus supports the lar ataxia should continue to be monitored for emergence diagnosis of ACA, but nystagmus is not universal.56 The of symptoms characteristic of OMAS.60,61 The presence of clinician may miss the diagnosis because opsoclonus in end-gaze nystagmus in this setting has a high positive pre- OMAS may be intermittent, subtle, or later appearing.57 dictive value for acute cerebellar ataxia. The presence of Gait ataxia, tantrums, hypotonia, and varied other signs opsoclonus has a high positive predictive value for OMAS, including reflex abnormalities and head tilt have been but its absence does not have a high negative predictive described in OMAS. At its peak, OMAS is severely dis- value. That is, because opsoclonus can be subtle, intermit- abling for the child, and extremely stressful for the family. tent, or late, clinicians and parents need to continue to In milder cases, the course of OMAS may be monophasic watch for it. Brain magnetic resonance imaging (MRI) and nonrelapsing. More severe cases may be prolonged, should be normal, and CSF unremarkable. No immune lasting months or years, with multiple relapses. studies are clinically established for this diagnosis. The Pathophysiology search for a neuroblastoma should be thorough and persis- A large proportion of children with OMAS have a tent in this clinical setting. Consultation with radiology and neuroblastoma, a potentially fatal neural crest tumor. oncology is recommended because certain modalities may Interestingly, in OMAS the neuroblastomas tend to have be favored depending on the institution. Useful imaging low-grade histology and favorable molecular markers may include computed tomography with contrast or MRI

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with gadolinium of the neck, chest, abdomen, and pelvis. Epilepsia Partialis Continua, Rasmussen’s Nuclear medicine scans using [131]I-MIBG (metaiodo- Encephalitis, and Myoclonia Continua benzylguanidine) or [111]In-penetreotide (somatosta- Clinical Features tin receptor ligand) may be used. Other useful positive Focal jerking, typically in a distal limb, occurs for findings are elevated 24-hour urine catecholamines and hours to weeks in epilepsia partialis continua (EPC). serum neuron-specific enolase. The utility of commer- This is discussed in this chapter because the phenom- cially available testing for paraneoplastic autoantibodies enology of the jerking may be myoclonus. Rasmussen’s and CSF studies is not clinically established. syndrome is a common cause of this rare condition in Treatment children and may manifest with focal myoclonus. Multimodal treatment is needed. The treatment for a Pathophysiology neuroblastoma may involve surgery, chemotherapy, or Pathophysiology involves either cortical or subcortical both depending on factors such as size, location, and pathology, as established with neurophysiologic and imag- indicators of malignant potential. If the child is diag- ing studies. Rasmussen’s syndrome is an autoimmune nosed with ACA first, treatment with steroids or intra- disease involving one hemisphere, with cortical inflamma- venous immune globulin may have been tried to shorten tion and atrophy, and thus this is a secondary myoclonus. the disease course. In many cases, these treatments will Pathophysiology is unknown. Despite the identification not be successful for OMAS. Adrenocorticotrophin of antiglutamate receptor antibodies in some children, (ACTH) protocols are often used, although based on immune-modulating therapies do not have long-term ben- expert consensus and clinical experience.60 The high- efit and only hemispherectomy is curative.66 A case has also dose ACTH protocol is 150 IU/m2 intramuscularly or been described after gliomatosis cerebri in two children.67 subcutaneously for 2 weeks, followed by a very gradual Some authors have suggested that EPC be used to designate taper. Relapses during the taper are common. Possible cases with cortical origin, and myoclonia continua be used complications include weight gain, hypertension, for those originating elsewhere in the nervous system.68 elevated blood glucose, ulcers, and infections. Exposure to other ill and febrile children should be avoided if pos- Treatment sible. In addition to steroids, IVIG, ACTH, and plas- Treatment is with anticonvulsant agents. mapheresis, other immune-modulating therapies have been described in case series, including azathioprine, Progressive Myoclonic Epilepsies mycophenolate, and cyclophosphamide. Rituximab Progressive myoclonic epilepsies (PMEs) are rare genetic is considered promising in children with CSF B-cell conditions clustered on the basis of common clinical 62 expansion. Symptomatic therapy for behavioral features of myoclonus, epilepsy, progressive enceph- problems, aggression, and insomnia may also be ben- alopathy, and ataxia. The five main causes are mito- eficial. Ulcer prophylaxis is recommended. Some also chondrial encephalomyopathies, Unverricht-Lundborg recommend infection prophylaxis with trimethoprim/ disease, Lafora disease, neuronal ceroid lipofuscino- sulfamethoxazole, and short-term antihypertensive ses, and sialidoses. Clinically, tonic-clonic, clonic, treatment may be needed. Physical therapy, occupa- myoclonic, and absence semiologies may be present. tional therapy, and speech therapy may be beneficial. Neurophysiologically, seizure types are more often generalized than partial. Myoclonus is often reflex, induced Postanoxic Myoclonus by light, sound, touch, emotional stress, movements, Clinical Features or posture. Spontaneous myoclonus or disabling action After diffuse hypoxic/ischemic insults, particularly cardiac myoclonus also occurs. Localization may be multifocal in arrest in adults, spontaneous and action myoclonus are the face and distal limbs, or bilateral and massive, result- well known. This has been less frequently described in ing in falls. Hyperexcitability in PMEs has been demon- children, but is described after neonatal ischemia.63,64 strated with giant somatosensory evoked potentials and Pathophysiology reduced intracortical inhibition measured with transcranial magnetic stimulation. Evidence supports origin of Pathophysiology involves cortical and/or Purkinje cell myoclonus in cortical, subcortical, and brainstem-retic- injury. ular loci, possibly related to the pervasively abnormal Treatment neural function in these degenerative diseases. Depending on the severity of injury, treatment may have Cerebellar dysfunction is also common, with hypoto- little influence on outcome. Postanoxic myoclonus may nia, dysmetria, intention tremor, speech abnormalities, respond to levetiracetam65 or other antimyoclonic agents. ocular movement disorders, and ataxia variably present.

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Neuroimaging may be normal or show cerebellar cofactors, and artificial electron acceptors, substances atrophy. Postmortem studies show loss of Purkinje cells to remove noxious metabolites, may be considered. For and dentate nucleus.69 This pathology may underlie seizures, anticonvulsants may be chosen based on usual the presence of action myoclonus in PMEs.70 principles. Sodium valproate is not a drug of choice, Our understanding of the biochemical and molecular because of concern for liver damage, but is not abso- pathophysiology of these diagnoses has expanded rap- lutely contraindicated for electron transport disorders. idly with the discovery of causative genes.71 However, The probability of liver damage is higher in disorders no rational therapies are available. of fatty acid oxidation and for children under age 2 with epilepsy and developmental delay. Mitochondrial Myopathies—Myoclonus Epilepsy and Ragged Red Fibers (MERRF) Unverricht-Lundborg Disease As mitochondria are ubiquitous, a multitude of neu- This condition, before clarification of the genetic rologic and systemic abnormalities may occur, but the etiology, was previously known by several names more frequent are short stature, hearing loss, neuropa- describing overlapping clinical presentations. These thy, diabetes, cardiomyopathy, strokes, migraines, and names included Mediterranean myoclonus, Baltic renal tubular acidosis. Children with muscle weakness, myoclonus, Ramsay-Hunt syndrome, and EPM1. ataxia, dementia, and eye movement abnormalities may Clinical Features have a lactic acidosis and stroke-like episodes (MELAS) Disease onset is in childhood, often between 6 and or progressive myoclonic epilepsy with ragged red fibers 15 years, with action myoclonus. Seizures are rare, (MERRF) on muscle biopsy.72 “Ragged red fibers” refers to the histologic, Gomori trichrome stain appearance usually tonic-clonic but on close observation may involve repeated massive myoclonic jerks.78 Multisystem of diseased muscle fibers with abnormal mitochondrial neurologic symptoms, in addition to myoclonic epi- proliferation. Diagnostic approaches combine identifica- lepsy, include dysarthria, ataxia, tremor, and cognitive tion of the classic clinical features, biochemical features decline but these are slow, over decades. Myoclonus is such as elevated serum lactate and pyruvate, radiologic stimulus sensitive and may or may not be linked to EEG features such as elevated lactate on magnetic resonance spikes. Photosensitivity is usually present. Some patients spectroscopy, and muscle biopsy findings. With increas- present with frequent blinking which may be initially ing availability of genetic testing for mitochondrial dis- wrongly diagnosed as tics or blepharospasm (see video). orders, consultation with a neurometabolic or genetic specialist may allow for appropriate diagnostic testing Pathophysiology and obviate the need for muscle biopsy in some cases. Unverricht-Lundborg disease is due to mutations in 71 Clinical Features cystatin B (CSTB, also known as EPM1), usually in the promoter region. Details of the genotype/pheno- Classic symptoms of MERRF are myoclonus, gener- type relationship require further investigation, but this alized seizures, ataxia, and myopathy. Age of onset of protein is believed to be a cysteine proteinase inhibi- MERRF varies within families, from early childhood tor whose role is protection against excessive, inap- to late adulthood.73 MRI may show atrophy of cerebel- propriate intracellular degradation by proteinases that lum or superior cerebellar peduncles.74 Serum lactate leak from lysosomes. A rarer form is due to mutations and pyruvate are characteristically elevated. in EPM1B. Sodium valproate is effective for seizure Pathophysiology control, whereas phenytoin may cause exacerbations. This disease is caused by point mutations in mitochondrial Lafora Disease DNA encoding tRNA. It is therefore inherited through the maternal line. The most common mutation occurs Clinical Features at position 8344, an A to G coding mutation leading to Clinical features of this disease include childhood onset, usu- adenine/guanine substitution.75 This results in defective ally between ages 6 and 19. Early symptoms are generalized translation of mitochondria-encoded DNA, and ulti- tonic-clonic seizures. Spontaneous and action myoclonus mately to defective function of the mitochondrial respi- then progress rapidly along with dementia, ataxia, dystonia, ratory chain. Of note, myoclonus has also been described and death within 10 years. Adult-onset cases have a slower in Leber’s hereditary optic neuropathy76 and in a patient course. EEG initially shows generalized epileptiform dis- with a polymerase gamma 1 mutation.77 charges with exacerbation from photic stimulation. Treatment Pathophysiology Therapies at this time are nonspecific and not very Lafora disease is caused in most cases by mutations in effective. A combination of oxygen radical scavengers, the EPM2A gene, which encodes a protein tyrosine

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phosphatase termed laforin.79 Subsequently, another Pathophysiology cause has been identified, mutations in EPM2B Sialidosis I and II are allelic, autosomal recessive dis- (also known as NHLRC1), which codes for malin, a eases caused by mutations in the neuraminidase gene,85 protein that probably acts in a common cellular path- with some correlation between disease severity and way.80 Postmortem studies show polyglucosan inclu- residual mutant enzyme activity.86 Galactosialidosis sions (Lafora bodies) in neurons and multiple organs, results from loss of activity of both enzymes beta- including sweat glands visible on skin biopsy. galactosidase and alpha-neuraminidase. This has been Neuronal Ceroid Lipofuscinoses shown to result from mutations in the gene encoding the “protective protein”/lysosomal cathepsin A, which There are (at least) 11 types of neuronal ceroid lipofus- stabilizes these enzymes and prevents their degrada- cinoses, which occur at various ages. They have been tion. Phenotype severity and age of onset are associated long named with eponyms and by age of onset, but with degree of residual protein activity.87 the current nosology is based on identified molecular defects. Angelman Syndrome Clinical Features Clinical Features These diseases have in common clinical features of Clinical features include chronic encephalopathy, with relentlessly progressive dementia and disability, and severe mental retardation, absent language, inappropri- often macular degeneration.81,82 Several forms have ate paroxysmal laughter, ataxic gait, tremor, myoclonus, PME, most notably type 2 (CLN2). Other movement and microcephaly with large-appearing mandible.15 disorders such as ataxia and parkinsonism may occur. There are multiple seizure types, including absence, Pathophysiology myoclonic, and myoclonic status epilepticus. The key feature of these heritable disorders is the pres- Pathophysiology ence of intracellular lipopigment. This storage material Angelman syndrome is a sporadic disorder that occurs seen using electron microscopy is granular osmophilic due to four related genetic mechanisms. The genetic (CLN1), curvilinear (CLN2), fingerprint (CLN3), and locus is chromosome 15q11-q13. In most cases there mixed, including rectilinear in the other forms. is de novo deletion at the site of three GABA receptor Diagnostic Approach subunits (GABRB3, GABRA5, and GABRG3) on the maternal chromosome (note that deletion at the same In the presence of characteristic features, supported by location in the paternal chromosome 15q causes Prader visual and electrophysiologic studies (see Chapter 15), Willi syndrome).88 In a small proportion of cases, the genetic or histologic testing may be performed. Biopsies cause is (1) disomy of chromosome 15 or (2) chromo- of conjunctiva, rectal mucosa, or muscle may be used somal imprinting defects. Most of the remaining cases to identify inclusions, seen by electron microscopy.83 are caused by mutations in ubiquitin-protein ligase Treatment E3A gene.89 Gene therapy delivery of CLN2 to 12 CNS sites with Treatment an adeno-associated viral vector is under investigation.84 There is no specific treatment. Genetic counseling for Supportive and palliative care are needed. Additional the family is complex, based on the complex genetics of details are found in Chapter 15. this disorder and variable recurrence risk.90 Sialidoses Two forms of defects in neuraminidase (also known as Hemifacial spasm sialidase) cause PME, as does a related defect causing Hemifacial spasm is a rare disorder in children. This galactosialidosis. topic is addressed in the chapter on myoclonus due to Clinical Features the rapid muscle contractions. Movements are charac- Sialidosis type I is milder, with later onset. Sialidosis terized by involuntary contractions of muscles inner- type II is more severe, with more dysmorphic features. vated by the facial nerve. Potential causes include Type II is also known as mucolipidosis I. These diseases facial nerve compression by vascular or brainstem are characterized by gradual visual failure, myoclonus, masses. Hemifacial spasms have also been reported tonic-clonic seizures, ataxia, and a cherry-red spot on in children with cerebellar astrocytomas96 and oti- the macula. Galactosialidosis is characterized by dwarf- tis media.97 Treatment includes carbamazepine and ism, hearing loss, seizures, mental retardation, macular other anticonvulsants, botulinum toxin,98 and surgical cherry-red spot, and myoclonus. decompression.99

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Summary of Diagnostic and 8. Use Web-based resources such as OMIM and Therapeutic Approach GeneClinics (see Appendix B). The molecular diagnosis of diseases with myoclonus is moving ahead, Myoclonus is highly prevalent but rarely occurs as an although specific therapy continues to lag far behind. isolated finding in children. Nonetheless, some general 9. For unclear neurologic phenotypes, consider refer- aid in diagnosis of pediatric neurologic disorders with ring for a second opinion. myoclonus may be gained from the usual principles of 10. Before genetic testing, consider consultation with neurologic diagnosis. genetics, which may allow for family education, First, the type of myoclonus may sometimes aid as well as facilitating counseling around issues of in accurate neuroanatomic localization, as outlined in confidentiality, guilt, and blame. Table 11-3. 11. Educate the family about the disease. Second, the co-occurring symptoms may provide a crit- 12. Provide referrals for supportive services, as needed, ical clue. For example, epilepsy is a clue that the substrate and encourage families to read about the disease for myoclonus is more likely to be diseased or disordered and join advocacy and research groups. cerebral cortex. The presence of encephalopathy or a diffuse 13. Provide referrals for other therapies, for example, neurodegenerative disease with dementia makes a cerebral, physical therapy if the patient is losing ambulation. subcortical, or brainstem source more likely. Secondary and progressive myoclonic epilepsies should be considered, Therapeutics based on clinical features and age of presentation. There are few rational, disease-specific treatments. The The following more specific steps may be helpful: mainstay symptomatic treatments are antiepileptics (sodium valproate, levetiracetam, and piracetam), as 1. Clarify that myoclonus is the movement disor- well as benzodiazepines. der. In some cases, this is challenging if there is a mixed phenomenology. In general, dystonia and tics should be distinguishable from myoclonus REFERENCES clinically. Ataxia with titubation versus myoclonus 1. Shibasaki H: Pathophysiology of negative myoclonus can be more challenging, and these can co-occur. and asterixis, Adv Neurol 67:199–209, 1995. 2. Use the age of onset, inheritance pattern, and 2. Bakker MJ, van Dijk JG, van den Maagdenberg AM, time course (acquired, static, chronic progressive, Tijssen MA: Startle syndromes. Lancet Neurology 5: episodic) to guide diagnostic decisions. 513–524, 2006. 3. Acute myoclonus is usually due to an insult such 3. Fahn S, Marsden CD, Van Woert MH: Definition and as an anoxic injury that is not obscure. In the pres- classification of myoclonus, Adv Neurol 43:1–5, 1986. ence of altered mental status, myoclonus is non- 4. Schrag A, Quinn NP, Bhatia KP, Marsden CD: Benign specific. 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[email protected] 66485438-66485457 Tremor O 12 O Introduction and Overview childhood. The many diseases where tremor is a nonspecific and not prominent symptom are covered in Community and clinic-based studies show high more detail in chapters on cerebellar, basal ganglia, and prevalence of tremor in adults. Prevalence of tremor in metabolic diseases. childhood is less well characterized. Tremor may be localized to hands only, or to other locations. Tremor may be Definition of Tremor primary, or idiopathic, meaning that pathophysiology is Tremor refers to oscillating, rhythmic movements related to relatively isolated dysfunction within tremor- about a fixed point, axis, or plane that occur when related nodes in the motor system with no recogniz- antagonist muscles contract alternately. Usually this O able cause and normal laboratory and imaging results. involves oscillation around a joint and produces a vis- Typically this refers to patients in whom the predomi- ible movement. Several alternating phenomena are not nant if not sole movement disorder is tremor. A parent tremor. Nystagmus is not considered tremor, although may also have tremor. Tremor may also be secondary, or it may be oscillatory or pendular. Repetitive move- symptomatic, resulting from a known cause. The time ments within a motor unit or muscle group, such as course can be acute and transient, subacute, chronic myokymia or fasciculation, are not included under and stable, or chronic and progressive. the rubric of tremor. Palatal myoclonus is included by In children, tremor can manifest from infancy some authors as a form of tremor, but since it involves through adolescence. Although tremor at any age may contractions of agonists only it does not fulfill the defi- distress parents, tremor tends to be brought to medi- nition of tremor. Athetosis or athetoid movements may cal attention either early in childhood or much later, be distal and accompany dystonia, as can tremor, but in adolescence. This is due to both the epidemiology the athetotic movements are generally more complex of the more common etiologies and to the age-related and less regular in their timing than tremor. impairment. Tremor may interfere with acquiring early fine motor skills. Therefore functional impairment Clinical Characteristics— with fine motor tasks often becomes apparent dur- Phenomenology of Tremor in ing preschool or early elementary school, with refer- Children rals generated by observations by parents, teachers, or therapists. The differential diagnosis is large, but often As with other movement disorders, various forms of a mild static encephalopathy is the cause of tremor at categorization of tremor are employed, based on fea- this age. In adolescents, social embarrassment drives tures of the tremor and the relationship to purpose- more referrals for tremor. At this age, prominent etiolo- ful movement. The most useful, primary distinction gies include enhanced physiologic tremor due to stress is based on the relation to voluntary movement, as or anxiety, drug-induced or substance abuse–induced described in Table 12-1. Nosologic terminology is not tremors, essential tremor, and psychogenic tremors. always consistent, with some authors, for example, Finally, a large variety of other neurologic condi- defining rest, action, and postural tremor as three dis- tions can manifest with tremor. Although most chil- tinct forms, and others subcategorizing postural and dren with tremor do not have a serious, progressive kinetic as subcategories of action tremor. In Table 12-1, neurologic condition, vigilance is still needed for out- the primary distinction employed is whether the motor liers. It is important to have a systematic approach to system involved is at rest or not. diagnosis, based on cardinal features, pathophysiology, Rest tremor is most common in hypokinetic syn- and developmental epidemiology. This chapter encom- dromes, such as Parkinson’s disease. This is not a common passes diseases and disorders resulting in clinical syn- form of tremor in children. It is discussed in greater dromes that may manifest with prominent tremor in detail in Chapter 14. The emphasis in this chapter will

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TABLE 12-1 clinical Features of Tremor inent when the patient resists and attempts to correct the abnormal dystonic posture and it diminishes or can Relationship to Action be completely abolished when the affected body part is Type of Tremor or Muscle State allowed to assume the dystonic posture (the so-called Rest When limbs are fully null point). supported against gravity Rubral (Holmes) tremor, also known as midbrain Action During movement of various or mesencephalic tremor, is a large-amplitude tremor types present at rest and increasing with posture and movement. The name relates to the red nucleus; however, • Postural While holding a limb or body part in a position, against the lesion may also lie nearby in the superior cerebellar gravity peduncle or in the thalamus.4 Myorhythmia is a slow (1 to 3 Hz), continuous or • Kinetic With directed voluntary movement intermittent, relatively rhythmic movement sometimes associated with palatal or ocular myoclonus, usually • Intention/terminal While moving the limb toward related to brainstem pathology. Facial myorhythmia, a target; this is not along with vertical ophthalmoparesis or ocular myoclo- synonymous with dysmetria but, like dysmetria, is nus, is a characteristic movement disorder in Whipple characteristic of cerebellar disease. origin Orthostatic tremor is an isometric tremor that occurs • Isometric While contracting muscle in the legs and trunk during standing, usually occur- without an observable ring a few minutes after assuming erect posture. This movement occurs rarely if at all in children. Trembling usually refers to the chin, as in isolated • Task-specific During performance of skilled 5–7 tremor tasks such as writing or hereditary chin tremor. playing a musical instrument Jitters/jitteriness is a transient high-frequency tremor in neonates, discussed in Chapter 5. Shuddering is brief episodes of shaking with no elec- be on action tremors, which are much more common troencephalogram (EEG) correlate, usually occurring in children, particularly the postural and kinetic trem- in infancy and possibly linked to essential tremor in ors. Body localization, for example, one hand or both adulthood, see Chapter 5 for further discussion.8 hands, is also important diagnostically, as a high degree of asymmetry is more common in secondary tremors. Because tremor is continuous and regular around Localization and Pathophysiology a fixed location, two key features set it apart from Tremor involves alternating, relatively symmetric con- other movement disorders: amplitude and frequency. tractions of agonist and antagonist muscles leading to Electromyography (EMG), accelerometers, and other movement around a fixed point, axis, or plane. Visually, instruments are sometimes used to quantitate tremors, the movements are oscillatory. The mathematical regu- but the clinical utility of this information, that is, its larity of these oscillations is demonstrable with instru- ability to improve diagnostic and/or therapeutic medi- mentation such as accelerometers, which allow for cal decision making, has not been demonstrated in chil- quantification of the frequency and amplitude of the dren.1 Results in adults suggest that tremor impairment tremor, and can also be seen when asking the patient to can be related mathematically to tremor amplitude.2 draw a freehand spiral. Clinical tremor rating scales are usually adequate for Tremor can be conceptualized as abnormal assessment of tremors and their response to therapy.3 movement resulting from the inappropriate or exces- Clinical Differentiation from Other sive transmission of oscillatory activity in the central Movement Disorders, and Some nervous system out to muscles. This central oscillatory activity is localized in part in the cortical-striato-pallidal- Special Types of Tremor thalamocortical circuits (see Chapter 1) and the corti- Tremor can co-occur with other movement disor- co-cerebellar-thalamocortical circuits (see Chapter 2). ders, and the distinction can be clinically challenging, These circuits subserve movement and contain nodes particularly when movement disorders are mixed. in which there is physiologic oscillatory or cycling Dystonic tremor is an irregular tremor in the pres- electrical activity. These nodes are sometimes called ence of underlying dystonia. The tremor is most prom- “central oscillators,” and information about them has

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been gained through direct cell recording in mammals, neurons in ventral thalamus in Parkinson’s disease was in cell culture and slice preparations, and from human demonstrated to have rates of firing that correlated with neurophysiology data obtained during functional neu- tremor in the contralateral hand,16 and, similarly, thal- rosurgery, particularly deep brain stimulation (DBS) amic neural activity has been shown to correlate with surgery. These central oscillators probably include the EMG recording of essential tremor.17 The frequency ventral thalamus,9,10 the inferior olive,11 the subtha- of tremor may be age dependent. Neuroanatomic/fre- lamic nucleus, and the globus pallidus externus.12–14 quency information is of scientific interest but not of Physiologic oscillating electrical activity in brain high clinical utility. circuits usually does not lead directly to observable, At the cellular and molecular level, there is growing oscillating motor activity, that is, tremor, unless one of scientific interest in ion channels and cyclic firing pat- several types of processes occurs. terns, because they seem to play an important role in the neuronal substrate of tremor. In olivary neurons, Central and Peripheral Processes Which there is a cycle of autorhythmic depolarization, hyper- May Result in Tremor polarization, and recurrent depolarization related to Ca2+ conductance.12 It is thought that one mechanism 1. Abnormal function of inhibitory or “damping” sys- of antitremorigenic action of thalamic DBS is desyn- tems. Acute, chronic, or progressive processes may chronization of pathologically synchronous oscillating cause inefficient neural transmission within inhibi- systems. tory systems. For example, damage to cerebral cor- Thus three main etiologic categories of tremor can tical inhibitory systems may allow transmission of be partially understood in terms of effects on central subcortical oscillatory neural activity to propagate oscillatory activity: to the motor system. 2. Changes within or among central oscillators. 1. Enhanced physiologic tremor—physiologic tremor Enhanced activity or pathologic synchronization that is normally measurable but not visible becomes of oscillatory activity can overload inhibitory sys- more apparent when stressors on the system allow tems and lead to propagation of the inappropriate for increased amplitude. Acute emotional stressors, activity out to the motor system. Selective damage fatigue, and stimulating substances such as caffeine, to certain critical cell types, for example, cerebellar amphetamines, and thyroid hormones may tran- Purkinje cells, due to hypoxia or toxins, affects cen- siently perturb the inhibitory systems that dampen tral oscillation patterns. normal oscillatory activity. 3. Changes in afferent neural activity to central 2. Essential tremor (ET), a primary tremor that oscillators. An example would be changes in occurs in the absence of other prominent neuro- pallido-thalamic transmission caused by upstream logic symptoms. The source of this tremor may nigrostriatal dopaminergic dysregulation. Another be abnormal activity in central oscillators in the example would be altered peripheral input through cerebellar-thalamocortical loop. This is supported muscle spindle feedback, related to stiffness or by the observation that adults with ET commonly external mass load on the limbs. This affects have some cerebellar symptoms (e.g., abnormal central oscillatory activity and alters components of tandem gait). ET case control studies demonstrate tremor frequency. This mechanical input dysregu- increased cerebellar and red nucleus activity during lation may influence the presentation of tremor in tremor, measured using positron emission tomog- children with spastic cerebral palsy, hypotonia, or raphy (PET).18–20 Alcohol use, which clinical obser- neuropathies. vation has shown improves ET symptoms, acts in The frequency of the spontaneous activity in these the anterior cerebellum to impair gait coordination. nodes has been shown in some cases to correspond to Alcohol also suppresses this cerebellar overactivity the tremor frequency recorded with EMG. Tremors of as quantified using PET,21 which may account for various frequencies appear, based on lesioning stud- its ability to improve ET. ies and clinical-pathologic correlations, to have char- 3. Symptomatic tremors—tremor due to injury that acteristic anatomic locations. For example, cerebellar affects central oscillators or proximate afferent or hemispheric lesions vary from 5 to 11 Hz,15 and den- efferent motor circuit nodes or pathways. Examples tate nucleus lesion results in slower, 6 to 8 Hz tremor. of somewhat anatomically selective processes Midbrain tremors are slower at 2 to 3 Hz, high brain- include the following: toxins (carbon monoxide— stem lesions have 5 to 7 Hz tremor, and low brain- basal ganglia), medications (dopamine receptor stem lesions have 8 to 11 Hz tremor. A population of blocking agents—basal ganglia; anticonvulsants—

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cerebellum), structural lesions (infarctions, tumors, Diagnostic Approach and Treatment cysts), and genetic and metabolic diseases (Wilson’s The diagnostic approach is guided by the history and disease—basal ganglia; galactosemia—Purkinje cells physical examination findings. Often no directed and cerebellar white matter). intervention and no medication are needed, just reassurance.

Diseases and Disorders Intermittent Tremor in the Young Child This section reviews some of the more common or In the vast majority of cases where there are episodes important diseases causing tremor in children. Note of tremor described by parents, but which are not that many secondary tremors are mixed movement dis- clearly present in the clinic, there is no underlying orders better covered in other chapters. For example, neurologic disease of any consequence. However, dili- tremor associated with dystonia is covered in greater gence is still necessary, for several reasons, depending detail in chapters on dystonia (see Chapter 10) and on the child’s age. parkinsonian disorders (see Chapter 14). Secondary If the child is young and the parents are highly anx- tremor may also occur in the presence of metabolic dis- ious about episodes of tremor, it is important to make orders (see Chapter 15) and static encephalopathies/ the parents feel that their concerns have been vali- cerebral palsy (see Chapter 17). Tremors as part of a dated. If this is not accomplished, parents may con- constellation of significant, static developmental motor tinue to “shop around” for other opinions or seek out difficulties with clumsiness are discussed in the chap- complementary medicine practitioners who prescribe ter on ataxia (see Chapter 13). The important features expensive, nonvalidated treatments. A careful history of drug-induced tremor (see Chapter 18) and psycho- followed by a detailed neurologic examination is thera- genic tremor (see Chapter 19) are covered briefly here peutic in this way, and adds credibility when explain- and in more detail in the dedicated chapters. ing the benign nature of the tremor to the parents. The careful history often reveals the trigger and this Primary Tremors can be addressed if necessary. Parents often describe excessive tremulousness on awakening in the morn- Enhanced Physiologic Tremor ing or after naps. In addition, intermittent tremor in Clinical Features the young child is often increased by frustration. The Physiologic tremor occurs in normal individuals and is clinician should note that if the frustration consistently not apparent visually. The tremor frequency increases occurs around performance of fine motor tasks, this through childhood, related to normal brain matura- child may have a developmental motor delay or mild tion. Certain environmental factors result in enhance- static encephalopathy. This is discussed in more detail ment of the tremor, such that it becomes apparent to in Chapter 13 in the section on clumsy children. In the child or parent. These factors are usually transient these children, there is usually some other evidence on in children. The tremor has often been witnessed, examination of subnormal motor function. Asking the repeatedly, by the parents but is not present during the child to manipulate small toys, write, or color a picture clinic visit. Parents of young children and adolescents in clinic may reproduce the tremor. These tremors may typically describe symmetric hand tremor, although also be brought out during a detailed motor examina- other body areas may also be involved. tion that fatigues the child—examining for postural tremor and intention tremor, and assessing fine rapid Pathophysiology and sequential finger movements without pausing Common factors that seem to trigger enhancement or allowing the child to rest his or her arms. Referral include stressors such as increased emotion (anxiety, to occupational therapy is sometimes warranted. anger, sadness, frustration), fatigue, fever, and hunger. Although there is no validated medical treatment, Because all children experience these stressors, but not all a follow-up neurologic examination in 12 months is children develop tremors, there are probably some innate recommended. Comparison at 12 months of the writ- factors that predispose certain children to develop a more ing and drawing samples, along with other recorded robust enhanced physiologic tremor. These factors are details of the examination, is critical for identifying the unknown. Endocrinologic conditions such as thyrotoxi- rare child with progressive neurologic disease. cosis and pheochromocytoma, as well as certain medications, can also result in enhanced physiologic tremor. The Intermittent Tremor in the Adolescent history and presence of other characteristic symptoms Adolescents often have bilateral hand tremor. In some guide diagnostic evaluation toward these conditions. cases, they have essential tremor (see later discussion)

[email protected] 66485438-66485457 Chapter 12 tremor 133 and describe tremor that is continuously present. In of patients with ET later develop clinical features of many cases, however, the tremor is intermittent and PD.22 The diagnosis of ET must also be approached probably represents stress-induced, enhanced physio- carefully in children, because tremor is a nonspecific logic tremor. Adolescence is a stressful time, for social symptom of many genetic and acquired neurologic reasons (parents, friends, sex), academic reasons, or diseases. Therefore, for both patient care and research, competitive extracurricular activities. At inopportune it has been important to designate consensus criteria moments, physical symptoms may ensue—headaches, for this diagnosis. Although no specific criteria have irritable or irregular bowel function, or enhanced been established for diagnosis of ET in children, there physiologic tremor. The tremor embarrasses the self- has been a general consensus on the diagnosis of ET in conscious adolescent. Again, a careful history and adults (Table 12-2). detailed physical examination can be therapeutic. The The duration criterion for adults allows time for the adolescent can answer questions about functional inter- diagnosis to solidify with an absence of progression to ference from tremor and can give a writing sample and PD. Since PD is extremely rare in children, the dura- perform a freehand spiral. Even if the tremor is inter- tion criterion can be relaxed. A follow-up examination mittent, it is important to take a family history and 1 year after initial clinic presentation to document that briefly examine both parents, if possible, for resting symptoms have persisted, with no or only slight pro- and action tremor. This is because sometimes the ado- gression, is probably adequate. lescent’s subtle, intermittent tremor reflects the onset The epidemiology of ET in children in the com- of essential tremor. Parents may not acknowledge their munity is not well characterized. Current estimates are own essential tremor by history, yet it is readily appar- based on small, clinic-referred samples.23–25 Such esti- ent on postural and finger-to-nose testing. mates may reflect various cultural preferences in refer- A review of systems, a medication and substance abuse ral patterns, and may demonstrate increased likelihood history, and a brief screen for signs of a mood disorder are of ascertainment of patients with co-occurring diagno- also important. Anxiety and other mood disorders often ses such as Tourette syndrome or dystonia. Childhood begin in adolescence, and the episodes of tremor may be presentation to specialty clinics may also reflect higher physical manifestations of these emotional problems. In likelihood of referral of cases with a positive family his- the presence of isolated, intermittent tremor, a thorough tory, or may be biased toward atypical presentations, diagnostic evaluation is rarely needed. Neuroimaging, with more body areas involved. Achieving a valid laboratory testing for anemia, endocrine disorders, rheu- estimate of age-related prevalence of ET will require matologic disorders, or testing for rare diseases such as community-based studies with direct observation. Wilson’s disease can be deferred at the initial consulta- Pathophysiology tion and reassurance provided. Referral for psychologic The pathophysiology is probably central, related to consultation is sometimes needed. As for the younger considerations described previously for central oscilla- child, a 1-year follow-up examination is important, or tors. Indirect evidence comes from clinical observations sooner if new symptoms develop. If symptoms clearly as well, such as abolition of ET symptoms after a cere- progress over 6 to 12 months, neuroimaging and other bellar stroke26 and reduction in symptoms with alcohol diagnostic studies are needed. or centrally acting medications. Despite high heritabil- Essential Tremor ity of ET, no unique causative gene has been identi- 27 Clinical Features fied. However, when the genome-wide scan of 452 ET patients was compared to that of 14,378 controls, The term essential tremor (ET) denotes relatively iso- a marker in intron 3 of the LINGO1 gene on chromo- lated tremor, normal brain imaging, and the absence of some 15q24.3 was found to be significantly associated other etiologies. ET lacks any specific biologic marker, with ET.28 Several loci of interest have been identified, but it is not solely a diagnosis of exclusion. The phe- but these are not part of routine clinical testing. These nomenology of ET is typically a bilateral postural hand have been designated EMT1 (chromosome 3q13) and tremor, although it may be asymmetric, sometimes EMT2 (chromosome 2p22-25). An additional locus at accompanied by head and voice tremor. 6p23 is also reported to be linked.27 ET diagnosis is more challenging in adults, because tremor is also a cardinal symptom of Parkinson’s dis- Diagnostic Approach ease (PD), which is highly prevalent in adult neurol- In the presence of a characteristic history of insidious ogy and movement disorder clinics. In contrast to most onset of bilateral, postural hand tremor, stable to ET, PD tremor is a unilateral, resting tremor. However, gradually progressive, continually present for longer than some clinical overlap is not uncommon and up to 20% 1 year, with normal detailed neurologic examination

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TABLE 12-2 consensus Criteria for Essential Tremor in Adults Inclusion—Required Permitted Exclusion Definite Bilateral postural hands Intention tremor Other abnormalities on examination (*except Froment sign) Visible tremor Involvement of other Causes of enhanced physiologic body parts (e.g., head) tremor Continuously present for longer Asymmetry Concurrent exposure to than 5 years tremorigenic medication Amplitude fluctuation Direct or indirect central nervous system (CNS) or peripheral nervous system (PNS) trauma Lack of functional Psychogenic tremor impairment Time course: sudden onset; stepwise deterioration

Probable Bilateral postural hand tremor Involvement of other Primary orthostatic with duration greater than body parts (e.g., head) 3 years Lack of hand involvement Isolated voice, tongue, (e.g., head only) chin tremor Position or task-specific tremor

Possible Criteria met for Definite or Probable, but • Other neurologic signs present • OR instead of both hands, body location is isolated voice, chin, tongue, one-hand only

*Froment sign is cogwheeling elicited by passively moving one limb while the patient voluntarily moves the other limb. The utility of this sign is not established in children, in whom there is commonly contralateral motor overflow. Source: Deuschl G, Bain P, Brin M: Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee, Mov Disord 13(suppl 3):2–23, 1998. Elble RJ: Diagnostic criteria for essential tremor and differential diagnosis, Neurology 54(11 suppl 4):S2-S6, 2000. otherwise, the diagnosis of ET is likely. The diagnosis months. If these findings are all stable over a 12-month of ET would be less likely if tremor is intermittent. period, follow-up thereafter may be as needed. Because a diagnosis of ET in a family member is helpful, it is reasonable to briefly examine one or both parents Treatment and use family history data. More significant neurologic The decision to treat is based on interference of activi- symptoms in the child or parent, such as gait problems, ties of daily living, such as writing, feeding, and social spasticity, ataxia, dysarthria, or dystonia, should prompt embarrassment. A tremor rating scale, the Tremor a more careful assessment of the child for other causes. Research Group (TRG) Essential Tremor Rating Scale Of course, a positive parental history of tremor does not (TETRAS), is currently being validated.3 A helpful, exclude the presence of another diagnosis in the child.29 easy-to-use scale for assessing tremor severity, the Brief It is helpful, in addition, to document the detailed neu- Tremor Rating Scale, may be used to assess severity of rologic examination, to obtain a writing sample and tremor (Table 12-3). freehand spiral with both hands, and to videotape the It is generally prudent to defer treatment if the score is key portions of the tremor examination (resting, pos- 0 or 1. For higher scores, it is reasonable to advise families tural, finger to nose). These can be used for compari- that treatment will be at best partially effective, and that son at a follow-up visit, at a reasonable interval of 12 possible side effects need to be weighed against benefits.

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TABLE 12-3 Brief Tremor Rating Scale Score Detail 0 Absent (no tremor or writing impairment) 1 Slight and infrequently present (mild tremor, writing, and drawing of spiral minimally impaired) 2 Moderate; bothersome to most patients (writing and drawing of spiral moderately impaired) 3 Severe tremor (writing and drawing severely impaired; interferes with many activities such as drinking liquids) 4 Marked tremor (interferes with most activities)

A reasonable goal is symptom reduction, not elimina- exert tremorigenic effects along with other neurologic tion, with reduction of tremor-related impairment. symptoms. These include heavy metals with both acute Expert consensus and clinical observation favor use and chronic exposure. Vitamin deficiencies are uncom- of primidone, starting at 25 mg at night and increasing mon in well-fed populations, but in developing nations, as needed to 125 to 250 mg at night (it is not known tremor may result from poor diet or diet deficient in key whether primidone or its metabolite PEMA is the more vitamins or minerals. Endocrine disorders and inborn effective component) or a beta-blocker, for example, pro- errors of metabolism are additional potential causes. pranolol 1-2 mg/kg/day up to 30 to 120 mg per day (twice A partial list of types of symptomatic tremor is in a day), consistent with the practice guideline for treat- Table 12-4. 30 ment in adults. Other possibilities include gabapentin, Treatment 31 pregabalin, and topiramate, based on small case series Treatment of clinically significant symptomatic tremor in adults. Botulinum toxin injections in the forearms, is directed, when possible, toward the underlying etiol- posterior neck muscles, or the vocalis muscle are often ogy. Otherwise, nonspecific tremor-suppressing med- used before recommending surgical treatment, namely ications used for essential tremor may be employed, 32 Botulinum toxin is considered the treatment of DBS. although benefit tends to be less. choice for dystonic tremor, discussed previously. Spasmus nutans is a transient condition that usually appears in the first year of life and is characterized by a Approach to Diagnosis and slow head tremor. Usually this is horizontal (“no-no”). Management Nystagmus usually occurs, either binocular or monoc- To summarize, when a child with tremor is seen for ini- ular. An abnormal head tilt and strabismus may occur. tial evaluation, a stepwise approach is helpful. Usually, See Chapter 5. the tremor is not an emergency, and a thoughtful Symptomatic Tremors assessment based on the history, examination findings, and common epidemiology can guide a cost-effective As is the case for myoclonus, symptomatic or secondary diagnostic evaluation. tremors can be caused by a vast number of conditions.60 Many of these processes affect nodes or pathways in 1. Clarify that tremor is the movement disorder. cortico-striato-pallido-thalamic circuits or cerebellar- Categorize: resting, action? Unilateral, bilateral? thalamic pathways, as described earlier in this chapter. 2. Stratify into a time-course group—acute, static, In addition, most of these secondary conditions manifest chronic progressive, episodic. with multiple types of abnormal movements and/or addi- 3. Perform a detailed neurologic examination for any tional neurologic symptoms, not merely isolated tremor. other motor findings attributable to cortical spinal Cerebellar malformations and cysts causing tremor tract dysfunction, peripheral dysfunction, basal are discussed in greater detail in Chapters 2 and 13. ganglia, or cerebellar dysfunction. Use this infor- Various congenital malformations involving the poste- mation to decide whether to obtain medical diag- rior cerebellar hemisphere and deep cerebellar nuclei nostic tests, including neuroimaging. may result in tremor. Malformations, neoplasms, and 4. For idiopathic, isolated, static tremor, clinical mon- infarctions in thalamus can also result in tremor. itoring without further testing may be adequate. Neurodegenerative diseases may cause tremor, but 5. For tremor that could be inherited, take a careful these typically also cause cognitive impairment, spasticity family history and examine parents and siblings, if or dystonia, or seizures. Similarly, a large number of toxins possible.

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TABLE 12-4 partial List of Types of Symptomatic Tremor Structural/Congenital Chromosomal Bobble-headed doll—third ventricular Aneuploidy extra X or Y chromosome dilation in infancy33 syndromes50 Pineal cyst, resolved with surgery35 Rhombencephalosynapsis36 Toxic 34 Thalamic cyst 51 4 Gas sniffing Thalamic infarction Lead, mercury52,53

Endocrine/Metabolic Nutritional Hepatic encephalopathy40 37 Indian infantile tremor syndrome (zinc, vitamin B12 Hyperthyroidism 54, 57–59 38 deficiency, vitamin C—multifactorial nutritional) Hyper-adrenaline state 55 39 Kwashiorkor (protein deficiency) Low magnesium Tetrahydrobiopterin deficiency56 Vitamin B (cobalamin) deficiency54 Metabolic 12 Biopterin synthesis defect43 Peripheral Neuropathy 41 Galactosemia Spinal Muscular Atrophy62 Phenylketonuria42 Medications (Iatrogenic) Degenerative Diseases Anticonvulsants, stimulants, tricyclic antidepressants, Ataxia with oculomotor apraxia46 61 neuroleptics, selective serotonin reuptake inhibitors, Huntington’s disease synthroid, cyclosporine, bronchodilators (see Chapter 18) Leukodystrophy45 Mitochondrial diseases49 Rett syndrome/MECP2 mutations 47,48 Wilson’s disease44

6. Unilateral or predominantly midline cerebellar REFERENCES signs may indicate focal cerebellar pathology. 7. Consider all possible treatable or curable causes of 1. Fusco C, Valls-Sole J, Iturriaga C, et al: Electrophysiological tremors. approach to the study of essential tremor in children 8. Rate the severity of the tremor on a clinical scale, and adolescents, Dev Med Child Neurol 45(9):624–627, and document the tremor via a video recording, to 2003. characterize the tremor and document its severity. 2. Elble RJ, Pullman SL, Matsumoto JY, et al: Tremor ampli- 9. Consider, in selected cases, use of quantitative tude is logarithmically related to 4- and 5-point tremor instruments, such as accelerometry, EMG, and rating scales, Brain 129(pt 10):2660–2666, 2006. 3. Elble RJ, Comella C, Fahn S, et al: The essential other electrophysiologic measures, to characterize tremor rating assessment scale (TETRAS), Mov Disord tremor and document its severity. 23(Suppl 1):S357, 2008. 10. Reassess tremor in 6 to 12 months. If a child’s tremor 4. Tan H, Turanli G, Ay H, Saatci I: Rubral tremor has clearly worsened during that time, an aggressive after thalamic infarction in childhood, Pediatr Neurol diagnostic evaluation is needed, including in most 25(5):409–412, 2001. cases brain magnetic resonance imaging (MRI). 5. Erer S, Jankovic J: Hereditary chin tremor in Parkinson’s 11. Before genetic testing, consider consultation with disease, Clin Neurol Neurosurg 109(9):784–785, 2007. genetics, which may allow for family education, 6. Goraya JS, Virdi V, Parmar V: Recurrent nocturnal as well as facilitating counseling around issues of tongue biting in a child with hereditary chin trembling, confidentiality, guilt, and blame. J Child Neurol 21(11):985–987, 2006. 12. Educate the family about the disease. 7. Johnson LF, Kinsbourne M, Renuart AW: Hereditary chin-trembling with nocturnal myoclonus and tongue- 13. Provide referrals for supportive services, as needed, biting in dizygous twins, Dev Med Child Neurol and encourage families to read about the disease 13(6):726–729, 1971. and join advocacy and research groups. 8. Kanazawa O: Shuddering attacks—report of four 14. Provide referrals for other therapies, for example, children, Pediatr Neurol 23(5):421–424, 2000. occupational, physical, or speech therapy if the 9. Lamarre Y: Tremorgenic mechanisms in primates, Adv patient’s function is below normal. Neurol 10:23–34, 1975.

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10. Lamarre Y, Filion M, Cordeau JP: Neuronal discharges 25. Tan EK, Lum SY, Prakash KM: Clinical features of of the ventrolateral nucleus of the thalamus during sleep childhood onset essential tremor, Eur J Neurol 13(12): and wakefulness in the cat. I. Spontaneous activity, Exp 1302–1305, 2006. Brain Res 12(5):480–498, 1971. 26. Dupuis MJ, Delwaide PJ, Boucquey D, Gonsette RE: 11. Llinas R, Muhlethaler M: Electrophysiology of Homolateral disappearance of essential tremor after cer- guinea-pig cerebellar nuclear cells in the in vitro brain ebellar stroke, Mov Disord 4(2):183–187, 1989. stem-cerebellar preparation, J Physiol (Lond) 404: 27. Deng H, Le W, Jankovic J: Genetics of essential tremor, 241–258, 1988. Brain 130(pt 6):1456–1464, 2007. 12. Bevan MD, Magill PJ, Terman D, et al: Move to the 28. Stefansson H, Steinberg S, Petursson H, et al: Variant in rhythm: oscillations in the subthalamic nucleus-exter- the sequence of the LINGO1 gene confers risk of essen- nal globus pallidus network, Trends Neurosci 25(10): tial tremor, Nat Genet 41(3):277–279, 2009. 525–531, 2002. 29. Nicholl DJ, Ferenci P, Polli C, et al: Wilson’s disease present- 13. Plenz D, Kitai ST: Generation of high-frequency ing in a family with an apparent dominant history of tremor, oscillations in local circuits of rat somatosensory cortex J Neurol Neurosurg Psychiatry 70(4):514–516, 2001. cultures, J Neurophysiol 76(6):4180–4184, 1996. 30. Zesiewicz TA, Elble R, Louis ED, et al: Practice param- 14. Plenz D, Kitai ST: Up and down states in striatal eter: therapies for essential tremor: report of the Quality medium spiny neurons simultaneously recorded with Standards Subcommittee of the American Academy of spontaneous activity in fast-spiking interneurons studied Neurology, Neurology 64(12):2008–2020, 2005. in cortex-striatum-substantia nigra organotypic cultures, 31. Ondo WG, Jankovic J, Connor GS, et al: Topiramate J Neurosci 18(1):266–283, 1998. in essential tremor: a double-blind, placebo-controlled 15. Cole JD, Philip HI, Sedgwick EM: Stability and tremor trial, Neurology 66(5):672–677, 2006. in the fingers associated with cerebellar hemisphere 32. Jankovic J: Disease-oriented approach to botulinum and cerebellar tract lesions in man, J Neurol Neurosurg toxin use, Toxicon 54(5):614–623, 2009. Psychiatry 51(12):1558–1568, 1988 [erratum: J Neurol 33. 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Jenkins IH, Bain PG, Colebatch JG, et al: A positron cephalosynapsis associated with infantile strabismus, emission tomography study of essential tremor: evidence Strabismus 16(1):23–27, 2008. for overactivity of cerebellar connections, Ann Neurol 37. Sherman J, Thompson GB, Lteif A, et al: Surgical man- 34(1):82–90, 1993. agement of Graves disease in childhood and adolescence: 19. Wills AJ, Jenkins IH, Thompson PD, et al: Red nuclear an institutional experience, Surgery 140(6):1056–1061, and cerebellar but no olivary activation associated with discussion 1061–1062, 2006. essential tremor: a positron emission tomographic study, 38. Brouwers FM, Eisenhofer G, Lenders JW, Pacak K: Ann Neurol 36(4):636–642, 1994. Emergencies caused by pheochromocytoma, neuroblas- 20. Wills AJ, Jenkins IH, Thompson PD, et al: A positron toma, or ganglioneuroma, Endocrinol Metab Clin North emission tomography study of cerebral activation asso- Am 35(4):699–724, 2006. ciated with essential and writing tremor, Arch Neurol 39. Flink EB: Magnesium deficiency. Etiology and clinical 52(3):299–305, 1995. spectrum, Acta Med Scand Suppl 647:125–137, 1981. 21. Boecker H, Wills AJ, Ceballos-Baumann A, et al: The 40. Wakamoto H, Manabe K, Kobayashi H, Hayashi M: effect of ethanol on alcohol-responsive essential tremor: Subclinical portal-systemic encephalopathy in a child a positron emission tomography study [see comment], with congenital absence of the portal vein, Brain and Ann Neurol 39(5):650–658, 1996. Development 21(6):425–428, 1999. 22. Shahed J, Jankovic J: Exploring the relationship between 41. Ridel KR, Leslie ND, Gilbert DL: An updated review essential tremor and Parkinson’s disease, Parkinsonism of the long-term neurological effects of galactosemia, Relat Disord 13(2):67–76, 2007. Pediatr Neurol 33(3):153–161, 2005. 23. Jankovic J, Madisetty J, Vuong KD: Essential 42. Perez-Duenas B, Valls-Sole J, Fernandez-Alvarez E, et al: tremor among children, Pediatrics 114(5):1203–1205, Characterization of tremor in phenylketonuric patients, 2004. J Neurol 252(11):1328–1334, 2005. 24. Louis ED, Dure LSt, Pullman S: Essential tremor 43. Factor SA, Coni RJ, Cowger M, Rosenblum EL: Paroxysmal in childhood: a series of nineteen cases, Mov Disord tremor and orofacial dyskinesia secondary to a biopterin 16(5):921–933, 2001. synthesis defect, Neurology 41(6):930–932, 1991.

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44. Machado A, Chien HF, Deguti MM, et al: Neurological Minamata and neighboring communities [see comment], manifestations in Wilson’s disease: report of 119 cases, Epidemiology 19(1):3–9, 2008. Mov Disord 21(12):2192–2196, 2006. 54. Garg BK, Srivastava JR: Infantile tremor syndrome, 45. Linnankivi T, Lundbom N, Autti T, et al: Five new cases Indian J Pediatr 36(257):213–218, 1969. of a recently described leukoencephalopathy with high 55. Thame M, Gray R, Forrester T: Parkinsonian-like trem- brain lactate, Neurology 63(4):688–692, 2004. ors in the recovery phase of kwashiorkor, West Indian 46. Mahajnah M, Basel-Vanagaite L, Inbar D, et al: Familial Med J 43(3):102–103, 1994. cognitive impairment with ataxia with oculomotor 56. Neville BG, Parascandalo R, Farrugia R, Felice A: apraxia, J Child Neurol 20(6):523–525, 2005. Sepiapterin reductase deficiency: a congenital dopa- 47. Einspieler C, Kerr AM, Prechtl HF: Is the early develop- responsive motor and cognitive disorder, Brain 128 ment of girls with Rett disorder really normal? Pediatr (pt 10):2291–2296, 2005. Res 57(5 pt 1):696–700, 2005. 57. Ratageri VH, Shepur TA, Patil MM, Hakeem MA: 48. Lundvall M, Samuelsson L, Kyllerman M: Male Rett Scurvy in infantile tremor syndrome, Indian J Pediatr phenotypes in T158M and R294X MeCP2-mutations, 72(10):883–884, 2005. Neuropediatrics 37(5):296–301, 2006. 58. Thora S, Mehta N: Cranial neuroimaging in infantile 49. Lee HF, Lee HJ, Chi CS, et al: The neurological evo- tremor syndrome (ITS), Indian Pediatr 44(3):218–220, lution of Pearson syndrome: case report and literature 2007. review, Eur J Paediatr Neurol 11(4):208–214, 2007. 59. Vora RM, Tullu MS, Bartakke SP, Kamat JR: Infantile 50. Tartaglia N, Davis S, Hench A, et al: A new look at tremor syndrome and zinc deficiency, Indian J Med Sci XXYY syndrome: medical and psychological features, 56(2): 69–72, 2002. Am J Med Genet Part A 146A(12):1509–1522, 2008. 60. Keller S, Dure LS: Tremor in childhood, Semin Pediatr 51. Remington G, Hoffman BF: Gas sniffing as a form of Neurol 16(2):60–70, 2009. substance abuse, Can J Psychiatry Rev Can Psychiatrie 61. Rasmussen A, Macias R, Yescas P, et al: Huntington 29(1):31–35, 1984. disease in children: Genotype-phenotype correlation, 52. Despres C, Beuter A, Richer F, et al: Neuromotor functions Neuropediatrics 31:190–194, 2000. in Inuit preschool children exposed to Pb, PCBs, and Hg, 62. Dawood AA, Moosa A: Hand and ECG tremor in Neurotoxicol Teratol 27(2):245–257, 2005. spinal muscular atrophy, Arch Dis Child 58:376–378, 53. Yorifuji T, Tsuda T, Takao S, Harada M: Long-term 1983. exposure to methylmercury and neurologic signs in

[email protected] 66485438-66485457 Ataxia O 13 O Introduction and Overview Stability of the head and trunk may be poor and there may be consistent bobbing movements. Walking or run- This chapter encompasses diseases and disorders of the ning may be clumsy, broad-based, and staggering. cerebellum and its connections. Ataxia, or cerebellar disorders and diseases more A vast number of conditions adversely affect generally, can adversely affect motor control of eyes, cerebellar function in children. The most common of speech, trunk, and limbs in characteristic ways. these problems are static and nonspecific, leading to Complex, multijoint movements are more impaired children who, relative to peers, are clumsy. A second than single-joint movements, with compensatory common category, acute ataxias, may result from responses contributing to some aspects of observed O intoxications, infections, post-infectious/inflamma- movement abnormalities. Inaccuracy is greater at high tory cerebellar conditions, vascular insults, or trauma. speed than slow speed.3 Hallmark findings are pre- Many other low-prevalence and rare neurologic condi- sented in Table 13-1. tions manifest with signs and symptoms of cerebellar dysfunction. Of particular importance are neoplasms, Localization and Pathophysiology because early detection is important. Genetic, degenerative ataxias are far rarer, but nonetheless will be Understanding a simplified model of cerebellar anatomy seen by neurologists in practice. Diagnosis is diffi- and neurotransmission is helpful and is addressed in cult and treatments very limited, but arriving at the greater detail in Chapter 2. Figures 13-1 through 13-5 most precise diagnosis possible has value for families. provide an overview of some types of cerebellar pathology Quantitative rating scales have been developed to in children and link these to symptoms in Table 13-1. follow the natural progression of ataxia and response to therapy.1 Diseases and Disorders

Definition of Ataxia Nonprogressive Ataxia I: The Uncoordinated Child Ataxia is defined as an inability to generate a nor- Clinical Features mal or expected voluntary movement trajectory that cannot be attributed to weakness or involun- One of the most common referrals to child neurology is tary muscle activity (chorea, dystonia, myoclonus, for a child with developmental delay. Often such children tremor) about the affected joints. Ataxia can result have problems with movement and coordination that from impairment of spatial pattern of muscle activity become apparent between ages 3 and 7 years. Parents, or from impairment of the timing of that activity, teachers, and primary physicians may be concerned or both2. about subnormal fine or gross motor skills. Usually, these children do not have progressive disease. More often it Clinical Characteristics— is because the child’s limited abilities are encountering Phenomenology of Ataxia more complex tasks and expectations in school. Typically, there is a nonspecific constellation of in Children motor symptoms. Parents may report tremor of hands The ataxic child may have generalized or localized motor and sometimes trunk noted on awakening, with fatigue coordination problems. Abnormal eye movements or stress, and particularly during fine motor tasks such of several kinds, notably nystagmus or oculomotor as drawing, using scissors, or playing with small toys. apraxia, may occur. Speech may be slow and/or slurred. Fine and/or gross motor skills may be developmen- Reaching-out of hands to a target or to perform a task tally delayed. Often, articulation problems are noted may demonstrate significant tremor and clumsiness. and referrals made for speech therapy. As time passes, 139 [email protected] 66485438-66485457 140 Section 4 Hyperkinetic and Hypokinetic Movement Disorders

TABLE 13-1 Hallmark Findings of Ataxia Eye movements Nystagmus—oscillatory, rhythmic movements of the eyes Impairment with maintaining gaze Difficulties with smooth visual pursuit Undershooting (hypometria) or overshooting (hypermetria) of saccades

Speech Dysarthria, imprecise production of consonant sounds Dysrhythmia of speech production Poor regulation of prosody; slow, irregularly emphasized (i.e., scanning) speech Figure 13-1. Diffuse cerebellar and brainstem volume loss Trunk movements Unsteadiness while standing or in a child with congenital pontocerebellar hypoplasia. sitting, such that the person In addition to severely abnormal cognition and involuntary may have to use visual input or movements, the child had intractable epilepsy and apnea, with hands for stabilization progressive CNS volume loss and death before age 10 years. Titubation—characteristic bobbing of the head and trunk

Limb movements Hypotonia—diminished resistance to passive limb displacement Pendular reflexes Rebound—delay in response to rapid imposed movements and then overshoot of the target Imprecise targeting of rapid distal limb movements Intention tremor—tremor at the end of movement seen on finger-to-nose and heel-to-shin testing Delays in initiating movement Dysynergia/asynergia— decomposition of normal, coordinated execution of movement—errors in the relative timing of components of complex multijoint movements Difficulties with spatial Figure 13-2. Coronal T1 MR image of child with coordination of hand and fine partial fusion of the anterior cerebellar lobes, a partial fractionated finger movements rhombencephalosynapsis. This child had predominantly Dysdiadochokinesia—errors nonprogressive gait ataxia with significant decompensation in rate and regularity of during periods of illness. A full syndrome includes cerebellar movements, including fusion and absence of vermis. Cerebral abnormalities and alternating movements epilepsy may also occur.79 Gait Broad-based, staggering gait Neurologic examination should typically reveal normal mental status and cranial nerves, with no nystagmus. additional problems with learning and behavioral regu- Strength and bulk should be normal, tone may be non- lation may become apparent. specifically low, and reflexes symmetric. Sensory exami- On general physical examination, special note should nation should be grossly normal. Fine motor skills, rapid be made of any dysmorphic features and cardiac findings. movements, and sequential finger movements may be

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Figure 13-3. Coronal and midline sagittal T2 MR images of an adolescent with congenital left cerebellar hemisphere hypoplasia, likely secondary to remote insult. The child had normal intelligence and normal gait, with clumsiness, intention and postural tremor in the left hand.

Figure 13-4. Dandy-Walker syndrome—enlarged fourth Figure 13-5. Coronal FLAIR MR image of 7-year-old girl ventricle, absence of cerebellar vermis. This infant has a with midline cerebellar ependymoma. The child had 2 months chromosome 3 deletion with relatively normal early motor of escalating headaches, nocturnal vomiting, fatigue, and milestones. Developmental disabilities are common but not finally double vision. Ataxia was not noted, but after tumor universal in children with Dandy-Walker syndrome.10,11 resection the child developed cerebellar mutism. This can occur after posterior fossa surgery and may be due to injury to vermis or dentate nucleus.34,80 Splitting the posterior, inferior mildly abnormal for age. A writing sample or drawing vermis can result in predominantly tandem gait difficulty.81 sample using the simple Gesell figures (circle, square, triangle, cross) and freehand spirals may be obtained for Diagnostic Approach current assessment and future comparison. In many cases where the problem appears to be static Pathophysiology but is relatively mild, and no skills have been lost, a The pathophysiology of routine clumsiness and difficul- detailed diagnostic evaluation with laboratory testing ties with fine motor, gross motor, or speech articulation and neuroimaging is not necessary. A follow-up exami- is variable and nonspecific. Sometimes a history of nation in 6 to 12 months to ensure that there is no prenatal or perinatal injury is present, other times not. regression suffices. Neuroimaging should usually be Most likely, in cases that are nonprogressive, a variety of obtained in several situations: (1) In cases where other genetic and environmental factors come into play. This abnormalities are identified on general examination, is similar to most developmental and behavioral diag- suggesting the presence of a syndrome. In these cases, noses, such as attention-deficit/hyperactivity disorder. karyotyping or genomic hybridization studies should

[email protected] 66485438-66485457 142 Section 4 Hyperkinetic and Hypokinetic Movement Disorders be considered as well. (2) In cases with clearly asym- have been associated with numerous chromosomal dis- metric motor findings, microcephaly, or more severe orders, gene mutations, inborn errors of metabolism, motor problems. “Ataxic cerebral palsy” has lower and teratogens.11 There is no specific medical therapy prevalence than spastic forms. The American Academy for these patients, but neurosurgical consultation for of Neurology Practice Guideline for the evaluation of shunting or fenestration of the ventricles or posterior the child with cerebral palsy recommends that neu- fossa cysts may be needed. Joubert’s syndrome is an auto- roimaging be obtained in children diagnosed with cere- somal recessive syndrome characterized by agenesis bral palsy.4 (3) In cases where nystagmus, headaches of the vermis, dysplasia and heterotopias of cerebellar in a young child, and acquired ocular malalignment nuclei, elongation of the superior cerebellar peduncles, are present. The imaging modality of choice is mag- and other brainstem anomalies. Clinically, patients netic resonance imaging (MRI), although ultrasound have episodic hyperpnea and apnea, abnormal eye through the open fontanel in infants is sometimes a movements, mental retardation, and ataxia. Cerebellar good choice. hypoplasia and pontocerebellar hypoplasia may be part of multiple syndromes that clinically include ataxia, as Treatment well as other neurologic or organ system dysfunction. Referral for occupational/physical/speech therapy or Examples include several familial autosomal recessive or special education evaluation may be helpful. In terms X-linked syndromes, multiple chromosomal trisomies, of anticipatory guidance for parents of young children, Smith-Lemli-Opitz syndrome, bilateral periventricular it should be pointed out that when motor problems nodular heterotopia/mental retardation syndrome, are present, there is a somewhat higher risk for devel- pontocerebellar hypoplasias types I and II, and congen- opment of cognitive and emotional problems as well. ital disorders of glycosylation syndromes types I and II. Encouragement of nonfrustrating motor activities that No specific medical therapies are available for the ataxia enhance coordination, such as participation in music, symptoms. Outcome varies with etiology. may produce positive central nervous system (CNS) changes that could be beneficial to motor control over Acute Ataxias time. There are not strong data on this point; however, a number of studies show structural differences related Overview of Clinical Features to music training that might be compensatory for Acute ataxia in a previously well child usually manifests clumsy children.5–8 with gait impairment. A large number of acute proc-esses (partial list in Table 13-2) can affect cerebellar function Outcomes in an acute or a subacute manner. These include intoxi- Outcomes are highly variable and likely explained cations/ingestions, ataxia associated with post-ictal or largely by etiology and by nonmedical therapies and non-convulsive status epilepticus, trauma, auto-immune. other positive environmental factors. A thorough history and examination is essential to iden- Nonprogressive Ataxia II: Ataxia tify serious causes. Pathophysiology, treatment, and out- Associated with Congenital Cerebellar comes are discussed by disease or category. may cause ataxia, sometimes in con- Malformations Intoxications junction with an acute confusional state. Anticonvulsant A large number of congenital malformation syndromes, medications, alcohol, stimulants, and other exposures as well as prenatal insults, may be associated with devel- can often be identified by history, and urine/serum opmental delay, hypotonia, tremor, and ataxia.9,10 drug screening. Pathophysiology relates to disrup- Clinical features relate to the anatomic distribution of tion of neural signaling in the cerebellum or damage the malformation. Unilateral cerebellar malformations to cerebellar pathways. Illicit sniffing or huffing of are generally acquired because of prenatal, perinatal, toluene-containing solvents can produce diffuse white or postnatal insults. Multiple syndromes are associated matter injury and signal change in cerebellar pedun- with dysgenesis of the midline cerebellar structures. cles, resulting in ataxia, kinetic tremor, titubation, and Dandy-Walker malformations, characterized by large visual loss.12,13 Acute ataxia and headache evolving to posterior fossa cystic dilation, upward displacement of cerebellar stroke after marijuana exposure was reported the tentorium, midline communication with the fourth in three cases, two of which were fatal.14 Treatment for ventricle, and complete or partial agenesis of the vermis, intoxications is mainly supportive, and outcomes in can manifest with early hydrocephalus and later cranial children are usually excellent. nerve palsies, nystagmus, truncal ataxia, seizures, or Acute cerebellar ataxia may occur after a clinical or sub- cognitive impairments. Dandy-Walker malformations clinical infection or vaccination. A variety of preceding

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Table 13-2 differential Diagnosis of Acute, Recurring, and Subacute Ataxias in Childhood Category Examples Clinical features Acute Toxic Acute Alcohol, Toddlers – accidental ingestion; Adolescents – substance abuse. ingestion anticonvulsants, Mental status changes common, urine/serum toxicology antihistamines, screen in Emergency Department may detect unsuspected benzodiazepines ingestions.

Inflammatory Acute cerebellar ataxia Symmetric cerebellar findings, gait impairment, truncal ataxia, titubation, nystagmus. Mental status normal. Usually postinfectious. Consider opsoclonus myoclonus ataxia syndrome.

Trauma/Vascular Stroke, vertebrobasilar Consider after neck trauma or if hypercoagulable. dissection. Recurring Metabolic Many inborn errors Can be triggered by intercurrent illness. of metabolism may occur intermittently

Migrainous Basilar migraine, Initial episode suggests focal pathology and in the young child, benign paroxysmal headache may not be prominent. Imaging needed to rule out vertigo other treatable causes.

Episodic Ataxias Episodic Ataxias Bouts of dysarthria, gait ataxia. Sometimes triggered. Type I and II

Functional Psychogenic Gait disturbance or abnormal tremor-like movements which Movement do not conform to usual pattern of disease and are not Disorders supported by typical neurological examination findings. Sudden onset, dramatic or variable symptoms. See chapter 19 Psychogenic Movement Disorders.

Subacute Guillain Barre Oculomotor paresis, bulbar weakness, hyporeflexia, pain. Risk Syndrome, including for respiratory/autonomic failure. Note – neuromuscular Miller Fischer Variant causes of weakness may masquerade as ataxia due to problems with limb control and gait.

Acute Disseminated Mental status changes; and multifocal neurologic deficits. Encephalomyelitis multiple discrete gray and white matter lesions on MRI. (ADEM)

Opsoclonus myoclonus Truncal ataxia, myoclonus, (transient) opsoclonus, behavioral ataxia syndrome irritability. Paraneoplastic (neuroblastoma) or post-infectious.

Mass lesions Posterior fossa Headaches, vomiting, papilledema, cranial nerve palsies. neoplasms infections, including enterovirus, parvovirus, and cells, were discovered in one recent case.16 Recovery is malaria, have been described. Symptoms of gait ataxia complete in approximately 90%, with mean time to nor- occur almost universally, with truncal ataxia less common mal gait of 2 to 3 months.15 Treatment is not currently and nystagmus in fewer than 25%.15 Cerebrospinal fluid recommended, although immune-modulating therapies (CSF) abnormalities, if present, are nonspecific: elevated are sometimes used.17 white blood cell count in 30% to 50%, elevated protein Subacute Ataxias in 6% to 27%. The pathophysiology is unclear but may be similar to paraneoplastic ataxia in adults. Antibodies to Opsoclonus-myoclonus-ataxia syndrome should be con- metabotropic glutamate receptor 2, expressed in Purkinje sidered carefully in the differential diagnosis of the

[email protected] 66485438-66485457 144 Section 4 Hyperkinetic and Hypokinetic Movement Disorders young child with subacute ataxia.18 The clinical fea- Metabolic Ataxias—Acute Intermittent tures are contained in the name of the syndrome, but it A number of metabolic disorders can cause paroxysmal is noteworthy that the classic eye movement abnormal- ataxias. Often, ataxia, or acute intermittent ataxia, does ity, opsoclonus (saccadomania), may be missed because not dominate the clinical picture. Specific examples of its transient nature, and truncal myoclonus may be of metabolic diseases that can cause intermittent atax- difficult to distinguish from truncal ataxia in a tod- ias include maple syrup urine disease (branched chain dler. Opsoclonus-myoclonus may be postviral or para- aminoaciduria), Vitamin E deficiencies, Hartnup dis- neoplastic, related to the solid tumor neuroblastoma. ease, hyperammonemia, biotinidase deficiency, mito- Additional details on the diagnostic testing process and chondrial disorders, and pyruvate dehydrogenase (PDH) management are in Chapter 11. complex deficiency. Acute disseminated encephalomyelitis (ADEM) is Pyruvate dehydrogenase (PDH) deficiency, resulting an immune-mediated condition that can manifest from mutations in components of the PDH enzyme in childhood with ataxia (18% to 65% of cases)19 complex, can cause intermittent bouts of ataxia that or movement disorders, although usually weakness last for days. Supportive laboratory findings include and lethargy are also prominent.19,20 Clinical features elevated serum pyruvate and alanine, and a CSF lac- correlate somewhat to the number and localization of tate level exceeding that in the serum. Administration central nervous system discrete lesions seen on mag- of 100 to 200 mg per day of thiamine (vitamin B1) and netic resonance imaging (MRI). Time course is usually reducing carbohydrate intake may diminish the dura- monophasic, lasting for weeks, with recurrence rate tion of symptoms and frequency of episodes. Cost/ben- estimates usually at less than 25%. The pathophysiol- efit ratio of the ketogenic diet for treatment of patients ogy is not known but is presumed to be autoimmune, with the intermittent phenotype is unclear. For a more triggered by viruses or in rare cases by vaccinations detailed description, refer to Chapter 15. and may overlap with other autoimmune ataxias.21 The diagnosis should be considered in a child with Episodic Ataxia Type 1 (EA1) subacute decline in mental status and motor function, Clinical Features and is generally confirmed through the characteristic MRI. This shows multifocal, multiple sclerosis–like Clinical features of EA1 include childhood onset, lesions involving both gray and white matter. Many brief (minutes) attacks of dysarthria, and incoordina- neurologists treat ADEM with immune-modulating tion. Sudden movement, anxiety, excitement, fevers, therapies such as steroids (intravenous [IV] methyl- and other factors can be triggers. Between attacks, prednisolone at 10 to 30 mg/kg/day up to a maximum myokymia—semirhythmic twitching in the hand, the of 1 g/day, followed by a 4- to 6-week oral taper), or tongue, or the skin around the eyes and mouth—is IV immunoglobulins (1 to 2 g/kg dose), and/or plas- usually present, although this may be subtle in children. mapheresis. This practice is based in part on clinical The cause of this disease is a mutation in the potas- 25 observations of benefit and based on analogies with sium channel gene KCNA1. Penetrance is believed multiple sclerosis. There are no randomized con- to be complete. Treatment, if desired, is with carbonic trolled treatment trials. Outcomes are largely good, anhydrase inhibitors (acetazolamide), up to 375 mg with more than 80% of children suffering no readily twice per day. This is not always effective chronically, apparent sequelae. and some patients take small doses intermittently, for Children with tick paralysis may have ascending example, before playing sports. paralysis, bulbar weakness, and occasionally ataxia,22 Episodic Ataxia Type 2 (EA2) due to a toxin carried in tick saliva.23 The pathophysiology is believed to involve a failure of neuromuscular Clinical Features transmission.24 The diagnosis should be considered in Clinical features of EA2 include episodes of ataxia lasting the proper clinical context, and the scalp of the child hours to days, with gaze-evoked nystagmus between epi- carefully inspected for ticks. Treatment is removal of sodes. Triggers for the ataxia episodes include emotional the tick, and supportive care until symptoms resolve, upset, exercise, alcohol, phenytoin, and caffeine. Some usually rapidly. patients ultimately have chronic, slowly progressive Acute Recurrent Ataxias ataxia. EA2 has been identified with both heterozygous point mutations and abnormally increased CAG repeats This category includes the metabolic diseases causing in the calcium channel subunit gene CACNA1A.26–28 acute recurrent ataxia as well as other genetic episodic Further increase in CAG repeats cause the allelic disorder ataxias. SCA6, which causes ataxia and dystonia in adulthood.29

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EA2 and SCA6 are also allelic with familial hemiple- well as many other resources, and is an invaluable diag- gic migraine, caused by a point mutation in this gene. nostic aid. After consulting with OMIM and refining Treatment of EA2 with doses of acetazolamide of 250 to the list of genetic disorders, the second extremely use- 750 mg per day can be dramatically effective.26 ful website is the National Institutes of Health–funded GeneTests website at www.geneclinics.org/. This pro- Chronic Progressive and vides helpful disease descriptions and expert reviews. Degenerative Ataxias More important, this site provides detailed information about types of genetic testing, as well as contact infor- Overview of Clinical Features and mation for laboratories where testing may be obtained. Diagnostic Approach A partial list of heritable ataxias that may occur in Chronic progressive ataxias include diseases with primar- childhood and associated features is in Table 13-3. ily ataxia and diseases where other motor, cognitive, and The next sections address inherited ataxias, focusing limbic systems are involved and cerebellar dysfunction on those that occur in children. The inheritance pat- is less substantial. In general, any child with apparently tern of a positive family history, when present, assists in worsening cerebellar symptoms and signs (see Table 13-1) narrowing the diagnosis. Therefore the most common needs a thorough diagnostic investigation. After review- pediatric forms of heritable ataxia will be presented, ing all the pertinent findings, including family history separated by inheritance pattern. and detailed general, ophthalmologic, and neurologic Autosomal Dominant Spinocerebellar examinations, the single most useful initial diagnostic test in virtually all of these cases is a brain MRI scan. IV Ataxias contrast should be used in cases with more rapidly pro- These are mainly the spinocerebellar ataxias (SCAs). gressive symptoms or when neoplasms or inflammatory Most are not known to occur in childhood and will conditions are in the differential diagnosis. not be addressed in this chapter. In general, the auto- In some cases, neuroimaging will identify a neo- somal dominant SCAs can be subcategorized into plasm or other space-occupying lesion. A thorough five groups: (1) CAG (polyglutamine) repeat expan- discussion of neoplasms and surgical lesions lies outside sion disorders within gene reading frames (SCAs 1, the scope of this textbook, but helpful recent reviews 2, 3, 7, 17); (2) disorders with noncoding repeats may be consulted.30–32 In general, it should be borne (SCAs 8, 10, 12); (3) disorders with known gene in mind, however, that the most common pediatric mutations which are not repeats (SCAs 5, 11, 13, brain tumors—pilocytic astrocytomas, primitive 14, 15); (4) disorders with chromosomal linkage neuroectodermal tumors (PNETs, also known as medu- only (SCAs 4, 19, 21); and (5) autosomal dominant loblastomas), ependymomas, and pontine gliomas—are episodic ataxias (EAs) (E1, EA2/SCA6).35 Research after more likely to occur in the posterior fossa in children. the identification of causative genes often broadens and Thus headache, brainstem findings, and ataxia may refines our understanding of the phenotype. Diseases develop. Of these tumors, the pilocytic astrocytomas are once thought to involve certain key features and ages of most amenable to surgery and have the best outcome.33 onset often have a more variable phenotype or earlier Surgical treatment of cerebellar tumors may be cura- onset than was initially appreciated. tive, but may also induce new neurologic problems Spinocerebellar Atrophy Type 1 (SCA1) such as cerebellar mutism. This is most common after resections of midline PNETs with brainstem invasion, Clinical Features and varying degrees of mutism and ataxia may persist Clinical features include slow saccades, optic atrophy, for greater than a year.34 nystagmus, amyotrophy, progressive ataxia, dystonia Often, a specific diagnosis will not be made after or chorea, and mild cognitive impairment. The disease MRI, but MRI findings may direct subsequent bio- is caused by a CAG expansion in the ataxin 1 gene.36 chemical, metabolic, or genetic investigations. Usually, onset is in adulthood. Genetic testing is avail- If a genetic cause is suspected, the use of updated able but there is no specific medical treatment. Web-based databases is recommended, see Appendix B. Spinocerebellar Atrophy Type 2 (SCA2) For example, the National Center for Biotechnology Information’s Online Mendelian Inheritance in Man Clinical Features (OMIM) at www.ncbi.nlm.nih.gov/Omim/ allows Clinical features are highly variable, with presentation searches based on several signs and symptoms, and each as ataxia or parkinsonism or both. Other symptoms clinical entry contains useful text and a clinical syn- include slow saccades, nystagmus, retinitis pigmentosa opsis in outline form. This is linked to PUBMED, as (rare), myoclonus, dementia, posterior spinal cord

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IU/kg/day vitamin E mg/kg/day.

45 100

may improve somewhat with trihexyphenidyl or botulinum toxin. IVIG if immune deficiency/ frequent infections. for life. Medical Treatment High-dose idebenone, with high doses: Treat None for ataxia. Dystonia None None None None None

in frataxin} CAG repeats in ataxin-1 CAG repeats in ataxin-2 CAG repeats in MJD1 CAG repeats (>> in childhood cases) in SCA7 gene the potassium voltage-gated channel subfamily C member 3 to confirm the diagnosis; genetic testing, DNA radiosensitivity, gene are sequencing the ATM often unnecessary D iagnostic Tests Genetic—>90 GAA expansion Low vitamin E levels Elevated AFP is usually sufficient Genetic testing reveals >40 Genetic testing reveals >33 Genetic testing reveals >74 Genetic testing reveals >36 Genetic—mutations in the KCNC3,

Inheritance AR AR AR AD AD AD AD AD

4 years at 1–

29 years) 35 years) 30 years) 15 years)

E arliest Age and Mean Age O nset >2 years, (mean Usually early childhood Movement disorder 15 years (mean 6 months (mean 10 years 1 year (mean Childhood [email protected] 66485438-66485457

disorder—ataxia, chorea, dystonia, athetosis; oculomotor signs, telangiectasias (later) infections rapid progression degeneration

neuropathy, areflexia, neuropathy, extensor plantar response, diabetes cardiomyopathy, pyramidal tract signs, brainstem symptoms, peripheral neuropathy slow saccades, tremor, hyporeflexia retinitis pigmentosa, dystonia Classic Features Gait ataxia, axonal Progressive ataxia, Progressive movement Recurrent sinopulmonary Ataxia, dysarthria, Ataxia, dysarthria, Ataxia, dystonia, spasticity, Ataxia, macular Ataxia, nystagmus

41 50 , 54 Selected Heritable Ataxias That May Manifest with Chronic P rogressive Ataxia in Childhood 55 , 57

50 , 6 5

47, 49

36 37 , 38 44 , 45

deficiency telangiectasia

D isease Friedreich ataxia Ataxia with vitamin E Ataxia SCA1 SCA2 SCA3/MJD type 1 SCA7 SCA 13 ataxia telangiectasia mutation; CAG/GAA, trinucleotide sequences; CACNA/KCNA, calcium and potassium channel alpha-fetoprotein; AR, autosomal recessive; ATM, AD, autosomal dominant; AFP, ataxia. subunit genes; IVIG, intravenous immune globulin; MJD, Machado-Joseph disease; SCA, spinocerebellar E 13-3 TABL Chapter 13 Ataxia 147

column degeneration, and peripheral neuropathy. and mild mental retardation may occur. Hyperreflexia Neuroimaging may show pontocerebellar hypotrophy. and hypotonia are also present, as is cerebellar atro- The disease is caused by CAG repeat expansion in the phy. Onset can occur in childhood. Disease progresses Ataxin 2 gene.37 Onset is usually in adulthood, but slowly.47,48 The pathophysiology involves mutations in pediatric cases have been described.38,39 Genetic testing KCNC3, the potassium voltage-gated channel sub- is available but there is no specific medical treatment. family C member 3.49 This mutation has a dominant negative effect and slows closing of potassium chan- Spinocerebellar Atrophy Type 3 (SCA3); also known nels, which prevents fast spiking critical for normal as Machado-Joseph Disease cerebellar function. The diagnosis should be consid- Clinical Features ered in the presence of autosomal dominant ataxia, but Clinical features include eye movement abnormalities, specific features, particularly in adults, do not narrow ataxia, spasticity, and dystonia. This disease is caused the differential diagnosis. Genetic testing is available. by a trinucleotide CAG repeat expansion in the ataxin Currently, there is no treatment. 40,41 3 gene. Onset is usually in adulthood, but some Autosomal Recessive Ataxias cases with rapid progression begin between ages 10 and 30. Genetic testing is available. Clinical studies Autosomal recessive ataxias may occur more com- of trimethoprim-sulfamethoxazole (TMP/SMZ) have monly in childhood.50 The most common autosomal been performed, based on data suggesting it could cor- recessive ataxias are Friedreich ataxia (FA) and ataxia rect abnormally low CSF biopterin and homovanillic telangiectasia. acid levels, thereby increasing levels of dopamine, nor- Friedreich Ataxia epinephrine, and serotonin. A randomized, placebo- controlled trial failed to confirm benefit suggested by Clinical Features open-label studies.42 Rapamycin is being studied in Clinical features of FA, which is the most prevalent laboratory models to reduce autophagy and toxicity in inherited ataxia, include childhood onset, progressive, diseases associated with polyglutamines.43 predominantly sensory cerebellar ataxia, dysarthria, areflexia, pyramidal leg weakness, sensorineural hear- Spinocerebellar Atrophy Type 7 (SCA7) ing loss, hypertrophic cardiomyopathy, and diabetes.51 Clinical Features Ambulation is lost by age 15 to 20 years. A variety of SCA7 is characterized by progressive ataxia, dysarthria, movement disorders, including tremor, dystonia, and 52 dysphagia, dysmetria, and slow saccades. Hyperreflexia, myoclonus, may be associated with FA. chorea, and dystonia also may occur. Visual loss caused Pathophysiology by macular and pigmentary retinal generation and optic Pathophysiology of FA results from expanded GAA atrophy set this apart from the other autosomal dominant triplet repeats within the first intron of the frataxin SCAs. There is genetic anticipation, particularly with pater- (FRDA) gene, causing impaired exon splicing and nal transmission, due to unstable CAG repeat expansion, reduced expression. Frataxin may function as an iron with age of onset correlating inversely with repeat number. storage or transport protein in mitochondria, and the In early childhood and infantile cases, progression to death excessive iron in mitochondria may increase oxidative is rapid.44 The pathophysiology of this disease is expanded or free radical damage. 45 CAG repeats in the ataxin 7 gene. Postmortem study Diagnosis shows severe neuronal loss and neuronal intranuclear inclusions in the inferior olivary nucleus.46 The diagno- The diagnosis should be considered in the presence sis should be considered in families with autosomal domi- of the characteristic clinical symptoms of ataxia with nant ataxia, particularly with retinal degeneration. Genetic weakness and areflexia. Genetic testing is available. testing is available. There is no specific treatment available, The discovery of the gene has led to recognition of and outcomes relate to the speed of disease progression, some milder forms, with longer life span and preserved with worse outcomes in children than adults. reflexes. Treatment Spinocerebellar Atrophy Type 13 (SCA13) The most recent treatment trials have focused on reduc- Clinical Features tion of free radical damage. A 12-month, random- Clinical features of SCA13 are pancerebellar. ized, blinded, placebo-controlled trial of idebenone, Nystagmus, ataxia of limbs and gait, and dysarthria a free radical scavenger, showed moderate improve- all occur. Motor and development may be delayed ment in echocardiographic measures of hypertrophy

[email protected] 66485438-66485457 148 Section 4 Hyperkinetic and Hypokinetic Movement Disorders but no improvement in ataxia.53 A follow-up placebo- Ataxia with Oculomotor Apraxias controlled, multidose study, however, suggested that Clinical Features higher doses, up to 45 mg/kg/day, might reduce ataxia, Clinical features of ataxia with oculomotor apraxias particularly if used earlier in the disease.54 Further (AOA) types 1 and 2 resemble AT, with slightly later testing of idebenone, as well as of iron chelators and onset and only the neurologic phenotype—oculomotor histone deacetylase inhibitors, is ongoing. apraxia, ataxia, and choreoathetosis, distal sensory axonal Ataxia Telangiectasia neuropathy, and marked cerebellar atrophy by brain imaging. Hypoalbuminemia and hypercholesterolemia Clinical Features were also present in AOA1.59 The etiology of AOA1 Ataxia telangiectasia (AT) manifests in early childhood. is autosomal recessive mutations in the histidine triad Gait, trunk, and limb movement abnormalities occur, (HIT) superfamily protein aprataxin (gene APTX).60 although patients may maintain surprisingly good bal- AOA2, like AT, has elevated alpha-fetoprotein. ance for the first few years. Early movement problems It is also referred to as autosomal recessive spinocerebel- may be ataxic, dystonic, or choreic, but gait and limb lar ataxia 1 (SCAR1). The etiology of AOA2 is muta- symptoms progress, leading to loss of ambulation in tions in senataxin.35 Genetic testing is available for both childhood.55 The movement disorder precedes the diseases. There is no specific medical treatment. onset of the characteristic oculocutaneous telangiectasias. Eye movement problems occur in most patients, Ataxia with Isolated Vitamin E Deficiency with difficulty initiating horizontal and vertical sac- Clinical Features cades. Immunologic deficiencies can lead to increased Ataxia with isolated vitamin E deficiency (AVED) symp- sinopulmonary infections. Risk of lymphoreticular toms vary from mild to severe. In severe cases occurring neoplasms is also increased. in childhood, initial misdiagnosis as Friedreich ataxia Pathophysiology has been described. Severe progressive cases develop generalized ataxia, hyporeflexia, weakness, strabismus, The pathophysiology of AT involves disruption of dementia, and cardiac arrhythmias. Retinitis pigmen- mechanisms of DNA damage responses. The etiology tosa61 and dystonia or myoclonus62 can also occur. of AT is mutations in the ATM (ataxia telangiectasia mutated) gene.56 This gene is phosphorylated and Pathophysiology activated in the presence of DNA damage, signaling Severe vitamin E malabsorption caused by gastroin- cell cycle checkpoints to facilitate DNA repair.57 Over testinal disease can also cause this clinical picture,63 time, damage occurs to cerebellar Purkinje and gran- but cases with isolated ataxia had been described for a ular cells, as well as other brain areas including basal number of years before a key case series in two families ganglia. with consanguinity and autosomal recessive inheri- Diagnosis tance pattern led to better characterizations of the phenotype.64 Shortly thereafter the genetic cause of AVED The diagnosis of AT should be considered in chil- was identified. AVED is caused by mutations in the dren with ataxia, dystonia, or chorea between ages alpha-tocopherol transfer protein, expressed in liver.65 18 months and 3 years, before the appearance of the Heterogeneity in phenotypes relates partly to variations 82 telangiectasias. The initial diagnostic test is the level in genotype.66 These patients are unable to incorporate of alpha-fetoprotein, which is abnormally and persis- vitamin E efficiently into very low density lipopro- tently elevated after infancy. Genetic testing is available, teins, leading to excessive vitamin E elimination. but is difficult and expensive. Additional diagnos- Pathologically, findings include degeneration of poste- tic testing, if necessary, may be obtained through the rior column axons and dorsal root ganglion cells and Ataxia Telangiectasia Children’s Project and Clinical mild loss of cerebellar Purkinje cells.61 Centers in the United States. Currently, in patients with recurrent infections, aggressive treatment with Diagnosis intravenous immune globulins is recommended. There The diagnosis should be considered in children or is no curative or preventive treatment for the ataxia and adults with progressive sensory ataxia and associated neurologic degeneration. When dystonia occurs, this neurologic symptoms described previously. Sporadic or can be treated medically with trihexyphenidyl or botu- sibling cases, as well as ethnicity, can also provide clues. linum toxin. Clinical trials to arrest neurodegeneration Although this is rare, it is important in cases of unex- have been directed toward reducing effects of oxidative plained ataxia to measure vitamin E levels. Genetic stress.57 Median survival is approximately 25 years.58 testing is available.

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Treatment and Outcomes Mutations in POLG1 can manifest with neurologic AVED usually responds to oral vitamin E supplemen- diseases in the absence of classic muscle mitochondrial tation, which must be continued for life. The dose is pathology.70,71 Genetic testing is available. at least 100 IU/kg/day of the most active d-form of Childhood Ataxia with Central Hypomyelination/ alpha-tocopherol. Synthetic, water-soluble forms may Vanishing White Matter Disease be better absorbed, for example, d-alpha tocopherol succinate. With early treatment, many symptoms may Clinical Features be reversed. Genetic counseling is also recommended, Childhood ataxia with central hypomyelination (CACH) as well as assessment for impairment related to driv- can occur as a rapidly progressive neurologic disease in ing and occupational counseling. Progression may children, with onset at ages 2 to 6, or more indolently still occur, and development of progressive dystonia, in adolescents or adults. Ataxia dominates the neurologic despite treatment, has been described.67 picture, with less prominent cognitive problems and spasticity. A striking feature is the occurrence after minor head Infantile-Onset Spinocerebellar Ataxia trauma or fever of episodes of rapid deterioration in func- Clinical Features tion with hypotonia, seizures, vomiting, and coma, with 72 Clinical features of infantile-onset spinocerebellar failure to return to baseline. Epilepsy is also common. ataxia (IOSCA) include onset at 10 to 18 months Pathophysiology with hearing and visual loss, ophthalmoplegia, ataxia, This is a leukodystrophy, caused by mutations in genes athetosis, hypotonia and hyporeflexia, sensory neu- encoding any of five subunits of the eukaryotic transla- ropathy, and cerebellar atrophy. The pathophysiology tion initiation factor eIF2B.73,74 The resulting changes of this disease is unclear, but the etiology is autosomal lead to disrupted function of oligodendrocytes and recessive mutations in genes for mitochondrial-specific astrocytes, with insufficient myelin and loss of myelin 68 helicase proteins Twinkle and Twinky. Genetic testing under stress, but sparing of neurons. is available. Diagnosis Mitochondrial Recessive Ataxia Syndrome Children with CACH are often diagnosed after Clinical Features neuroimaging, particularly in the context of the striking Clinical features of mitochondrial recessive ataxia syn- episodes of deterioration. MRI shows prominent, non- drome (MIRAS) include ataxia, involuntary move- enhancing, diffuse white matter rarefaction or cystic ments, dysarthria, mild cognitive impairment and destruction, with signal characteristics close to those epilepsy, psychiatric symptoms, and peripheral neu- of CSF on FLAIR images (Fig. 13-6). Additional ropathy. Etiology of this progressive ataxia appears to MRI criteria have been outlined.72 The differential be a variation in polymerase gamma 1 (POLG1).69 diagnosis in a child with marked ataxia and mental

Figure 13-6. Serial, sagittal T1 weighted MRI scans in a child with CACH at ages 1.5 years (left) and 2.5 years (right) showing progressive white matter destruction and replacement by fluid. (From van der Knaap MS, Pronk JC, Scheper GC: Vanishing white matter disease, Lancet Neurol 5:413–423, 2006.)

[email protected] 66485438-66485457 150 Section 4 Hyperkinetic and Hypokinetic Movement Disorders status changes with fever includes encephalitis and in the bile acid biosynthesis pathway.77 Treatment acute disseminated encephalomyelitis (ADEM). with chenodeoxycholic acid (750 mg/day or 15 mg/ ADEM involves multifocal lesions in both white and kg/day orally divided three times daily) expands the gray matter. The MRI findings in CACH are readily deficient bile acid pool and reduces elevated plasma distinguished from ADEM. cholestanol, partially reversing neurologic symptoms. Treatment and Outcomes HMG CoA reductase inhibitors, for example, simvastatin 10 to 40 mg daily or pravastatin 10 mg daily, are As no effective treatment is currently available, outcome also helpful.83 in childhood-onset cases is progressive deterioration and death. Later-onset cases may have longer survival but still may have acute deteriorations. Genetic counseling Diagnostic Approach is recommended and prenatal diagnosis is available. When treating a child with ataxia, a flexible, stepwise approach is helpful. Metabolic Ataxias—Chronic Progressive 1. Clarify that ataxia is the movement disorder. A number of metabolic diseases can cause progressive 2. Localize the lesion. Unilateral or predominantly ataxias, some of which have already been discussed. midline cerebellar signs may indicate focal cerebel- Examples of chronic progressive metabolic ataxias lar pathology. Consider brain MRI. Possible causes include ataxia with vitamin E deficiency, Refsum of focal cerebellar disease include congenital mal- disease, and cerebrotendinous xanthomatosis. Ataxia formation, neoplasm, demyelination, abscess, or occurs as one part of a complex presentation in other vascular event. Treatment of focal neoplasms may neurodegenerative diseases, including Neimann-Pick be surgical and depends on the cause identified or type C, gangliosidoses, adrenoleukodystrophy, late- suspected. onset Tay-Sachs disease, abetalipoproteinemia, and 3. Stratify into a time-course group—acute/subacute, galactosemia. static, chronic progressive, episodic. Refsum Disease (Heredopathia Atactica 4. Look for associated features outside of the cerebel- Polyneuritiformis) lum that narrow the differential. Clinical Features 5. For acute/subacute, likely acquired ataxias, assess for intoxications, signs of infection, or inflammation. Clinical features include onset between ages 10 and 6. For static ataxias, monitor clinically, consider brain 20 of impaired night and peripheral vision caused MRI. by retinitis pigmentosa, and ataxia, polyneuropathy, 7. For all other ataxias that could be inherited, take nystagmus, anosmia, and ichthyosis occurring later. a careful family history and examine parents and There is also an infantile form with a severe peroxi- siblings, if possible. somal disease phenotype. Pathophysiology is due to 8. Order tests judiciously. If possible, aim for a spe- elevated plasma phytanic acid and deposition in brain, cific genetic/molecular diagnosis. spinal cord, and nerves. The etiology of this autosomal 9. For unclear neurologic phenotypes, consider refer- recessive disease is mutations in the gene encoding ring for a second opinion. phytanoyl-CoA hydroxylase (PAHX).75 or the gene 76 10. Before genetic testing, consider consultation with encoding peroxin-7 (PEX7). Reducing dietary intake genetics and with psychology for counseling. of phytanic acid–containing meats, dairy products can 11. Educate the family about ataxia in general as well be helpful. as the specific disease, if identified. 12. Provide referrals for supportive services, as needed, Cerebrotendinous Xanthomatosis and encourage families to read about the disease Clinical Features and join advocacy and research groups. Clinical features include progressive ataxia, spasticity, 13. Provide referrals for other therapies, for exam- neuropathy, and dementia. Tendon xanthomas and ple, physical therapy if the patient is losing cataracts, associated with elevated serum cholestanol ambulation. levels, are present. The pathophysiology is absence 14. Remember the other organs. Clinicians should be of chenodeoxycholic acid, used in bile acid synthesis, mindful of the effects of progressive disorders on resulting in deposits of cholesterol and cholestanol in nonneurologic organ systems, because these may be multiple tissues. The etiology of this autosomal reces- more amenable to therapy; for example, cardiomyo- sive disease is point mutations in the gene encod- pathy, or bone demineralization due to immobility, ing sterol 27-hydroxylase (CYP27), a key enzyme which can be treated using bisphosphonates.78

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Patient and Family Resources 12. Kelly TW: Prolonged cerebellar dysfunction associated with paint-sniffing, Pediatrics 56:605–606, 1975. One advantage of a specific molecular diagnosis is that 13. Uchino A, Kato A, Yuzuriha T, et al: Comparison it helps families network with other affected families between patient characteristics and cranial MR find- and keep track of research. The Clinical Trials website ings in chronic thinner intoxication, Eur Radiol 12: http://clinicaltrials.gov/ct2/home lists studies enrolling 1338–1341, 2002. patients and can be searched by specific disease or dis- 14. Geller T, Loftis L, Brink DS: Cerebellar infarction in ease category. At present, there are seven clinical trials adolescent males associated with acute marijuana use, enrolling patients. Pediatrics 113:e365–e370, 2004. 15. Connolly AM, Pestronk A, Mehta S, et al: Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: SUMMARY an analysis of antigenic targets in neural tissues, J Pediatr 130:878–884, 1997. A large number of congenital, degenerative, and 16. Shiihara T, Kato M, Konno A, et al: Acute cerebellar acquired processes affect cerebellar function, produc- ataxia and consecutive cerebellitis produced by glu- ing ataxia. Diagnosis of inherited, chronic progressive tamate receptor delta2 autoantibody, Brain Dev 29: forms is complex, but advancing rapidly. There is hope 254–256, 2007. that rational therapeutic advances may follow. 17. Go T: Intravenous immunoglobulin therapy for acute cerebellar ataxia, Acta Paediatr 92:504–506, 2003. 18. Pranzatelli MR, Tate ED, Wheeler A, et al: Screening for REFERENCES autoantibodies in children with opsoclonus-myoclonus- ataxia, Pediatr Neurol 27:384–387, 2002. 1. du Montcel ST, Charles P, Ribai P, et al: A composite 19. 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Ophoff RA, Terwindt GM, Vergouwe MN, et al: Familial 9. Miller G: Ataxic cerebral palsy and genetic predisposi- hemiplegic migraine and episodic ataxia type-2 are caused tion, Arch Dis Child 63:1260–1261, 1988. by mutations in the Ca2+ channel gene CACNL1A4, Cell 10. Steinlin M: Non-progressive congenital ataxias, Brain 87:543–552, 1996. Dev 20:199–208, 1998. 29. Spacey SD, Materek LA, Szczygielski BI, Bird TD: Two 11. Imataka G, Yamanouchi H, Arisaka O: Dandy-Walker novel CACNA1A gene mutations associated with epi- syndrome and chromosomal abnormalities, Congenit sodic ataxia type 2 and interictal dystonia, Arch Neurol Anom (Kyoto) 47:113–118, 2007. 62:314–316, 2005.

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30. Kestle JR: Pediatric hydrocephalus: current manage- 47. Herman-Bert A, Stevanin G, Netter JC, et al: Mapping of ment, Neurol Clin 21:883–895, 2003. spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 31. Partap S, Fisher PG: Update on new treatments and in a family with autosomal dominant cerebellar ataxia and developments in childhood brain tumors, Curr Opin mental retardation, Am J Hum Genet 67:229–235, 2000. Pediatr 19:670–674, 2007. 48. Stevanin G, Durr A, Benammar N, Brice A: 32. Weinberg JS, Freed DL, Sadock J, et al: Headache and Spinocerebellar ataxia with mental retardation (SCA13), Chiari I malformation in the pediatric population, Cerebellum 4:43–46, 2005. Pediatr Neurosurg 29:14–18, 1998. 49. Waters MF, Minassian NA, Stevanin G, et al: Mutations 33. Fisher PG, Tihan T, Goldthwaite PT, et al: Outcome in voltage-gated potassium channel KCNC3 cause analysis of childhood low-grade astrocytomas, Pediatr degenerative and developmental central nervous system Blood Cancer 51:245–250, 2008. phenotypes, Nat Genet 38:447–451, 2006. 34. Robertson PL, Muraszko KM, Holmes EJ, et al: 50. Fogel BL, Perlman S: Clinical features and molecular Incidence and severity of postoperative cerebellar mutism genetics of autosomal recessive cerebellar ataxias, Lancet syndrome in children with medulloblastoma: a pro- Neurol 6:245–257, 2007. spective study by the Children’s Oncology Group, 51. Ribai P, Pousset F, Tanguy ML, et al: Neurological, car- J Neurosurg 105:444–451, 2006. diological, and oculomotor progression in 104 patients 35. Moreira MC, Klur S, Watanabe M, et al: Senataxin, the with Friedreich ataxia during long-term follow-up, Arch ortholog of a yeast RNA helicase, is mutant in ataxia- Neurol 64:558–564, 2007. ocular apraxia 2, Nat Genet 36:225–227, 2004. 52. Hou JG, Jankovic J: Movement disorders in Friedreich’s 36. Banfi S, Servadio A, Chung MY, et al: Identification and ataxia, J Neurol Sci 206:59–64, 2003. characterization of the gene causing type 1 spinocerebel- 53. Mariotti C, Solari A, Torta D, et al: Idebenone treat- lar ataxia, Nat Genet 7:513–520, 1994. ment in Friedreich patients: one-year-long random- 37. Pulst SM, Nechiporuk A, Nechiporuk T, et al: ized placebo-controlled trial [see comment], Neurology Moderate expansion of a normally biallelic trinucleotide 60:1676–1679, 2003. repeat in spinocerebellar ataxia type 2, Nat Genet 14: 54. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH: 269–276, 1996. Neurological effects of high-dose idebenone in patients 38. Abdel-Aleem A, Zaki MS: Spinocerebellar ataxia with Friedreich’s ataxia: a randomised, placebo-con- type 2 (SCA2) in an Egyptian family presenting with trolled trial, Lancet Neurol 6:878–886, 2007. polyphagia and marked CAG expansion in infancy, 55. Crawford TO, Mandir AS, Lefton-Greif MA, et al: Quanti- J Neurol 255:413–419, 2008. tative neurologic assessment of ataxia-telangiectasia, 39. Dirik E, Yis U, Basak N, et al: Spinocerebellar ataxia type Neurology 54:1505–1509, 2000. 2 in a Turkish family, J Child Neurol 22:891–894, 2007. 56. Savitsky K, Bar-Shira A, Gilad S, et al: A single ataxia 40. Kawaguchi Y, Okamoto T, Taniwaki M, et al: CAG telangiectasia gene with a product similar to PI-3 kinase, expansions in a novel gene for Machado-Joseph disease Science 268:1749–1753, 1995. at chromosome 14q32.1, Nat Genet 8:221–228, 1994. 57. Lavin MF, Gueven N, Bottle S, Gatti RA: Current and 41. Schols L, Vieira-Saecker AM, Schols S, et al: Trinucleotide potential therapeutic strategies for the treatment of ataxia- expansion within the MJD1 gene presents clinically telangiectasia, Br Med Bull 81–82:129–147, 2007. as spinocerebellar ataxia and occurs most frequently 58. Crawford TO, Skolasky RL, Fernandez R, et al: Survival in German SCA patients, Hum Mol Genet 4:1001– probability in ataxia telangiectasia, Arch Dis Child 1005, 1995. 91:610–611, 2006. 42. Schulte T, Mattern R, Berger K, et al: Double-blind 59. Aicardi J, Barbosa C, Andermann E, et al: Ataxia-ocular crossover trial of trimethoprim-sulfamethoxazole in motor apraxia: a syndrome mimicking ataxia-telangi- spinocerebellar ataxia type 3/Machado-Joseph disease ectasia, Ann Neurol 24:497–502, 1988. [see comment], Arch Neurol 58:1451–1457, 2001. 60. Date H, Onodera O, Tanaka H, et al: Early-onset ataxia 43. Berger Z, Ravikumar B, Menzies FM, et al: Rapamycin with ocular motor apraxia and hypoalbuminemia is alleviates toxicity of different aggregate-prone caused by mutations in a new HIT superfamily gene, proteins, Hum Mol Genet 15:433–442, 2006. Nat Genet 29:184–188, 2001. 44. Enevoldson TP, Sanders MD, Harding AE: Autosomal 61. Yokota T, Uchihara T, Kumagai J, et al: Postmortem dominant cerebellar ataxia with pigmentary macular study of ataxia with retinitis pigmentosa by mutation dystrophy. A clinical and genetic study of eight families, of the alpha-tocopherol transfer protein gene, J Neurol Brain 117(pt 3):445–460, 1994. Neurosurg Psychiatry 68:521–525, 2000. 45. David G, Abbas N, Stevanin G, et al: Cloning of the 62. Angelini L, Erba A, Mariotti C, et al: Myoclonic dystonia SCA7 gene reveals a highly unstable CAG repeat expan- as unique presentation of isolated vitamin E deficiency in sion, Nat Genet 17:65–70, 1997. a young patient, Mov Disord 17:612–614, 2002. 46. Holmberg M, Duyckaerts C, Durr A, et al: Spinocerebellar 63. Sokol RJ, Guggenheim MA, Iannaccone ST, et al: ataxia type 7 (SCA7): a neurodegenerative disorder with Improved neurologic function after long-term correc- neuronal intranuclear inclusions, Hum Mol Genet 7:913– tion of vitamin E deficiency in children with chronic 918, 1998. cholestasis, N Engl J Med 313:1580–1586, 1985.

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64. Ben Hamida M, Belal S, Sirugo G, et al: Friedreich’s 74. van der Knaap MS, Leegwater PAJ, Konst AAM, et al: ataxia phenotype not linked to chromosome 9 and Mutations in each of the five subunits of translation associated with selective autosomal recessive vitamin E initiation factor eIF2B can cause leukoencephalopa- deficiency in two inbred Tunisian families, Neurology thy with vanishing white matter, Ann Neurol 51:264– 43:2179–2183, 1993. 270, 2002. 65. Ouahchi K, Arita M, Kayden H, et al: Ataxia with 75. Jansen GA, Ofman R, Ferdinandusse S, et al: Refsum isolated vitamin E deficiency is caused by mutations disease is caused by mutations in the phytanoyl-CoA in the alpha-tocopherol transfer protein, Nat Genet 9: hydroxylase gene, Nat Genet 17:190–193, 1997. 141–145, 1995. 76. Jansen GA, Waterham HR, Wanders RJ: Molecular basis 66. Cavalier L, Ouahchi K, Kayden HJ, et al: Ataxia with of Refsum disease: sequence variations in phytanoyl-CoA isolated vitamin E deficiency: heterogeneity of mutations hydroxylase (PHYH) and the PTS2 receptor (PEX7), and phenotypic variability in a large number of families, Hum Mutat 23:209–218, 2004. Am J Hum Genet 62:301–310, 1998. 77. Cali JJ, Hsieh CL, Francke U, Russell DW: Mutations in 67. Roubertie A, Biolsi B, Rivier F, et al: Ataxia with vitamin the bile acid biosynthetic enzyme sterol 27-hydroxylase E deficiency and severe dystonia: report of a case, Brain underlie cerebrotendinous xanthomatosis, J Biol Chem Dev 25:442–445, 2003. 266:7779–7783, 1991. 68. Nikali K, Suomalainen A, Saharinen J, et al: Infantile 78. Henderson RC, Lark RK, Kecskemethy HH, et al: onset spinocerebellar ataxia is caused by recessive muta- Bisphosphonates to treat osteopenia in children with tions in mitochondrial proteins Twinkle and Twinky, quadriplegic cerebral palsy: a randomized, placebo-con- Hum Mol Genet 14:2981–2990, 2005. trolled clinical trial, J Pediatr 141:644–651, 2002. 69. Hakonen AH, Heiskanen S, Juvonen V, et al: 79. Toelle SP, Yalcinkaya C, Kocer N, et al: Mitochondrial DNA polymerase W748S mutation: a Rhombencephalosynapsis: clinical findings and neuroim- common cause of autosomal recessive ataxia with ancient aging in 9 children, Neuropediatrics 33:209–214, 2002. European origin, Am J Hum Genet 77:430–441, 2005. 80. Kusano Y, Tanaka Y, Takasuna H, et al: Transient cer- 70. Hopkins SE, Somoza AD, Gilbert DL: Rare autosomal ebellar mutism caused by bilateral damage to the den- dominant POLG1 mutation in a family with meta- tate nuclei after the second posterior fossa surgery. Case bolic strokes, posterior column spinal degeneration, and report, J Neurosurg 104:329–331, 2006. multi-endocrine disease, Mov Disord 23:S39, 2008. 81. Bastian AJ, Mink JW, Kaufman BA, Thach WT: Posterior 71. Van Goethem G, Luoma P, Rantamaki M, et al: POLG vermal split syndrome, Ann Neurol 44:601–610, 1998. mutations in neurodegenerative disorders with ataxia but 82. Cabana MD, Crawford TO, Winkelstein JA, Christensen no muscle involvement, Neurology 63:1251–1257, 2004. JR, Lederman HM: Consequences of the delayed diag- 72. van der Knaap MS, Pronk JC, Scheper GC: Vanishing nosis of ataxia-telangiectasia, Pediatrics 102(1 Pt 1):98– white matter disease, Lancet Neurol 5:413–423, 2006. 100, 1998. 73. Leegwater PA, Vermeulen G, Konst AA, et al: Subunits 83. Peynet J, Laurent A, De Liege P, et al: Cerebrotendinous of the translation initiation factor eIF2B are mutant in xanthomatosis: treatments with simvastatin, lovastatin, leukoencephalopathy with vanishing white matter [see and chenodeoxycholic acid in 3 siblings. Neurology. Mar comment], Nat Genet 29:383–388, 2001. 41(3):434–436, 1991.

[email protected] 66485438-66485457 14 Parkinsonism O Introduction limb can be moved with difficulty into arbitrary postures, but once placed in a posture, will remain there Parkinsonism is a constellation of signs and symptoms against gravity. If there is superimposed tremor, the that are characteristically observed in Parkinson’s disease rigidity can feel ratchety, like a cog-wheel. It is impor- (PD), but that are not caused by PD. Parkinsonism is tant to note that “cog-wheeling” is due to underlying the primary type of hypokinetic movement disorder. It tremor and is not a required feature of parkinsonian is sometimes referred to as the hypokinetic-rigid syn- rigidity. Postural instability manifests as increased likeli- drome or akinetic-rigid syndrome. As discussed else- hood of falling and is due to dysregulation of postural where in this text, hyperkinetic movement disorders reflexes. Clinically, it is evaluated with the “pull test,” in are far more common in children than is parkinsonism. which the patient stands, facing away from the exam- Parkinsonism can arise from many different causes in iner with feet apart at shoulder width. The examiner children, including juvenile-onset PD. However, true gives a gentle pull backward at the shoulders bilaterally. Ojuvenile-onset PD is quite rare. Parkinsonism may be A normal individual may take a step backward, but an seen in isolation or in conjunction with other neuro- individual with parkinsonian postural instability will logic signs or symptoms. take many steps backward (retropulsion) or may fall backward with no attempt to compensate. Clinical Features of Parkinsonism Pathophysiogy of Parkinsonism Parkinsonism is usually defined by the presence of two or more of the cardinal signs of PD, but several other Adult-onset idiopathic PD is associated with the loss criteria have been proposed and validated.1 These signs of nigrostriatal dopamine neurons.3 However, lesions are tremor at rest, bradykinesia (or akinesia), rigidity, involving nigrostriatal dopamine neurons, the nigro- and postural instability. Rest tremor is rare in childhood striatal pathway, the striatum, or other components parkinsonism. It is more likely to be seen in juvenile PD of the basal ganglia-thalamocortical circuitry can all or drug-induced parkinsonism than in parkinsonism result in parkinsonism (see Chapter 1).4–6 It has been due to other causes. When present, the tremor is typi- suggested that parkinsonism results from excessive or cally in the frequency range of 4 to 6 Hz, and is most disordered inhibitory output from the internal glo- prominent at rest but may reemerge with sustained bus pallidus (GPi) and substantia nigra pars reticulata, posture. Bradykinesia is slowness of movement that is regardless of cause.5,7–9 Other conditions that are associ- not due to weakness or ataxia. Parkinsonian bradyki- ated with decreased efficacy of nigrostriatal dopamine nesia is commonly accompanied by progressive reduc- neurotransmission, including dopamine-depleting or tion of movement amplitude with repeated rhythmic dopamine-blocking medications and inborn errors of movements, such as finger tapping or pronation and dopamine synthesis, can also cause parkinsonism. The supination of the forearm. There may also be akine- pathogenesis of individual disorders causing parkin- sia, with paucity of movement, reduced spontaneous sonism will be discussed in the context of those spe- movements, or in some cases the inability to move at all cific disorders later in this chapter. It does appear that (freezing). Akinesia commonly manifests as diminished there may be a common pathophysiology of the cardi- spontaneous facial expression (masking or hypomimia), nal signs of parkinsonism, regardless of specific cause. soft speech (hypophonia), and reduced arm-swing dur- Almost all data on the pathophysiology of parkinsonism ing walking. Parkinsonian rigidity is increased muscle come from studies in adult patients or nonhuman pri- tone that is equal in all directions of movement, does mate models, but the principles are likely to apply to not increase with increased velocity of passive move- parkinsonism in children. Although PD is generally ment, and does not have a particular preferred posture.2 considered an adult-onset neurodegenerative disorder, Rigidity may have a “lead pipe” quality, in which the there is an emerging evidence that at least a subset of 154 [email protected] 66485438-66485457 Chapter 14 Parkinsonism 155

patients with parkinsonism may start with fewer than decreased agonist activation, there is often excessive normal dopaminergic neurons from birth, and as a co-contraction of the antagonist during movement19 result of age-related attrition reach the critical threshold and muscular co-contraction at rest.20 This abnormal of about 60% loss of dopaminergic neurons by the fifth co-contraction can combine with the abnormally or sixth decade, and are then diagnosed with PD.10 reduced contraction of the agonist to cause slowing of movement. People with parkinsonism are often more Tremor impaired when relaxing muscles to reduce force than The pathophysiology of tremor in PD is poorly under- when activating muscles to generate force.21–23 Thus stood. It is generally agreed that parkinsonian tremor is an inability to “turn off” the antagonist may be more O largely due to central tremor generators, possibly located impaired than the ability to “turn on” the agonist. in the thalamus.11,12 There is evidence that peripheral It has also been suggested that individuals with PD afferent activity can modulate and even entrain tremor have more difficulty performing sequences of move- in PD.12 However, parkinsonian tremor persists after ments than individual movements.24–26 When subjects deafferentation13 and has been shown to persist with- with PD performed a task involving a grasp and elbow out frequency change in wrist flexors after complete flexion separately, simultaneously, or sequentially, they radial nerve palsy.14 Thus, although there may be some were slower than normal in all conditions. However, modulation of PD tremor by muscle afferent activity, they were slower on simultaneous and sequential central mechanisms are critical for its production. It movements than they were on the individual compo- has long been known that thalamotomy, particularly nents.24,25 Subjects with PD are equally slow when they of the ventral intermediate nucleus (VIM), is effec- draw the sides of a pentagon sequentially as when they tive in reducing or eliminating parkinsonian tremor.15 repeatedly draw one side five times, suggesting that Abnormal oscillatory neuronal activity has been there is progressive slowing of movement with repeti- recorded in the VIM, subthalamic nucleus (STN), and tion, but not a specific sequencing deficit.27 Despite the GPi of parkinsonian subjects.15–17 However, the oscilla- evidence that sequential movements are more impaired tory rate of STN and GPi neurons is twice that of the in PD, even single stimulus-triggered movements are tremor, and VIM neurons more reliably correlate with slow.18,28 This suggests that the fundamental deficit in parkinsonian tremor.17 Interestingly, the VIM nucleus PD is not one of sequencing, but that sequential or is thought to be the site of cerebellar rather than basal repetitive movements may exacerbate the deficit. ganglia input to the thalamus. It is not known to Akinesia what degree cerebellar mechanisms might be involved in PD tremor, but it has been suggested that tremor The paucity of movement and “freezing” in parkin- results from downstream mechanisms that attempt to sonism has been attributed to a defect of movement compensate for basal ganglia dysfunction in PD.17 The initiation. Indeed some, but not all, people with PD fundamental mechanisms causing tremor in PD con- do have prolonged reaction times in stimulus-triggered tinue to be investigated in PD and in primate models. movements, suggesting that in some cases there is delayed initiation of movement.28 However, it is not Bradykinesia clear that the delayed initiation is due to basal ganglia Bradykinesia is a hallmark of parkinsonism.1 However, dysfunction. Instead, the delayed initiation may be due it should be noted that voluntary movements are slow to the loss of dopamine input to prefrontal, premotor, in almost any disease that affects the motor system. or motor cortex.29–31 Animals with focal lesions of the What distinguishes the different conditions is the qual- dopamine input to prefrontal cortex have prolonged ity of the impairment. In PD, there is slowness and reaction times,32 but animals with lesions of the basal reduced amplitude of individual movements that typi- ganglia output (globus pallidus pars interna [GPi] or cally worsens as movements proceed. The classic exam- substantia nigra pars reticulata [SNpr]) usually do not.5 ple of this is the micrographia of PD where handwriting It is also possible that the prolonged reaction time can be near normal at the beginning of a line, but the in PD is not due to dysfunction of movement initia- size of letters and velocity of strokes decreases as the tory systems. Muscle activity may begin at the normal writing continues. The slowness of movement in par- time in relation to movement, but the magnitude of kinsonism has been associated with reduced magnitude the initial muscle activity may not be sufficient to over- of agonist muscle activity during movement.18 The come inertial and viscoelastic forces rapidly,28 and the reduced agonist amplitude often results in a succession mechanically detected onset of movement is delayed. of multiple small-amplitude submovements instead of Alternatively, an inability to inhibit unwanted pos- a larger-amplitude single movement. In addition to tural reflexes may delay the onset of movement because

[email protected] 66485438-66485457 156 section 4 Hyperkinetic and Hypokinetic Movement Disorders of competition of antagonistic motor mechanisms Primary parkinsonisms are children is rare, but recogni- (see later discussion). In either case, the initiatory tion of these entities is important. In discussion of the commands may be normal, but other factors cause the etiology of parkinsonism in children, primary causes or onset of movement to be delayed. juvenile Parkinson’s disease will be considered first followed by important secondary causes of parkinsonism. Rigidity Treatment of parkinsonism will be discussed in a sec- People with PD have increased resistance to passive tion following delineation of the etiologic disorders. muscle stretch. It is not known if this clinical sign Juvenile Parkinson’s Disease reflects mechanisms that interfere with movement, since bradykinesia and rigidity can vary independently. Juvenile Parkinson’s disease ( JPD) typically manifests However, stiffness and an inability to completely relax with leg dystonia in younger children and bradykinesia are common complaints in PD. The rigidity of PD has and rigidity in older children. Tremor is less common been attributed in part to hyperactivity of long-latency in JPD than in adult PD. It should be noted that dis- (transcortical) stretch reflexes.20,33,34 The monosynaptic orders causing JPD may not manifest until adulthood, stretch reflex is normal in PD. so unlike many other movement disorders of children, childhood onset is not defining. Postural Instability This most common cause of autosomal recessive People with PD have an inability to inhibit long- young-onset PD is PARK2, due to mutations in the 39,40 latency reflexes other than the transcortical stretch parkin gene, located on chromosome 6q25.2–27. reflex. Although it is often stated that PD is accom- In 12 Japanese families, the mean age of onset was 27 41 panied by a “loss of postural reflexes,” it appears years, with a range from 9 to 43. The most prominent that there is inability to inhibit long-latency postural symptoms were retropulsion, dystonia of the feet, and reflexes that accounts for the postural instability of classic parkinsonism. Symptoms of tremor, rigidity, and PD. When normal subjects are subjected to a perturba- bradykinesia were mild. There was good symptomatic tion in the anterior-posterior dimension while stand- benefit from levodopa, but dopa-induced dyskinesias ing, they have a stereotyped pattern of muscle activity and wearing-off phenomena occurred relatively early in 42 in the legs and trunk that maintains upright stance. the disease course. Lohmann and colleagues compared If they then sit down and are subjected to the same 146 PD patients with parkin mutations to 250 PD perturbation, this activity no longer occurs. By con- patients without parkin mutations. Patients with parkin trast, patients with Parkinson’s disease have an inap- mutations had an earlier and more symmetric onset, a propriate co-contraction of leg and back muscles in slower progression of disease, and a greater response to response to perturbation from upright stance. When l-dopa at lower doses. Age of onset in the parkin group the same subjects are subjected to a perturbation in a was 7 to 70 years. In families with autosomal recessive sitting position, they continue to have the same pat- parkinsonism, more than 80% of patients with age of 42 tern of muscle activity. Thus they are not able to inhibit onset of 20 years or younger had parkin mutations. appropriately the postural reflexes that were active dur- Heterozygous mutations in the parkin gene have been ing stance.35 These data, together with the proposed identified in some patients with later-onset disease, mechanism of rigidity (see previous discussion) and raising the possibility that heterozygous mutations may 43 the fact that so-called primitive reflexes are abnormally confer increased susceptibility to the disease. active in Parkinson’s disease,36 suggest that there may The pathology of parkin-associated PD does not be an inability to suppress unwanted reflex activity show Lewy bodies, the pathologic hallmark of adult- generally. onset idiopathic PD, although there is neuronal loss and neurofibrillary tangles. Fluoro-dopa positron emis- Etiology of Parkinsonism in sion tomography (PET) scanning shows decreased Children uptake, indicating a presynaptic abnormality consistent with degeneration of the nigro-striatal pathways.44,45 It In children, parkinsonism can be a manifestation of has been hypothesized that parkin interacts with alpha- several different disorders.37 It is often associated with synuclein such that parkin normally ubiquitinates a dopaminergic deficit, and since dopaminergic defi- alpha-synuclein and this process is defective in parkin cits can produce dystonia in children, dystonia may mutations. This leads to pathologic accumulation be present as well.38 Most parkinsonism in children of a non ubiquitinated, glycosylated form of alpha- is secondary to a neurologic disorder that causes par- synuclein.46 Indeed, it appears that parkin interacts with kinsonism in addition to other signs and symptoms. the other proteins implicated in young-onset PD, PINK1

[email protected] 66485438-66485457 Chapter 14 Parkinsonism 157

and DJ-1 (see later discussion), to form a ubiquitin gene on chromosome 4.57 This disorder is character- E3 ligase complex that promotes ubiquitination and ized by a combination of dystonia, chorea, myoclo- degradation of parkin substrates, including parkin itself.47 nus, behavioral abnormalities, ataxia, and ultimately Thus mutations in any of these three genes may influ- dementia. When HD begins in childhood, the typical ence the same biochemical pathway. presentation is parkinsonism or dystonia, and not cho- Less common genetic causes of young-onset PD are rea. This has been referred to as the Westphal variant mutations in the DJ-1 or PINK1 genes. DJ-1 muta- of HD.58,59 The age of onset is earlier for children with tions (PARK7) are associated with onset of symp- a higher number of repeats.60 There tends to be ampli- toms before age 40 years with rest tremor, postural fication of the number of repeats, particularly when it tremor, bradykinesia, postural instability, and asym- is transmitted from father to child, and therefore most metric onset.48,49 No cases of childhood or adoles- cases of juvenile HD are inherited from the father and cent onset have been reported to date. Mutations in a involve repeat lengths that are significantly higher than PTEN-induced kinase (PINK1; PARK6) are associated those seen in adults. with autosomal recessive early-onset PD.50 The age of Diagnosis is based on identification of the trinu- onset for this disorder is typically young adulthood. cleotide repeat sequence. Although at least 38 repeats To date, no cases have been reported to start during are usually required for the occurrence of symptoms in childhood or adolescence. adults, a larger number of repeats would be expected when symptoms occur in childhood.58,60 Magnetic Secondary Parkinsonism resonance imaging (MRI) shows atrophy of the caudate heads and, in later stages, generalized cerebral and cer- Secondary causes of parkinsonism in children include a ebellar atrophy. wide variety of disorders (Table 14-1). In most of these In teenagers, the initial presentation of HD may be disorders, parkinsonism is accompanied by other neu- with psychiatric illness, and in particular, major depres- rologic signs and symptoms and this diagnosis is guided sion may be the initial symptom.61 Dystonia or chorea by the constellation of manifestations. However, in usually supervene later. The pathology includes basal some disorders parkinsonism can be the dominant ganglia, cerebellar, and cortical degeneration.62–64 In feature or seen in association only with dystonia, a children, there may be a relatively symmetric loss of both common accompaniment of parkinsonism. D1-bearing and D2-bearing medium spiny neurons, Structural Lesions Parkinsonism can result from infarcts or other struc- TABLE 14-1 etiology of Parkinsonism tural lesions, primarily those that affect the basal ganglia in Children or their connections. Parkinsonism has been reported in association with brain tumors in adults,51,52 but this Structural Infectious/Parainfectious has not been reported in children. Parkinsonism has Stroke Encephalitis lethargica been reported following cranial radiation treatment Brain tumor Viral encephalitis Hydrocephalus Mycoplasma 53 of a brain tumor in an adolescent. Parkinsonism has Hereditary/ Metabolic been reported as a presenting sign in hydrocephalus54 Degenerative Dopa-responsive dystonia or as a result of shunt malfunction.55 Parkinsonism Juvenile Parkinson (see Chapters 10, 15) due to hydrocephalus can be dopa-responsive.54,55 disease ALAAD deficiency Hemiparkinsonism-hemiatrophy is a static or progres- Huntington’s disease (see Chapter 15) (Westphal variant) Rapid-onset dystonia- sive disorder in which perinatal and early childhood PKAN parkinsonism cerebral injury appears to play an important role.56 (see Chapter 15) (see Chapter 10) Rett syndrome Fahr syndrome Hereditary/Degenerative Diseases Niemann Pick type C Drugs/Toxins (see Chapter 15) (see Chapter 18) Many of the hereditary degenerative disorders that Juvenile NCL Antipsychotics produce parkinsonism are discussed in other chapters. (see Chapter 15) Antiemetics See Table 14-1 for references to those chapters where Neuronal intranuclear Reserpine appropriate. inclusion disease Isoniazid Kufor-Rakeb Calcium channel blockers Huntington’s Disease syndrome (PARK9) Meperidine Pallido-pyramidal Chemotherapy Huntington’s disease (HD) is autosomal dominant, syndrome caused by a trinucleotide repeat expansion of the IT-15

[email protected] 66485438-66485457 158 section 4 Hyperkinetic and Hypokinetic Movement Disorders which could account for the primarily dystonic and dal syndrome is more appropriately called “parkin- parkinsonian rather than choreatic presentation.65,66 sonism-pyramidal syndrome” and should be listed as Treatment of parkinsonism caused by HD can be one of the monogenic causes of parkinsonism (PARK difficult. However, in some cases the parkinsonism classification).75 responds to levodopa.67 Prognosis is poor for childhood- Kufor-Rakeb Syndrome onset HD, and the movement disorder is expected to worsen progressively over the years following diagnosis. Kufor-Rakeb syndrome was initially described in a con- 78 Life expectancy depends on the severity of symptoms sanguineous Jordanian family. The clinical features and the number of repeats, but typically children will include autosomal recessive pattern of inheritance, survive 10 to 15 years from the time of diagnosis. mask-like face, rigidity, and bradykinesia. Tremor was not reported. Spasticity, supranuclear upgaze paresis, Rett Syndrome and dementia were also reported in most individu- Rett syndrome is discussed in Chapter 7. The char- als. In addition, facial-faucial-finger mini-myoclonus, acteristic movement disorder of Rett syndrome is visual hallucinations, and oculogyric dystonic spasms 79 stereotypies. However, many girls with Rett develop par- have been reported. Age of onset was between 12 and kinsonism as the disorder progresses.68 Imaging studies 16 years and symptoms progressed rapidly. MRI scans have shown mild reduction of fluorodopa uptake of the brain showed globus pallidus atrophy and later and of dopamine D2 receptor binding.69 Response to generalized brain atrophy. In this condition, there is l-dopa or dopamine agonists has not been studied in variable but often dramatic improvement, limited to Rett syndrome. extrapyramidal manifestations, within 48 hours in all affected subjects in response to levodopa therapy.78 Over Neuronal Intranuclear Inclusion Disease time, the response to l-dopa wanes, with narrowing of Neuronal intranuclear inclusion disease (NIID) is a the therapeutic window and emergence of peak-dose rare neurodegenerative disorder with a heterogeneous dyskinesias.79 Kufor-Rakeb syndrome is caused by loss- clinical picture that variably includes parkinsonism, of-function mutations in a predominantly neuronal behavioral changes, abnormal eye movements (includ- P-type ATPase gene, ATP13A2.80 ing oculogyric crises), ataxia, pyramidal tract signs, and motor neuron signs. It can manifest as juvenile par- Infectious and Postinfectious Diseases kinsonism70 or dopa-responsive dystonia.71 It is char- Postencephalitic parkinsonism was classically described acterized by the presence of eosinophilic intranuclear following the pandemics of encephalitis lethargica in inclusions in neuronal and glial cells.72 The age of onset the 1920s.81 These cases were mostly in adults; the exact is between 3 and 12 years. Initial symptoms typically cause has not been determined. Parkinsonism has also include slow cognitive and behavioral decline with been described as a consequence of viral encephalitis,82 mood alteration.73 NIID may be diagnosed with a full- Mycoplasma pneumoniae infection, or following vacci- thickness rectal biopsy. nation for measles.83 In many cases, the parkinsonism responded to levodopa or anticholinergic medications. Pallido-Pyramidal Syndrome This syndrome was initially described by Davison,74 Metabolic Diseases who reported five patients with juvenile-onset parkin- Most metabolic diseases that cause parkinsonism are sonism and pyramidal tract signs. In one case, lesions discussed in Chapter 15. However, Fahr syndrome will of the pallidum, ansa lenticularis, substantia nigra, be discussed in this chapter. and pyramidal tract were described on neuropathology.74 The clinical phenotype consists of an autosomal Fahr Syndrome recessive, juvenile-onset, progressive parkinsonism Fahr syndrome is characterized by basal ganglia with hyperreflexia, spasticity, and Babinski signs, and calcification, as well as calcification of other gray matter which is slowly progressive. Recently, this disorder has structures, including cerebellar nuclei and punctate been associated with mutations in the FBX07 gene calcifications in thalamus and sometimes cortex.84,85 in several families.75,76 Some individuals have psychi- This is usually an adult-onset disease, but in some atric symptoms. Response to levodopa is variable, cases can occur in the second decade of life. When it ranging from marked and sustained to moderate and does, it is characterized by microcephaly, hypertonia, unpredictable. FBOX07 codes for an F-box protein and choreoathetosis. However, parkinsonism may be that is thought to be a component of an E3 ubiquitin a prominent feature. The etiology is often unknown, ligase.77 It has been proposed that pallido-pyrami- but in some cases is due to hypoparathyroidism and

[email protected] 66485438-66485457 Chapter 14 Parkinsonism 159

therefore parathyroid function should be checked. It adults have shown that levodopa provides more benefit is autosomal dominant, with reduced penetrance in than dopamine agonists.6 most families, and appears to be slowly progressive. Secondary parkinsonisms are variably responsive to Diagnosis is based on evidence of calcification detected medications. Bradykinesia is the primary symptom that by head computed tomography (CT) scanning.85–87 is responsive to treatment in childhood parkinsonism. Treatment is supportive, unless a specific disorder of It is usually assumed to be due to dopamine deficiency, parathyroid hormone can be found, in which case and therefore is treated with levodopa or dopamine ago- specific treatment will be available. nists. Levodopa is combined with a peripheral decarboxylase inhibitor such as carbidopa to reduce side Drug-induced Parkinsonism effects and increase delivery to the brain. Treatment Many medications are known to be able to cause is often initiated with a single dose of levodopa, parkinsonism. The most important of these are drugs 1 mg/kg (or 50 to 100 mg total), given in the morn- that block dopamine receptors or impair dopamine syn- ing to evaluate for potential side effects including nau- thesis. The most potent dopamine receptor blocking sea or postural hypotension. If this dose is tolerated for medications are the antipsychotic neuroleptic medi- 3 to 4 days, therapeutic treatment can be initiated three cations. The older high-potency medications such as times per day. Unless symptoms are present at night the haloperidol are more likely to cause parkinsonism than doses are usually given during the daytime to maximize the newer atypical antipsychotics. Nonetheless, atypical effect. Dosage can be increased to a maximum of 10 to antipsychotics with even weak dopamine D2 receptor 15 mg/kg/day depending on effectiveness. In addition blockade can cause parkinsonism. In addition, some to nausea and hypotension, common side effects can antiemetics can be important causes of parkinsonism include dystonia, agitation, sleeplessness, and behavior with chronic use. In this regard, metoclopramide has changes. The dosage must be adjusted gradually to find emerged as the most common cause of drug-induced the optimal dose, and the optimal dose may change as parkinsonism and tardive dyskinesia.88 Dopamine the child grows. Additional carbidopa may be given to depletors such as tetrabenazine, reserpine, and alpha- decrease nausea. methylparatyrosine are not used commonly in chil- In adults and children with PD, long-term treat- dren but are well known to have parkinsonism as a ment with dopamine or dopamine agonists will even- side effect.89 Chemotherapy agents have been reported tually lead to dyskinesias and freezing episodes that to cause parkinsonism in rare cases.82 Other medica- can limit its use. Some authors have advocated “dop- tion classes that can cause parkinsonism are listed in amine-sparing” strategies that involve the early use of Table 14-1. Cessation of the medication is usually dopamine agonists such as pergolide, pramipexole, or sufficient to reverse the parkinsonism. A broader ropinirole, or dopamine breakdown inhibitors such as discussion of drug-induced movement disorders is entacapone or selegeline.90 This approach remains con- contained in Chapter 18. troversial and it has not been studied in children. Amantadine may be used to treat dyskinesias 91 Treatment of Parkinsonism associated with acute or chronic use of levodopa, and it has some antiparkinsonian effects as well.92,93 JPD is levodopa-responsive, at least in the early years. Anticholinergic medication will improve parkinsonism, It will also respond to anticholinergic medication, dop- but it is more commonly used to treat associated amine agonists, and inhibitors of dopamine break- dystonia. Deep-brain stimulation in the internal down. However, escalating doses are required, and globus pallidus or subthalamic nucleus has met with children typically develop dopa-induced dyskinesias tremendous success in ameliorating symptoms of similar to those seen in adults on chronic dopamin- adult Parkinson’s disease.94,95 Whether similar neuro- ergic therapy. It is important to differentiate this dis- surgical procedures would be effective in children is order from dopa-responsive dystonia, as well as other not known. disorders that may respond to dopaminergic medica- Failure of dopaminergic transmission can be divided tion, since the prognosis is different. Some authors rec- into presynaptic and postsynaptic forms. In presynaptic ommend use of dopa-sparing medications, including failure, there is reduced production or release of dop- dopamine agonists or inhibitors of dopamine break- amine at nigro-striatal nerve terminals. This is typical in down, to prolong the efficacy and delay the onset of juvenile Parkinson’s disease and dopa-responsive dysto- dyskinesia. However, strong evidence to support this nia. In postsynaptic failure, there is injury to the striatal strategy is lacking. No prospective studies of treatment targets. This is typical following encephalitis or hypoxic in childhood-onset PD have been reported. Studies in injury. Treatment with dopaminergic medication is

[email protected] 66485438-66485457 160 section 4 Hyperkinetic and Hypokinetic Movement Disorders most successful when there is presynaptic failure. 17. Rosin B, Nevet A, Elias S, et al: Physiology and pathophys- If injury is primarily postsynaptic, there may be some iology of the basal ganglia-thalamo-cortical networks, mild benefit from dopaminergic medication, but the Parkinsonism Relat Disord 13(Suppl 3):S437–S439, effect will be limited. 2007. 18. Hallett M, Khoshbin S: A physiological mechanism of bradykinesia, Brain 103:301–314, 1980. 19. Hayashi A, Kagamihara Y, Nakajima Y, et al: Disorder REFERENCES in reciprocal innervation upon initiation of voluntary movement in patients with Parkinson’s disease, Exp Brain 1. Jankovic J: Parkinson’s disease: clinical features and diag- Res 70:437–440, 1988. nosis, J Neurol Neurosurg Psychiatry 79:368–376, 2008. 20. Berardelli A, Sabra AF, Hallett M: Physiological mecha- 2. 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34. Tatton WG, Lee RG: Evidence for abnormal long- rial tumours sparing the basal ganglia, Acta Neurochir loop reflexes in rigid parkinsonian patients, Brain Res (Wien) 133:22–29, 1995. 100:671–676, 1975. 52. Yoshimura M, Yamamoto T, Iso-o N, et al: 35. Horak FB, Nutt JG, Nashner LM: Postural inflexibility Hemiparkinsonism associated with a mesencephalic in parkinsonian subjects, J Neurol Sci 111:46–58, 1992. tumor, J Neurol Sci 197:89–92, 2002. 36. Vreeling FW, Verhey FRJ, Houx PJ, Jolles J: Primitive 53. Voermans NC, Bloem BR, Janssens G, et al: Secondary reflexes in Parkinson’s disease, J Neurol Neurosurg parkinsonism in childhood: a rare complication after Psychiatry 56:1323–1326, 1993. radiotherapy, Pediatr Neurol 34:495–498, 2006. 37. Riederer P, Foley P: Mini-review: multiple developmen- 54. Curran T, Lang AE: Parkinsonian syndromes associated tal forms of parkinsonism. The basis for further research with hydrocephalus: case reports, a review of the liter- as to the pathogenesis of parkinsonism, J Neural Transm ature, and pathophysiological hypotheses, Mov Disord 109:1469–1475, 2002. 9:508–520, 1994. 38. Yokochi M: Development of the nosological analysis 55. Racette BA, Esper GJ, Antenor J, et al: Pathophysiology of of juvenile parkinsonism, Brain and Development parkinsonism due to hydrocephalus, J Neurol Neurosurg 22(Suppl 1):S81–S86, 2000. Psychiatry 75:1617–1619, 2004. 39. Huynh DP, Scoles DR, Nguyen D, Pulst SM: The auto- 56. Wijemanne S, Jankovic J: Hemiparkinsonism-hemiatrophy somal recessive juvenile Parkinson disease gene product, syndrome, Neurology 69:1585–1594, 2007. parkin, interacts with and ubiquitinates synaptotagmin 57. Li SH, Schilling G, Young WS 3rd, et al: Huntington’s XI, Hum Mol Genet 12:2587–2597, 2003. disease gene (IT15) is widely expressed in human and rat 40. Ruiz-Linares A: Juvenile Parkinson disease and the tissues, Neuron 11:985–993, 1993. C212Y mutation of parkin, Arch Neurol 61:444, 2004 58. Quinn N, Schrag A: Huntington’s disease and other 41. Ishikawa A, Tsuji S: Clinical analysis of 17 patients in 12 choreas, J Neurol 245:709–716, 1998. Japanese families with autosomal-recessive type juvenile 59. Topper R, Schwarz M, Lange HW, et al: Neurophysiological parkinsonism, Neurology 47:160–166, 1996. abnormalities in the Westphal variant of Huntington’s 42. Lohmann E, Periquet M, Bonifati V, et al: How much disease, Mov Disord 13:920–928, 1998. phenotypic variation can be attributed to parkin geno- 60. Langbehn DR, Brinkman RR, Falush D, et al: A new type? Ann Neurol 54:176–185, 2003. model for prediction of the age of onset and penetrance 43. Wang Y, Clark LN, Louis ED, et al: Risk of Parkinson for Huntington’s disease based on CAG length, Clin disease in carriers of parkin mutations: estimation using Genet 65:267–277, 2004. the kin-cohort method, Arch Neurol 65:467–474, 61. Tost H, Wendt CS, Schmitt A, et al: Huntington’s disease: 2008. phenomenological diversity of a neuropsychiatric condi- 44. Khan NL, Valente EM, Bentivoglio AR, et al: Clinical tion that challenges traditional concepts in neurology and subclinical dopaminergic dysfunction in PARK6- and psychiatry, Am J Psychiatry 161:28–34, 2004. linked parkinsonism: an 18F-dopa PET study, Ann 62. de la Monte SM, Vonsattel JP, Richardson EP Jr: Neurol 52:849–853, 2002. Morphometric demonstration of atrophic changes in 45. Pal PK, Leung J, Hedrich K, et al: [18F]-Dopa positron the cerebral cortex, white matter, and neostriatum in emission tomography imaging in early-stage, non-parkin Huntington’s disease, J Neuropathol Exp Neurol 47: juvenile parkinsonism, Mov Disord 17:789–794, 2002. 516–525, 1988. 46. Shimura H, Schlossmacher MG, Hattori N, et al: 63. Myers RH, Vonsattel JP, Stevens TJ, et al: Clinical and Ubiquitination of a new form of alpha-synuclein by neuropathologic assessment of severity in Huntington’s parkin from human brain: implications for Parkinson’s disease, Neurology 38:341–347, 1988. disease, Science 293:263–269, 2001. 64. Vonsattel JP, Myers RH, Stevens TJ, et al: 47. Xiong H, Wang D, Chen L, et al: Parkin, PINK1, Neuropathological classification of Huntington’s disease, and DJ-1 form a ubiquitin E3 ligase complex promot- J Neuropathol Exp Neurol 44:559–577, 1985. ing unfolded protein degradation, J Clin Invest 119: 65. Albin RL, Reiner A, Anderson KD, et al: Striatal and 650–660, 2009. nigral neuron subpopulations in rigid Huntington’s dis- 48. Abou-Sleiman PM, Healy DG, Quinn N, et al: The role ease: implications for the functional anatomy of chorea of pathogenic DJ-1 mutations in Parkinson’s disease, and rigidity-akinesia, Ann Neurol 27:357–365, 1990. Ann Neurol 54:283–286, 2003. 66. Augood SJ, Faull RL, Emson PC: Dopamine D1 and D2 49. van Duijn CM, Dekker MCJ, Bonifati V, et al: PARK7, receptor gene expression in the striatum in Huntington’s a novel locus for autosomal recessive early-onset disease, Ann Neurol 42:215–221, 1997. parkinsonism, on chromosome 1p36, Am J Hum Genet 67. Jongen PJ, Renier WO, Gabreels FJ: Seven cases of 69:629–634, 2001. Huntington’s disease in childhood and levodopa induced 50. Albanese A, Valente EM, Romito LM, et al: The PINK1 improvement in the hypokinetic-rigid form, Clin Neurol phenotype can be indistinguishable from idiopathic Neurosurg 82:251–261, 1980. 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69. Dunn HG, Stoessl AJ, Ho HH, et al: Rett syndrome: 82. Pranzatelli MR, Mott SH, Pavlakis SG, et al: investigation of nine patients, including PET scan, Can J Clinical spectrum of secondary parkinsonism in child- Neurol Sci 29:345–357, 2002. hood: a reversible disorder, Pediatr Neurol 10:131– 70. O’Sullivan JD, Hanagasi HA, Daniel SE, et al: Neuronal 140, 1994. intranuclear inclusion disease and juvenile parkinsonism, 83. Alves RS, Barbosa ER, Scaff M: Postvaccinal parkin- Mov Disord 15:990–995, 2000. sonism, Mov Disord 7:178–180, 1992. 71. Paviour DC, Revesz T, Holton JL, et al: Neuronal intra- 84. Manyam BV: What is and what is not Fahr’s disease, nuclear inclusion disease: report on a case originally diag- Parkinsonism Relat Disord 11:73–80, 2005. nosed as dopa-responsive dystonia with Lewy bodies, 85. Oliveira JR, Spiteri E, Sobrido MJ, et al: Genetic hetero- Mov Disord 20:1345–1349, 2005. geneity in familial idiopathic basal ganglia calcification 72. Lindenberg R, Rubinstein LJ, Herman MM, Haydon GB: (Fahr disease), Neurology 63:2165–2167, 2004. A light and electron microscopy study of an unusual wide- 86. Koller WC, Cochran JW, Klawans HL: Calcification of spread nuclear inclusion body disease. A possible resid- the basal ganglia: computerized tomography and clinical uum of an old herpesvirus infection, Acta Neuropathol correlation, Neurology 29:328–333, 1979. 10:54–73, 1968. 87. Koller WC, Klawans HL: Cerebellar calcification 73. Goutieres F, Mikol J, Aicardi J: Neuronal intranuclear on computerized tomography, Ann Neurol 7:193– inclusion disease in a child: diagnosis by rectal biopsy, 194, 1980. Ann Neurol 27:103–106, 1990. 88. Kenney C, Hunter C, Mejia N, et al: Metoclopramide: 74. Davison C: Pallido-pyramidal disease, J Neuropathol Exp an increasingly recognized cause of tardive dyskinesia, Neurol 13:50–59, 1954. J Clin Pharmacol 48:379–384, 2008. 75. Di Fonzo A, Dekker MC, Montagna P, et al: FBXO7 89. Kenney C, Jankovic J: Tetrabenazine in the treatment of mutations cause autosomal recessive, early-onset parkinso- hyperkinetic movement disorders, Expert Rev Neurother nian-pyramidal syndrome, Neurology 72:240–245, 2009. 6:7–17, 2006. 76. Shojaee S, Sina F, Banihosseini SS, et al: Genome- 90. Jenner P: Dopamine agonists, receptor selectivity and wide linkage analysis of a parkinsonian-pyramidal syn- dyskinesia induction in Parkinson’s disease, Curr Opin drome pedigree by 500 K SNP arrays, Am J Hum Genet Neurol 16(Suppl 1):S3–S7, 2003. 82:1375–1384, 2008. 91. Furukawa Y, Filiano JJ, Kish SJ: Amantadine for 77. Winston JT, Koepp DM, Zhu C, et al: A family of mam- levodopa-induced choreic dyskinesia in compound malian F-box proteins, Curr Biol 9:1180–1182, 1999. heterozygotes for GCH1 mutations, Mov Disord 19: 78. Najim al-Din AS, Wriekat A, Mubaidin A, et al: Pallido- 1256–1258, 2004. pyramidal degeneration, supranuclear upgaze paresis and 92. Crosby NJ, Deane KH, Clarke CE: Amantadine for dys- dementia: Kufor-Rakeb syndrome, Acta Neurol Scand kinesia in Parkinson’s disease, Cochrane Database Syst Rev 89:347–352, 1994. 2003 CD003467. 79. Williams DR, Hadeed A, al-Din AS, et al: Kufor 93. Paci C, Thomas A, Onofrj M: Amantadine for dyski- Rakeb disease: autosomal recessive, levodopa-respon- nesia in patients affected by severe Parkinson’s disease, sive parkinsonism with pyramidal degeneration, supra- Neurol Sci 22:75–76, 2001. nuclear gaze palsy, and dementia, Mov Disord 20: 94. Germano IM, Gracies JM, Weisz DJ, et al: Unilateral 1264–1271, 2005. stimulation of the subthalamic nucleus in Parkinson 80. Ramirez A, Heimbach A, Grundemann J, et al: Hereditary disease: a double-blind 12-month evaluation study, parkinsonism with dementia is caused by mutations in J Neurosurg 101:36–42, 2004. ATP13A2, encoding a lysosomal type 5 P-type ATPase, 95. Peppe A, Pierantozzi M, Bassi A, et al: Stimulation of the Nat Genet 38:1184–1191, 2006. subthalamic nucleus compared with the globus pallidus 81. Von Economo C: Encephalitis lethargica. Its sequelae and internus in patients with Parkinson disease, J Neurosurg treatment, London, 1931, Oxford University Press. 101:195–200, 2004.

[email protected] 66485438-66485457 [email protected] 66485438-66485457 Inherited Metabolic 15 Disorders Associated with ExtrapyramidalO Symptoms

Numerous metabolic disorders, many rare, can result in neurotransmitters involved in these diseases are the movement abnormalities. Most conditions are inherited, monoamines, which include serotonin and cate- although it is important to recognize that “inherited” cholamines (dopamine and norepinephrine), and does not imply “congenital,” with many manifesting in gamma-aminobutyric acid (GABA).1,2 childhood and adolescence, and uncommonly in adult- Monoamine-related neurotransmitter diseases can Ohood. Many disorders have a variety of clinical presen- be divided into separate categories based on the site tations with acute symptoms in the neonatal period of abnormality in the metabolic pathway, for example, and slower, more gradual, presentations at a later age. those affecting (1) the cofactor tetrahydrobiopterin Further, many conditions are typified by evolving and (BH4), (2) enzymes of monoamine biosynthesis, and differing movements, such as chorea, dystonia, and par- (3) catabolic enzymes (Fig. 15-1). Despite their differ- kinsonism. In this chapter, a variety of metabolic dis- ing etiologies, however, these disorders have many com- orders with a movement disorder phenotype will be mon symptoms, including developmental delay, axial discussed, using a disease-based framework (Box 15-1). hypotonia, rigidity, movement abnormalities, speech problems, feeding difficulties, abnormal eye move- Pediatric Neurotransmitter ments, and autonomic symptoms. Diagnostic studies Diseases include cerebrospinal fluid (CSF) for analysis of monoamines (dopamine, serotonin, norepinephrine), neu- The term has been pediatric neurotransmitter diseases rotransmitter metabolites (homovanillic acid [HVA]), applied to a broad spectrum of relatively uncommon 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy- genetic disorders that affect the synthesis, metabolism, 4-hydroxylphenylglycol (MHPG), pterin (biopterin and catabolism of neurotransmitters. The primary and neopterin), quantitative plasma and urine catecholamines, and phenylalanine loading profiles with Box 15-1 Disease-Based Classification of and without BH4. The concentrations of these metab- Metabolic Disorders Causing Movement olites and other products, however, vary markedly from Disorders one individual to another and any abnormalities may A. Pediatric neurotransmitter disorders not be necessarily specific for a particular disorder. B. Disorders of i. Mineral accumulation Tetrahydrobiopterin (BH4) Metabolism ii. Lysosomes iii. Amino acids Tetrahydrobiopterin is an essential cofactor for the neu- iv. Organic acids rotransmitter synthesizing enzymes tyrosine hydroxylase v. Glycolysis, pyruvate metabolism, and (which catalyzes the conversion of tyrosine to l-dopa) tricarboxylic acid cycle vi. Mitochondria and tryptophan hydroxylase (which catalyzes the conver- vii. Purine metabolism sion of tryptophan to 5-hydroxytryptophan [5-HTP]), viii. Creatine metabolism as well as for phenylalanine hydroxylase (which converts ix. Cofactors phenylalanine to tyrosine). BH4 itself is synthesized in a x. Other multistep pathway starting from guanosine triphosphate 164 [email protected] 66485438-66485457 Chapter 15 Inherited Metabolic Disorders 165

GTP GTPCH-1

Neopterin Dihydroneopterin triphosphate PTS

6-pyruvoyl-tetrahydropterin SPR DHPR Arginine Phenylalanine Tyrosine Tryptophan BH4 O BH2 NOS PAH TH TPH PCD cit + NO • Tyrosine L-DOPA 5-HTP Pterin 4a-carbinolamine COMT AADC-B6 MAO 3-O-MD DOPAMINE SEROTONIN 5-HIAA DBH MAO

NE DOPAC HVA MAO COMT COMT EPI Normetanephrine DHPG MHPG VMA

Figure 15-1. Abbreviations: AADC, aromatic L-amino acid decarboxylase; B6, pyridoxine; COMT, catechol-O-methyltransferase; DBH, dopamine β-hydroxylase, PCD, MHPG etc., DHPR, dihydropteridine reductase; GTPCH-1, GTP-1 cyclohydrolase; MAO, monoamine oxidase; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase, PCD, pterin 4a-carbinolamine reductase, PTS,6-pyruvoyl-tetrahydropterin synthase; SPR, sepiapterin reductase; TH, tyrosine hydroxylase, TPH, tryptophan hydroxylase. (Source: Swoboda KJ, Hyland K: Diagnosis and treatment of neurotransmitter-related disorders, Neurol Clin 20:1143-1161, 2002.)

(GTP) and, when formed, requires several enzymes to Clinical presentation maintain it in its active state (Fig. 15-2). In the neonatal period, presumably due to hyperphen Several enzymatic defects have been identified in ylalaninemia, hypotonia, poor suck, diminished move- BH4 metabolism, for example, deficiencies in the first ments, and microcephaly may be present. Generally, and rate-limiting synthesizing enzyme GTP-1 cyclohy- beginning several months later, more monoaminergic drolase (GTPCH-1), in the second and third enzymatic symptoms appear, including autonomic symptoms steps, namely 6-pyruvoyl-tetrahydropterin synthase (hypersalivation, temperature instability, excessive (6-PTS) and sepiapterin reductase (SPR), respectively, diaphoresis, and blood pressure lability), oculogyric and in the maintenance enzyme dihydropteridine crises, swallowing difficulties, variable hypokinetic reductase (DHPR). Although one might expect that a and hyperkinetic movements, seizures, and cognitive defect in BH4 metabolism would be readily detectable impairment.3,5,6 These patients can be detected by neo- based on the presence of hyperphenylalaninemia, which natal screening for phenylketonuria (PKU). In DHPR occurs because of a deficiency of phenylalanine hydrox- deficiency, a secondary reduction in central nervous ylase activity, this is not always present. Hence, classi- system (CNS) folate has led to perivascular basal gan- fication of BH4 metabolism defects can be based on glia calcification and multifocal subcortical perivascu- presentations with or without hyperphenylalaninemia. lar demyelination.7,8 Follow-up testing of urine pterins (biopterin and neopterin) and measurement of DHPR BH4 Defects with activity in blood is necessary to pinpoint the defect.1 Hyperphenylalaninemia Individuals in this group have onset in the neonatal Autosomal recessively inherited forms of GTPCH-1 period and include those with autosomal recessively deficiency (autosomal recessive, 14q22.1-22.2). inherited forms of GTPCH-1 deficiency, 6-PTS defi- Although one most commonly thinks of the autosomal ciency, pterin 4a-carbinolamine reductase deficiency dominant form of the disease, that is, Segawa’s disease (PCD), and DHPR deficiency.1,3,4 Since each produces or dopa-responsive dystonia, there is an autosomal hyperphenylalaninemia and reduced synthesis of mono- recessive form of GTP cyclohydrolase deficiency. The amines, clinical signs and symptoms tend to overlap. autosomal recessive form has hyperphenylalaninemia,

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Guanosine triphosphate (GTP)

GTP-1 cyclohydrolase (GTPCH-1)

Neopterin Dihydroneopterin-triphosphate

6-Pyruvoyl-tetrahydropterin synthase (6-PTS)

6-Pyruvoyl-tetrahydropterin

Sepiapterin reductase (SPR)

Tetrahydrobiopterin (BH4)

Pterin-4a-carbinolamine Dihydropteridine reductase (DHPR)

Pterin-carbinolamine reductase (PCD)

Dihydrobiopterin (BH2) Biopterin

Figure 15-2. Tetrahydrobiopterin synthesis.

due to a deficiency of hepatic phenylalanine hydroxylase similar to 6-PTS deficiency, and a juvenile-onset form activity, and typical symptoms as described previously. with progressive cognitive deterioration, seizures, long- tract signs, extrapyramidal signs, and cerebellar signs.11 6-PTS deficiency (autosomal recessive, A phenylalanine loading test may be abnormal, but this locus 11q22.3-23.3). test is no longer widely used. CSF shows elevated lev- This enzyme catalyzes dihydroneopterin-triphosphate els of BH2, low to normal levels of BH4, and reduced to form 6-pyruvoyl-tetrahydropterin. Patients have HVA and 5-HIAA. Basal ganglia calcifications may be reduced catecholamine and serotonin metabolites and an reversible with folinic acid supplementation.12 increased neopterin to biopterin level in the CSF. This is Treatment the most prevalent form of hyperphenylalaninemia not attributed to phenylalanine hydroxylase deficiency. Two Therapy for the hyperphenylalaninemia BH4 defects variants have been described, each having elevated levels includes a low-phenylalanine diet, correction of central of phenylalanine in newborn screening tests. The classic monoamine deficits, and prevention of folate deficiency. severe form shows persistent delays and progressive neu- Oral BH4 (5 mg/kg) will correct the peripheral metabolism rologic deterioration, with diffuse hypotonia, hypokinesis, of phenylalanine when the defect is not due to a DHPR extrapyramidal signs (cogwheel rigidity, choreoatheto- deficiency. Treatment of central monoamine deficits is sis, dystonia), and autonomic symptoms.9 Patients with achieved by the use of carbidopa/levodopa (see Chapter milder phenotypes have deteriorated following adminis- 10 and Appendix A for dosing) and 5-hydroxytryptophan tration of folate antagonists; the latter interferes with a in combination with carbidopa and catechol-O-methyl- conversion of BH2 to BH4 (see Figures 15-1 and 15-2), transferase (COMT) inhibitors, since BH4 does not read- via dihydrofolate reductase.2 A non-CNS, “peripheral ily cross the blood-brain barrier. Therapy with folinic acid form” has been reported that has no biochemical abnor- i.e. leukovorin, is used. If response is suboptimal, follow malities in the CSF, mild phenylalaninemia, and the up lumbar puncture for CSF folate levels may be useful potential for normal neurologic development with appro- and monitoring of CSF folate are recommended. 10 priate treatment. A form of 6-PTS deficiency without BH4 Defects without hyperphenyl-alaninemia is discussed later in this chapter. Hyperphenylalaninemia DHPR deficiency (autosomal recessive, locus 4p15.31). Dopa-responsive dystonia (DRD) Two forms have been described: the more common DRD, also known as Segawa’s disease, hereditary progres- neonatal form with progressive clinical symptoms sive dystonia, and DYT5, is the hallmark disorder of BH4

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metabolism without hyperphenylalaninemia. DRD is an plasma phenotype/tyrosine ratio of greater than 7.5. autosomal dominant disorder caused by heterozygous The authors suggested that if the plasma phenylala- mutations, spanning a 30 kb region with six exons, in the nine does not reach a minimum of 600 mg/dL the test gene for GTPCH-1 located on chromosome 14q22.1- is probably not valid and plasma tetrahydrobiopterin 22.2.13,14 This enzyme is the rate-limiting step in tetra- should be measured. GTP cyclohydrolase activity can hydrobiopterin synthesis. New mutations are frequent, also be measured in fibroblasts. clinical penetrance is incomplete (increased in females), Neuroimaging can occasionally be helpful to distin- and variable expressivity has occurred in families.15 guish DRD from juvenile parkinsonism. The density Although the spectrum of presentations is wide, patients of pre-synaptic dopamine terminals in striatum should typically seek treatment in midchildhood (5 to 6 years) appear normal in DRD but reduced in juvenile parkin- with dystonic posturing of leg or foot affecting the gait in sonism, as demonstrated either by use of fluorodopa a child with normal cognition. Symptoms progressively positron emission tomography or by single-photon worsen and about one-quarter develop hyperreflexia and emission tomography with [123I]beta-CIT. Post spasticity, leading some to be inappropriately labeled with synaptic terminal D2 receptor density, using raclo- the diagnosis of cerebral palsy. Diurnal variation occurs in pride PET, may be increased or normal, but positron all forms with progressive worsening throughout the day emission tomography of D2 dopamine receptors and improvement in the morning, after sleep. Cases with- suggests increased binding in both symptomatic and out diurnal changes, however, have been reported. Other asymptomatic carriers of GTP cyclohydrolase muta- presentations include arm dystonia (writer’s cramp), ret- tions as well as in some juvenile parkinsonism cases.23,24 rocollis, torticollis, poor coordination, or features of par- If genetic analyses do not demonstrate mutations in kinsonism, that is, bradykinesia, rigidity, masked facies, GTPCH1,25 it is important to ascertain whether analy- hypophonic speech, and postural instability.1,16 An unusual sis included sequencing the entire gene. case with myoclonus-dystonia syndrome, that is, myoclonic jerks beginning in childhood, has been described.17 DHPR deficiency without hyperphenylalaninemia 26 Older patients have a greater prevalence of obsessive-com- This disorder has been reported in several cases. pulsive disorder and major depressive disorder.18 Neurologic symptoms include psychomotor retarda- Patients respond dramatically and in a sustained fash- tion, microcephaly, spasticity, dystonia, oculomotor ion to low-dose levodopa (or dopamine agonist), making it apraxia, and hypersomnolence. The oral phenylalanine important to properly diagnose this disorder. Some DRD loading test in these patients was abnormal, despite the patients have also shown a good response to anti‑cho- lack of hyperphenylalaninemia. CSF measurements linergics such as trihexyphenidyl.19 Tetrahydrobiopterin show reduced monoamines and their metabolites may be helpful but is rarely used. Since dopamine syn- but normal BH4 and neopterin levels. Treatment thesis is more affected than serotonin, serotonin reuptake of this disorder includes the use of levodopa and inhibitors are not typically used. 5-hydroxytryptophan in combination with carbidopa to correct central monoamine deficits. Diagnosis Diagnosis is typically based on clinical symptoms and Sepiapterin reductase (SPR) deficiency (autosomal response to levodopa. In unclear cases or to distinguish recessive, locus 2p14-p12) DRD from other metabolic diseases or forms of par- SPR deficiency is another inherited disorder of BH4 kinsonism, Genetic Testing of GTPCH1 or CSF test- metabolism characterized by the signs and symptoms ing, as above, may be helpful. CSF analysis showing related to monoamine neurotransmitter deficiency, but markedly decreased HVA, normal or low 5-HIAA, without hyperphenylalaninemia. SPR catalyzes the final reduced BH4 and neopterin levels. two-step reduction of the intermediate 6-pyruvoyl- The phenylalanine loading test has been advocated tetrahydropterin (PTP) to BH4. Phenylalaninemia for detection of both affected and nonmanifesting is absent, since other reductases in the liver, but not GTPCH-1 gene carriers.20,21 Since individuals with brain, can substitute for this enzyme. SPR deficiency PKU would show similar abnormalities, DRD car- has been reported in a small number of patients with riers are distinguished by correction of the loading progressive psychomotor retardation, dystonia, dyski- test after administering biopterin. The sensitivity and nesias, athetosis, seizures, hypotonia, and hypersomno- specificity of the phenyalanine loading test, however, lence.27 CSF measurements show severe CSF dopamine has been questioned. In one study, oral challenge of and serotonin deficiencies and (presumably because phenylalanine (100 mg/kg) was administered to 11 of low dihydrofolate reductase activity) high levels of individuals with DRD and one nonmanifesting gene biopterin and dihydrobiopterin (BH2).6,12,27 Several carrier.22 Only 50% were found to have a 4-hour mutations in the SPR gene have been identified. [email protected] 66485438-66485457 168 section 5 selected secondary movement disorders

Treatment of formed neurotransmitter, and an anticholinergic, e.g. Non-hyperphenylalaninemia BH4 deficiencies can be trihexyphenidyl, starting at 1 mg daily and gradually treated with low-dose levodopa. titrating upward to effect by 1 mg/day each week.6,37

Primary Defects of Monoamine Biosynthesis Aromatic l-Amino Acid Decarboxylase (ALAAD or Defects of monoamine biosynthesis have been defined AADC) Deficiency (Autosomal Recessive, Locus 7p12.1-12.3) at three sequential enzymatic steps: (1) tyrosine hydroxylase (TH), the rate-limiting step catalyzing the conversion ALAAD, a pyridoxine-dependent enzyme, catalyzes of tyrosine to l-dopa in the formation of dopamine and both the formation of dopamine from l-dopa and sero- norepinephrine; (2) aromatic l-amino acid decarboxylase tonin from 5-hydroxytryptophan (5-HTP). Deficiency (ALAAD or AADC), which converts l-dopa to dopamine; of this enzyme leads to a profound reduction of CSF and (3) dopamine β-hydroxylase (DβH), the enzyme that serotonin and catecholamines. Clinical symptoms usu- converts dopamine to norepinephrine (see Fig. 15-1). ally begin between 2 months and 1 year of age and tend to be similar to severe BH4 deficiency.38,39 Problems Tyrosine Hydroxylase Deficiency (Autosomal include developmental delay, hypotonia, paroxys- Recessive, Locus 11p15.5) mal movements with arm and leg extension, dystonia, Tyrosine hydroxylase (TH), the rate-limiting enzyme athetosis, myoclonus, torticollis, and oculogyric crises. in the biosynthesis of dopamine, catalyzes the conver- Autonomic symptoms have included ptosis, miosis, sion of l-tyrosine to l-dihydroxyphenylalanine. At least sweating, temperature instability, hypotension, and gas- eight different point mutations have been identified in troesophageal reflux. Symptoms may also include spas- the TH gene, and alternate splicing of TH pre-mRNA ticity, disordered sleep, and a diurnal variation.1,3,40,41 If can lead to at least four different isoforms.28 Varying untreated, affected children develop a characteristic phe- phenotypes have been described including severe early- notype of extrapyramidal movements often preceded onset encephalopathy, progressive gait disorder, juvenile by oculogyric crises and convergence spasms.3 Milder parkinsonism, and hypotonia with ataxia.29–35 In cases forms have been described in older individuals with with a severe reduction of TH activity, onset occurs in ataxia, speech impairments, and autism.42,43 Magnetic infancy with symptoms of psychomotor retardation, resonance imaging (MRI) scans may have mild cortical rigidity, hypokinesia, axial hypotonia, and oculogyric atrophy and EEGs spike or polyspike bursts.44 crises. In other presentations, cases have had parkin- Diagnosis sonism, gait disorders, stiffness after exercise, tremor, dystonia, and ataxia. One case had a static encephalop- Diagnosis of an ALAAD deficiency is made by measur- athy with spastic paraplegia with the later development ing CSF neurotransmitters and metabolites: marked of a progressive dystonic-dyskinetic syndrome.36 Neuro reductions of dopamine, HVA, serotonin, 5-HIAA, imaging is normal whereas electroencephalograms NE, and MHPG. Levels of the l-dopa metabolite, (EEGs) may show nonspecific background abnor- 3-O-methyldopa, are elevated, since l-dopa cannot be malities.30,31 The possibility of an autosomal dominant decarboxylated to dopamine. Genetic testing for AADC presentation has been observed in one family.34 is available. The activity of ALAAD can be measured in fibroblasts. A secondary deficiency of ALAAD caused by Diagnosis a lack of pyridoxal 5-phosphate, has been reported.45 Diagnosis is confirmed by genetic analysis, and bio- Treatment chemical testing showing reduced CSF reduced levels of dopamine, norepinephrine, HVA, and MHPG, with Treatments are designed to maintain any levels of dop- normal 5-HIAA, biopterin, and neopterin levels. Since amine and serotonin that are produced by use of mono- TH is primarily expressed in brain and adrenal gland, amine oxidase inhibitors (tranylcypramine, selegiline) enzymatic assessment is generally not feasible. and to stimulate dopaminergic neurotransmission by use of dopamine agonists (bromocriptine, pergolide, Treatment pramipexole, ropinerole). Medications have improved Treatment involves the administration of conservative some symptoms, but not signs of developmental delay. doses of levodopa/carbidopa, see Appendix A. because tol- l-dopa is not expected to be beneficial, although rarely erance for l-dopa or dopamine agonists is low. Medication some patients do improve.20,46 Many patients obtain responses are inconsistent, effect may be delayed, and substantial benefit from dopamine agonists.39 Similarly, severe dyskinesias have occurred.35 Additional therapeu- since B6 is a cofactor for ALAAD, high dose pyridoxal tic recommendations include a monoamine oxidase B phosphate is also recommended. Serotoninergic agents (MAO-B) inhibitor (selegiline) to prevent breakdown have not been of benefit.6,38

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GABA-Related Neurotransmitter Disease Mineral Accumulation Succinic Semialdehyde Dehydrogenase Deficiency Wilson’s Disease (Hepatolenticular Degeneration) (4-Hydroxybutyric Acidurias, Autosomal Recessive, (Autosomal Recessive, Locus 13q14.3) Locus 6p32) Pathophysiology Succinic semialdehyde dehydrogenase (SSADH) works The gene for Wilson’s disease encodes for a protein in conjunction with GABA transaminase to convert (copper-transporting P-type ATPase, ATP7B) localized gamma-aminobutyric acid (GABA) to succinic acid in the trans-Golgi network and responsible for excretion (Fig. 15-3). of copper out of the hepatocyte and the incorporation SSADH deficiency results in increased concentrations of copper into ceruloplasmin (Fig. 15-4).56 A large vari- of GABA and 4-hydroxybutyric acid (GHB). Mean ety of mutations have been described.57,58 These abnor- age of onset is about 11 months, but diagnosis is often malities lead to failure to excrete copper in the bile and delayed until a mean of 6.6 years.47 Clinical phenotype is the subsequent accumulation in liver, brain, cornea, variable and nonspecific with a variety of neurologic and kidney, bones, and blood. Intestinal absorption of cop- psychiatric symptoms. Findings include mental retarda- per is normal and serum levels of ceruloplasmin, an tion, disproportionate language dysfunction, autistic alpha-2-globulin that binds and transports copper mol- traits, hypotonia, ataxia, aggression, anxiety, halluci- ecules, are nearly always reduced. Increased excretion nations, hyperactivity, and occasionally choreoatheto- of copper in the urine is insufficient to prevent copper sis, and about two thirds have seizures.48,49 About 10% accumulation. ATP7A, structurally similar to the have a severe phenotype characterized by developmental Wilson’s disease ATP7B, affects copper absorption and regression and extrapyramidal manifestations.50 is responsible for systemic copper deficiency (decreased Diagnosis serum copper and ceruloplasmin) and the X-linked Atrophy of the cerebellum and T2 hyperintensities Menkes disease (kinky hair, developmental regression, (especially in the white matter and globus pallidus) hypotonia progressing to spasticity and paresis). may be present on MRI, although imaging is normal Clinical features in 40% of cases.51 EEG may show diffuse background The typical childhood clinical presentation of Wilson’s slowing and generalized or multifocal abnormalities. disease is hepatic dysfunction (asymptomatic hepato- Diagnosis is made by detection of massive increases in megaly, acute transient or fulminant hepatitis) begin- GHB in urine, plasma, or CSF and confirmed using ning about age 12 years.59 The mean age for the enzyme analysis in leukocytes and molecular genetic appearance of neurologic symptoms is approximately analysis of the only known causative gene, Aldehyde 19 years, although symptoms have been reported in a Dehydrogenase 5 family member A1 (ALDH5A1). 6-year-old.60–62 Symptoms tend to be insidious and vari- Prenatal testing/pre-implantation testing is available, including alterations in speech, drooling, pharyn- able.52,53,55 Prenatal diagnosis is possible. geal dysmotility, motor function, and mental changes. Treatment Dysarthria described by Wilson63 as a “trifling indistinct- Treatment is symptomatic, with anticonvulsants and ness of speech,” clumsiness, tremor, or mental changes medication for behavior problems. Valproic acid is may be the initial presentation. In contrast, others have contraindicated. Vigabatrin (gamma-vinyl GABA), suggested that tremor, chorea, dystonia, and cerebellar which blocks GABA transaminase,54 has been tried impairment are the earliest manifestations.64,65 Several with mixed results. variable phenotypes have been described, including an

Succinic semialdehyde dehydrogenase GABA transaminase (SSADH) GABA Succinic semialdehyde Succinic acid

Gamma-hydroxybutyrate (GHB) (4-hydroxybutyric acid)

Figure 15-3. Succinic acid synthesis.

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ATP7A (Menkes disease) Oral intake Intestinal absorption Plasma albumin

Urine Cu Ceruloplasmin Apoceruloplasmin

ATP7A Cu (I) LIVER

ATP7B Bile (Wilson’s disease)

Figure 15-4. Copper transport. akinetic-rigid and a generalized dystonic type.66 a decisive tool, but testing must include screening for all Psychiatric symptoms precede the neurologic abnor- variants, which is currently not practical.71 However, in malities in 20% of cases, ranging from subtle changes in cases not established with clinical features and biochemical personality and behavior (“a childishness seen in facile testing, identification of both mutated alleles is definitive laughter, or irritability, or caprice”) or a decline in school with a sensitivity of 95%. In children ages 6 and up with performance, to frank psychosis.63,68 Tremor, although neurologic symptoms suggestive of Wilson Disease, the common in Wilson’s disease, can have variable char- appropriate first test is a serum ceruloplasmin. Detection acteristics including being unilateral or bilateral, and of a level of .20 g/L or lower has a sensitivity of approxi- appearing at rest, during postural maintenance, with matley 95%. Levels of ceruloplasmin, an α2-glycoprotein movement, or in any combination of the aforemen- acute-phase reactant, are increased in hepatitis and by tioned. When present as an action tremor, it is typically other inflammatory disorders. In addition, values may dif- coarse and irregular and when elicited with arms for- fer in local populations.72 ward and flexed may have the classical “wing-beating” MRI abnormalities include increased signal intensity or proximal quality.67 With progression of the disease, on T2-weighted images of the basal ganglia.73 Other spasmodic dystonia of the head or body and dyskine- reported findings include the “face of the panda” in sias involving the face (facial grimacing, sardonic smile, the midbrain and the “bright claustrum” signs.74,75 blepharospasm, and tongue dyskinesia) are common. A Pathologically, copper accumulates extensively in the possible trend has been reported between genotype and basal ganglia, where it can cause necrosis, as well as dif- psychopathologic symptoms and personality traits.69 fusely in the cortex and adjacent white matter. Although The Kaiser-Fleischer ring, a yellow-brown deposition of MRI findings can improve with copper chelation ther- copper in the periphery (Descemet’s membrane) of the apy,76 brain content of copper may remain elevated and cornea, is characteristic of the disease when it involves prominent neuropathologic features persist.77 70 the CNS. Although identifiable on examination, Treatment especially in individuals with lightly pigmented corneas, Treatment for Wilson’s disease is divided into acute and they are best observed by slit-lamp examination. lifelong maintenance therapy.78 Penicillamine is a pow- Diagnosis erful copper chelating agent, but because of potential Early diagnosis is critical in order to reverse symptoms and side effects, including sudden and possibly permanent prevent further complications. Diagnosis is made in the worsening of neurologic symptoms, its use is contro- proper clinical setting through a combination of studies versial.59,79–81 Ammonium tetrathiomolybdate (TM) is a including measurement of serum ceruloplasmin (reduced), newer and less toxic medication that is currently being quantification of 24-hour urine copper (elevated, typically evaluated in clinical trials. Trientine (triethylene tetramine exceeds 100 mg/24 hours), slit-lamp examination for detec- dihydrochloride) is not benefical for the acute treatment tion of the Kayser-Fleischer ring, and most definitively by of patients with neurologic symptoms, because it does liver biopsy with histologic assessment and determina- not mobilize copper from the brain. It is useful, however, tion of copper content. Direct molecular diagnosis can be as maintenance therapy and in the treatment of patients

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with pure hepatic disease. Zinc, which induces the syn- neurodegeneration (PKAN), also known as NBIA type thesis of metallothionein in the intestine, has a slower one, now refers only to individuals with mutations in a onset of action and is only used as maintenance therapy gene that encodes pantothenate kinase 2 (PANK2). or in case of very early diagnosis. See Appendix A. Pantothenate Kinase–Associated Ceruloplasmin oxidase activity and serum-free cop- Neurodegeneration (PKAN) per concentrations should be monitored in patients receiving chronic therapy to prevent iatrogenic copper PKAN is a rare autosomal recessive disorder (chromosomal deficiency.82 Recovery of neurologic problems typically locus 20p12.3-p13) caused by mutations (point muta- does not begin until after about 6 months of treatment. tions, insertions, and deletions in all seven exons) in the Although radiographic improvement on brain MRI gene for pantothenate kinase 2 (PANK2). Pantothenate may be seen for up to 4 years, disabilities that persist kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) from vitamin B (pantothenate) for longer than 2 years after initiation of therapy tend 5 to be permanent. Orthotopic liver transplantation may (Fig. 15-5). Pathologically, this disorder is associated with be life saving for patients with fulminant liver failure or abnormal iron deposition and high concentrations of for those unresponsive to medical therapy.83 lipofuscin and neuromelanin in the substantia nigra pars reticulata and the internal segment of the globus pallidus. Aceruloplasminemia (Autosomal Recessive Disorder, Clinical features Localized to Chromosome 3) PKAN has variable presentations and has been divided This disorder is due to mutations altering the func- into (a) a more classic early-onset form (diagnosis evi- tion of the ceruloplasmin gene.84 Initial manifestations dent before age 6 years), which is subdivided into sub- usually occur in adulthood with evidence of diabe- type α, which follows a rapidly progressive course, tes mellitus secondary to pancreatic involvement and and subtype β, which follows a slower course; and (b) hepatic iron overload.85 A progressive neurologic dis- “atypical forms,” which are subdivided into a late-onset ease begins a few years later with dystonia, dysarthria, type (diagnosis evident between ages 10 and 18 years) bradykinesia, rigidity, cerebellar ataxia, and demen- and an adult variant.90,91 tia.86,87 Anemia with low serum iron, low transferrin The classic form is characterized by onset in early saturation, but elevated serum ferritin is usually pres- childhood with progressive motor difficulties, personal- ent. MRI shows severe iron accumulation in the basal ity changes, cognitive decline, dysarthria, and spasticity. ganglia with prominent deposition in astrocytes.88 Extrapyramidal dysfunction is typically present but may be Neurodegeneration with Brain Iron Accumulation delayed for several years. Dystonia is common (orobucco- (NBIA) lingual and limb), and rigidity, choreoathetosis, and a rest- The nosology of this group of disorders continues to ing or action tremor may also be present. Ophthalmologic undergo revision based on genetic advances and revelations abnormalities include pigmentary retinal degeneration in about Julius Hallervorden’s involvement in World War II about two thirds of patients and optic atrophy, which is atrocities. Initially labeled Hallervorden-Spatz syndrome less common. Seizures can also occur. The most frequently (HSS), this heterogeneous group of conditions with neu- reported systemic manifestation is acanthocytosis, occur- rodegeneration associated with the accumulation of iron ring in about 8% of classic patients.91 The course of the has been reclassified.89 Pantothenate kinase–associated early-onset form is variable and is divided into a rapidly

Pantothenate kinase (PANK) Pantothenate (B5) Phosphopantothenate

Cysteine

Pantothenoyl- PANK Phosphopantothenoyl- cysteine L-cysteine

PANK Pantetheine Phosphopantetheine

Coenzyme-A

Figure 15-5. PANK-mediated reactions. [email protected] 66485438-66485457 172 section 5 selected secondary movement disorders and a slowly progressive type. The rapidly progressive early-onset type has a short transition from spasticity to severe movements with opisthotonos, and death within 1 to 2 years. In contrast, the more prevalent slowly progressive early-onset type progresses at a nonuniform rate and symptoms decline more slowly; progressive dystonia and spasticity lead to being wheelchair-bound by the teens, with death occurring within 20 years. In the “atypical” late-onset childhood form, patients often have speech defects (palilalia, tachylalia, and dysarthria) as an early sign and often develop significant psychiatric symptoms (personality changes, impulsivity, episodic outbursts, depression).92,93 Although affected individuals are often described as clumsy, motor involvement is a later feature, and spasticity ultimately limits ambulation. Freezing during ambulation, especially when turning or encountering irregular surfaces, Figure 15-6. 94 MRI findings in NBIA type 1 showing has been described. In general, the course of atypical decreased T2-weighted and proton density signal in the PKAN is less severe and more slowly progressive than the globus pallidus- the “Eye of the Tiger” sign. early-onset types. The PKAN phenotype may be due to a combination of product deficit (CoA depletion) and Treatment substrate (pantothenate, pantothenoyl-cysteine, and There is no specific treatment for PKAN/NBIA pante‑theine) accumulation. In those brain regions that (HSS), although theoretically the downstream deliv- use this pantothenate kinase, a reduction in CoA could ery of phosphopantothenate or products in the coen- affect essential metabolic pathways including the Krebs zyme A pathway may be therapeutic. Iron chelation cycle, fatty acid synthesis and degradation, and acetyla- therapy with desferrioxamine has not been effective, tion. Accumulation of the cysteine moiety, present in but response may be better with the use of newer both pantothenoyl-cysteine and pantetheine, can cause agents.101 Therapy for movement disorders and spasticity 100 neurotoxicity. Additionally, since cysteine is also an is symptomatic. Oral baclofen has been helpful in early iron chelator, iron accumulation can further contribute stages but intrathecal infusion has provided only limited to oxidative stress ansd neurodegeneration. benefit.102 Deep brain stimulation has benefited some Diagnosis children with HSS ages 10 and older who have not lost The diagnosis of PKAN depends on the presence of ambulation, and pallidotomy and thalamotomy have obligate features: onset in the first two decades, pro- produced limited and transient benefit.103–105 gressive course, extrapyramidal symptoms, and classic HARP syndrome MRI findings showing decreased T2-weighted and pro- HARP syndrome has been used to define a phenotype ton density signal in the globus pallidus and substan- that includes hypoprebetalipoproteinemia, acanthocy- tia nigra (Fig. 15-6). The presence of a hyperintense tosis, retinitis pigmentosa, and pallidal degeneration.106 area within the hypodense areas, named the “eye of the This disorder has been shown to be caused by mutations tiger sign,” is thought to be almost pathognomonic for in PANK2, the gene that causes PKAN.91 A few other PKAN.95,96 Hyperdense lesions are present in presymp- patients have been reported with symptoms of acan- tomatic patients and as the disease progresses hypoden- thocytosis, retinitis pigmentosa, facio-bucco-lingual sities appear and ultimately predominate.95,97 Supportive dyskinesia, and the “eye of the tiger sign” (see Fig. 15-6), diagnostic signs and symptoms include spasticity, but with normal serum lipoproteins.107 Acanthocytes extensor plantar signs, progressive intellectual impair- are believed to be caused by lipid peroxidation, a process ment, ophthalmologic problems, abnormal cytosomes stimulated by iron. in lymphocytes, and sea-blue histiocytes in bone marrow (typical of ceroid-lipofuscin accumulation).90,98 Other Neurodegeneration with Cultured skin fibroblasts have been reported to accu- Brain Iron Accumulation Disorders mulate 59Fe-transferrin. Patients homozygous for null Initially, this classification was suggested for patients mutations show typical PKAN phenotypes. In individ- who met the diagnostic criteria for NBIA type uals who are compound heterozygous for null/missense 1/ Hallervorden-Spatz syndrome, but lacked mutations mutations, the course of disease may be atypical.99 in PANK2.91 Although affected individuals share many [email protected] 66485438-66485457 Chapter 15 Inherited Metabolic Disorders 173

clinical features in common with PKAN, several clinical, Neuronal Storage Diseases imaging, and pathologic features assist in distinguishing Neuronal storage diseases such as GM1 and GM2 gan- the group. In non PKAN NBIA, many patients have gliosidosis, Gaucher disease, and Niemann-Pick disease, the early diagnosis of moderate to severe mental retar- are typically characterized by the presence in infancy dation, seizures are common, and the disease tends to of progressive cognitive and motor deterioration, be static until adolescence, when there is a rapid deteri- seizures, retinopathy, and in some cases hepatosple- oration with prominent dystonia. Radiographically, the nomegaly. In general, it is the more slowly progressive globus pallidus is uniformly hypodense on T2-weighted variants of these disorders, that is, those that have only images and the “eye of the tiger” is absent. Pathologically, partial deficiencies of enzyme activity, which tend to NBIA typically has cerebellar atrophy and iron depo- have extrapyramidal signs. sition in the red nucleus and dentate, both of which are uncommon in PKAN. Several specific disorders are GM 1 gangliosidoses described below. It has been suggested that the different GM 1 gangliosidoses are caused by a deficiency of β- types of neurodegeneration with brain iron accumula- galactosidase activity resulting in a failure to cleave the tion can be reliably distinguished with T2 and T2 fast terminal β-galactose from the GM1 ganglioside.115 Three spin echo brain MRI.108 types of GM1 gangliosidosis have been defined based on Neuroferritinopathy (NBIA type 2) is an autosomal age of onset and the extent of enzyme activity (very low dominant disorder characterized by mutations in the β-galactosidase activity in the infantile form but residual FTL gene, which codes for ferritin light polypeptide, activity in the older forms).116 At least 102 mutations in on chromosome 19q13. The mean age of onset is the β-galactosidase gene have been described. the most 40 years and presentation includes chorea, dystonia, common infantile form with onset between birth and prominent oromandibular dyskinesias, and parkin- 6 months is characterized by coarse facial features, devel- sonism.109,110 Patients have low serum ferritin levels and opmental failure, dysostosis multiplex, hepatospleno- MRI is abnormal even early in the disease.111 megaly, hypotonia, cherry-red macular spot, seizures, Infantile neuroaxonal dystrophy (INAD) is an auto- vacuolated lymphocytes, skeletal dysostosis, and death somal recessive disorder with mutations in the PLA2G6 by 1 to 2 years of age. A single case has been reported gene, which encodes a calcium-independent phospholi- with basal ganglia calcifications.117 Type 2 the late-infan- pase A , on chromosome 22q13.112 INAD is characterized 2 tile or juvenile form begins between 1 and 3 years of by progressive motor and sensory impairment, spastic age with seizures, spasticity, ataxia, extrapyramidal signs, tetraplegia, hyperreflexia, and visual impairment. Some and mental impairment. Dysmorphic features, corneal individuals, however, with mutations in PLA2G6 have an clouding, and hepatosplenomegaly, a part of the type extrapyramidal syndrome with dystonia, parkinsonism, 1 form, are lacking in types 2 and 3. Cherry-red spots and choreoathetosis that can be clinically indistinguish- may be present in type 2. Type 3 GM1 gangliosidosis, able from the phenotype of patients with PANK2 gene which occurs in children or adults (ages 3 to 30 years), mutations.113 Cerebellar atrophy may also be present in is a slowly progressive disorder with dysarthria, dystonia, patients with PLA2G6 mutations.114 rigidity, bradykinesia, and gait abnormalities.118–121 MRI Aceruloplasminemia, See prior section in this chapter. in type 3 shows symmetric hyperintense signal inten- Lysosomal Disorders sities on proton-density and T2-weighted sequences in the caudate and putamen.118,119,121 Intracytoplasmic stor- Lysosomes are intracytoplasmic vesicles that contain a age and cell loss is most prominent in the caudate and variety of degradative enzymes that are used to catabo- putamen, with lesser involvement in the globus pallidus, lize complex substrates such as sphingolipids, ganglio- Purkinje cells in the cerebellum, and amygdala.122 The sides, cerebrosides, sulfatides, mucopolysaccharides, and molecular mechanisms leading to disease symptoms are glycoproteins. incompletely understood. Diagnosis Treatment Diagnosis of these diseases is based on levels of lyso- There is no specific treatment for GM1 gangliosidosis, somal enzyme activity which are readily assayed in but substrate reduction therapy and chaperone-mediated serum, white blood cells, or cultured fibroblasts. The enzyme replacement therapy may prove feasible.123,124 inherited absence of a specific enzyme activity, in turn, results in the excessive accumulation of the undegrad- GM2 gangliosidoses able substance in the lysosome, with subsequent disrup- GM2 gangliosidoses are a group of recessively inherited tion of either neuronal or myelin function (Fig. 15-7). disorders characterized by the accumulation of the GM2

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O GM1-gangliosidosis ββ β NAGA

N GLUC GAL β GAL

NANA

O GM2-gangliosidosis ββ β NAGA

N GLUC GAL

O Gaucher disease β

N GLUC

+ OPCH2CH2N (CH3)3 Niemann-Pick disease β N

Figure 15-7. Neuronal storage diseases.

ganglioside within neuronal cells secondary to a defi- ments, athetoid posturing of the hands and extremities, ciency in β-hexosaminidase activity. β-Hexosaminidase and seizures, with death by the midteens.126 Several cases has two major isozymes, hexosaminidase A (HEX A), have had progressive proximal muscle weakness and were which is composed of alpha and beta subunits, and hexo- initially misdiagnosed as having spinal muscular atrophy saminidase B (HEX B), containing only beta subunits. (SMA) type III (Kugelberg-Welander disease).127,128 Thus a genetic defect encoding alpha subunits (chromo- Adult or chronic GM2 gangliosidosis has a slowly pro- some 15) would affect only HEX A, whereas a defect gressive course with neurologic symptoms including encoding beta subunits (chromosome 5) would affect cerebellar ataxia, dysarthria, weakness, and atrophy both HEX A and B. The three major forms of GM2 (similar to a motor neuron disease), a combined spi- gangliosidosis include Tay-Sachs disease and its variants nocerebellar ataxia, oculomotor disturbances, and due to a HEX A deficiency (also known as the B types); involvement of the peripheral and autonomic nervous Sandhoff disease with a deficiency of both HEX A and system.129,130 Psychiatric symptoms, including depres- HEX B (also called the O type); and the AB variant sion, psychosis, and dementia, also occur in this variant caused by an abnormality of the GM2-activator protein. and may be a presenting feature.131 The classic infantile forms of Tay-Sachs and Sandhoff disease are characterized by early neurologic deteriora- Niemann-Pick Diseases tion, loss of developmental milestones, exaggerated The eponym Niemann-Pick disease encompasses a startle response to auditory stimuli, motor weakness, variety of different lysosomal lipid storage diseases. progressive blindness, cherry-red spots in the macular Individuals with type A have an acute neuropathic region, seizures, and early death. Hepatosplenomegaly form with visceromegaly, pulmonary involvement, may be present in Sandhoff disease. MRI findings on and death in infancy. Those with type B have chronic T2-weighted images include hyperintensities in both visceral disease without neurologic involvement. In basal ganglia and thalamus.125 Why specific subpopula- both the type A and B autosomal recessive disorders, tons of neurons are targeted remains unclear. sphingomyelin accumulates in various tissues and the Juvenile GM2 gangliosidosis (deficiency of hexos lysosomal enzyme sphingomyelinase is deficient. aminidase A) has an age of onset of 2 to 6 years and is char- Niemann-Pick type C is characterized by normal acterized by combinations of psychomotor deterioration, sphingomyelinase levels, the lysosomal accumulation progressive ataxia, dysarthria, spasticity, dystonic move- of unesterified cholesterol, and glycosphingolipids.

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In the brain there is abnormal neuronal storage of lipids is more heterogeneous, occurring in children or adults, with a ballooned appearance. Mutations in the NPC1 with affected individuals having organomegaly, Gaucher gene on chromosome 18q11-12 account for about 95% cells in the bone marrow, and some form of neurologic of human cases.132 The NPC1 protein is a key partici- involvement. An unusual number of cases of type 3 pant in intracellular sterol trafficking. A juvenile-onset Gaucher disease have been identified in the Norrbottnian form is characterized by learning difficulties, cognitive region of Sweden.145 Neurologic signs include myoclonus, deterioration, supranuclear vertical gaze palsy, cerebel- myoclonic epilepsy, supranuclear ocular paresis, rigidity, lar ataxia, cataplexy, dysarthria, gait problems, seizures, facial grimacing, mild spastic paraparesis, slow mental and hepatosplenomegaly. Movement disorders, includ- deterioration, Parkinson-like symptoms, and generalized ing dystonia (begins in the extremities and gradually epilepsy.146–148 It has been suggested that abnormal corti- becomes generalized), chorea, athetosis, and parkin- cal inhibition is common and correlates with the degree sonism are also part of the neurologic picture.133–137 of cognitive deficit.149 Enzyme replacement therapy with Peripheral neuropathy is a rare complication.138 Death recombinant glucocerebrosidase reverses most of the sys- occurs in the second decade due to progressive dys- temic manifestations, but rarely the neurologic deficits phagia and inanition. An imbalance between induction because it does not cross the blood-brain barrier.147 and flux through the autophagic pathway is postulated Neuronal Ceroid Lipofuscinoses to contribute to cell stress and neuronal loss.139 Neuronal ceroid lipofuscinoses (NCLs), also known as Diagnosis Batten disease, are a group of neurodegenerative diseases In the setting of characteristic symptoms, biochemical usually beginning in childhood. The NCLs are auto- testing is most useful. Cultured fibroblasts are tested for somal recessive, lysosomal storage disorders that are char- abnormal esterification of exogenous cholesterol and acterized by the accumulation of autofluorescent ceroid accumulation in lysosomes (seen with filipin staining). lipopigment in brain tissue and various organs, including MRI of the brain in Niemann-Pick type C ranges from sweat glands and muscle. Historically, three classic forms normal to mild posterior periventricular white mat- have been described in children based on the age of onset, ter hyperintensity. Bone marrow testing, which shows clinical symptoms, and electron microscopic evaluation foamy cells or sea-blue histiocytes, is rarely needed. of the storage material.150,151 More recently, a genetic clas- Sphingomyelinase activity is normal in cultured skin sification, based on the gene defect for each disorder, has fibroblasts and peripheral leukocytes. been implemented. NCL disorders result from mutations Treatment in different CLN genes (CLN1 to CLN9). Six of the genes have been cloned (CLN1-3, 5, 6, and 8) and shown to There is no specific treatment for this disorder. Miglustat, encode soluble and transmembrae proteins located in an iminosugar that inhibits glucosylceramide synthase, 152,153 140 endosomes/lysosomes or the endoplasmic reticulum. improved or stabilized several clinical markers. Unfortunately, mutations do not strictly coincide with Gaucher Disease clinical classifications based on age of presentation, symp- Gaucher disease, an autosomal recessive trait, results from toms, or type of inclusion. For example, mutations in the CLN1 gene can be associated with infantile, late-infantile, defects of acid β-glucosidase (chromosome 1q21; more than 200 mutations) with the subsequent accumulation of juvenile, or adult variants of the disease (Table 15-1). its substrate glucocerebroside. Gaucher disease is divided Infantile NCL (INCL, Haltia-Santavuori Disease) into three conventional types, with visceral involvement INCL has its onset from 6 months to 2 years. Following in all and neuronopathic symptoms in two of the three an initial period of normal development, there is forms.141–143 Diagnosis is usually based on the presence of regression of developmental milestones, deceleration Gaucher cells in the bone marrow aspirate and confirma- of head growth, hypotonia, motor clumsiness, ataxia, tion by enzymatic assay and molecular analysis. Gaucher- irritability, seizures, and visual failure. By age 2 to 3 like cells can also be found in hematologic disorders years, affected children have lost all motor and social such as leukemia, Hodgkin’s lymphoma, and multiple skills and are blind. Death occurs before the early teen- myeloma. Type 1, the most common form, is a chronic age years. Storage cytosomes typically show granular nonneurologic disorder causing hepatosplenomegaly and osmiophilic deposits. This variant is caused by muta- hematologic (anemia, thrombocytopenia, leukopenia) tions in CLN1, the gene encoding the enzyme palmi- problems. Extensive skeletal disease is typical. Type 2, the toyl protein thioesterase 1 (PPT1), which removes fatty rarest and most severe form, is found in infants and is acids from a variety of fatty acylated proteins. PPT1 characterized by hepatosplenomegaly, progressive severe deficiency leads to caspases 9 activation154 and impairs CNS deterioration, and death by age 5 years.144. Type 3 synaptic vesicle recycling of nerve terminals.155

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Late-Infantile (LINCL, Jansky-Bielschowsky Disease) JNCL is usually caused by mutations in CLN3, a gene Classic LINCL begins between 2 and 4 years of age encoding a lysosomal transmembrane protein that in with epilepsy and myoclonus as initial symptoms neurons also localizes to synapses. The search for the and the later development of progressive cognitive unifying mechanism of CLN3/battenin is ongoing.160 regression, ataxia, pyramidal and extrapyramidal signs, Diagnosis and retinopathy. Lysosomal accumulations have curvilinear profiles. Classic LINCL is caused by mutations Diagnosis of NCLs is based on clinical presentation, in the CLN2 gene leading to tripetidyl peptidase 1 ophthalmologic findings, electroretinography, MRI, (TPP1) deficiency; TPP1 cleaves tripeptides from the evidence of storage (Electron microscopy of leukocytes, amino termini of partially unfolded proteins. skin, or conjunctival biopsy), measurement of PPT1 and TPP1 activities, and molecular genetic studies. Juvenile ( JNCL, Batten Spielmeyer-Vogt-Sjögren disease) Mutational analysis of CLN1 and CLN2 adds little to JNCL usually starts between 4 and 7 years of age, with the diagnosis, if a prior enzyme deficiency has been estab- rapidly progressing visual failure due to pigmentary lished. Prenatal testing using a combination of enzyme retinal degeneration. Speech disturbances, a slow assay and mutation testing is reliable in families where 161 decline in cognitive function, epilepsy, behavioral the biochemical and genetic diagnosis is established. problems, and parkinsonism appear over the next sev- There is no effective treatment for the NCL disorders. eral years. The most typical extrapyramidal symptoms include impaired balance, rigidity, hypokinesis, stooped 156,157 White Matter (Dysmyelinating) posture, and shuffling gait. Fingerprint profiles Disorders are observed in biopsy material and in lymphocytes. SPECT and PET studies in JNCL have demonstrated Dysmyelinating disorders are associated with deficien- a significant reduction of striatal dopamine transporter cies of lysosomal enzymes: Krabbe disease has deficient density, more prominent in the putamen than caudate, galactocerebroside beta-galactosidase and metachro- and reduced striatal D1 but not D2 receptors.157,158 matic leukodystrophy (MLD), deficient arylsulfatase A. MRIs in NCLs show progressive diffuse atrophy.159 These disorders occur because both central and

TABLE 15-1 Classification of Human Neuronal Ceroid-Lipofuscinoses Gene Chromosome Gene Product Product Type Stored Protein Onset CLN1 1p32 PPT1 (palmitoyl Soluble enzyme Sphingolipid Infantile, late infantile, protein activator juvenile, and adult thioesterase 1) proteins

CLN2 11p15 TPP1 (tripeptidyl Soluble enzyme Subunit c of Late infantile, juvenile, peptidase 1) mitochondrial and protracted ATP synthase (SCMAS)

CLN3 16p12 CLN3/battenin Lysosomal SCMAS Juvenile, adult transmembrane protein

CLN4 — Unknown Unknown SCMAS Adult CLN5 13p22 CLN5 Lysosomal SCMAS Late infantile, juvenile, glycoprotein and protracted (may have soluble form)

CLN6 15q21-23 CLN6 Transmembrane SCMAS Late infantile protein (ER) CLN7 — MFSD8 Membrane SCMAS Late infantile (variant) channel protein

CLN8 — CLN8 Transmembrane SCMAS Late infantile (variant) protein (ER) CLN9 — CLN9 Unknown SCMAS Juvenile

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peripheral myelins contain cerebrosides and sulfatides, finding.166 Several hypotheses have been proposed for substances that require specific enzymes for degrada- the pathophysiology in classic homocystinuria includ- tion. Krabbe disease and MLD typically manifest in ing dysfunctions of S-adenosylmethionine, serine and infancy with symptoms and signs of progressive motor glutathione metabolism. difficulties, spasticity, peripheral neuropathy, and optic Homocystinuria can also be due to remethylation atrophy. Extrapyramidal symptoms in these disorders defects, such as cobalamin C disease,167 methionine are rare, although a dystonic phenotype has been synthase deficiency (CblG), or methylene tetrahydrofo- reported in an individual with juvenile MLD.162 late reductase deficiency. In these disorders, in contrast to deficiencies of cystathionine β-synthase, plasma methio- Amino Acid Disorders nine concentrations are low, and there is neither skeletal involvement nor ectopia lentis. Patients have a wide range Homocystinuria of neurologic problems, including psychomotor delay, In the most common form of homocystinuria, the cognitive impairment, seizures, and microcephaly. A defi- metabolic defect involves the enzyme cystathionine ciency of choline-containing compounds has been identi- β-synthase, which catalyzes the formation of cysta- fied in the brain, possibly due to depletion of labile methyl thionine from homocysteine and serine (Fig. 15-8). groups produced by the transmethylation pathway.168 The primary pathologic alterations are intimal thick- ening and fibrosis in vessels of all calibers, which Hartnup Disease lead to arterial and venous thromboses occurring Hartnup disease is an inherited autosomal recessive in multiple organs, for example, skeletal, ophthal- defect in amino acid transport due to mutations in the mologic, and nervous systems. CNS dysfunction SLC6A19 gene.169 This gene encodes a neutral amino acid includes intellectual retardation, motor delays, transporter (B(0)AT1) that mediates neutral aminoacid and stroke syndromes. Extrapyramidal abnormali- transport from the luminal compartment into the cells. ties, primarily dystonia, have occurred in both chil- Affected individuals have a selective monoamino-mono- dren and adolescents with homocystinuria.163–165 carboxylic (neutral) aminoaciduria (alanine, asparagine, Seizures and psychiatric disturbances can also be citrulline, glutamine, histidine, isoleucine, leucine, phe- present. MRI studies have shown cerebral infarc- nylalanine, serine, threonine, tyrosine, tryptophan, and tion, atrophy, venous occlusions, and bilateral low- valine), but with normal or low levels in plasma. Skin intensity lesions in the basal ganglia on T2-weighted changes, resembling findings in pellagra (light-sensitive imaging. Leukoencephalopathy is an uncommon dermatitis due to nicotinamide deficiency), are usually

Methionine Serine Glycine

Dimethylglycine THF SAM B12 N5-10 methyline THF

SAH Betaine N5-10 methyl THF

Homocysteine N5-10 methylene THF reductase

Serine Cystathionine b-synthase

Cystathionine

a-Ketobutyrate g-Cystathionase

Cysteine

Sulfite oxidase

SO4

Figure 15-8. Metabolism of homocysteine. [email protected] 66485438-66485457 178 section 5 selected secondary movement disorders the first clinical signs, occurring in the late infantile or 12q24.1. PKU is classified into the classic and mild juvenile period. Neurologic and psychiatric issues begin forms. Untreated infants have growth failure, seizures, about 2 to 10 years after the appearance of dermato- developmental delay, and microcephaly as the result of logic changes. Intermittent recurrent ataxia lasting for the accumulation of toxic by-products of phenylalanine, days to weeks is the most common neurologic symp- a deficiency of tyrosine and its products including mel- tom with exacerbations of variable intensity. Other, less anin, l-thyroxine, and catecholamines.175 and possibly common symptoms include spasticity, intention tremor, stimulation of peroxisome proliferator-activated receptor dysarthria, headaches, and psychiatric symptoms rang- (PPAR)-gamma receptors.176 In older patients, pyramidal ing from emotional lability to acute psychosis. One case signs (increased tone, hyperreflexia, and extensor plan- with intermittent dystonia and two cases with dystonic tar responses) and an irregular, rapid, small-amplitude features have been reported.170,171 Nicotinamide therapy tremor of the hands are common. Bizarre twisting move- improves the dermatitis and neurologic problems, but ments, repetitious movements of the fingers, stereotypies, spontaneous improvement also occurs with maturation. and overt parkinsonian features may also be present.177,178 A meta-analysis of neuropsychological symptoms in Maple Syrup Urine Disease treated adolescents and adults showed significant reduc- This disease is an autosomal recessive disorder caused by tions in full-scale IQ, processing speed, reduced atten- defective activity of the branched-chain alpha-ketoacid tion, and control and inhibitory activities.179 White dehydrogenase enzyme complex. This alpha-ketoacid matter abnormalities have been identified in the brains dehydrogenase complex consists of three catalytic com- of adults with PKU.180 Reduced cerebral Fluoro-DOPA ponents (a thiamine pyrophosphate dependent carboxy- uptake has been identified in adult patients.181 In general, lase [E1], a transacylase [E2], and a dehydrogenase [E3]) the level of disability remains stable after early childhood, and two regulatory enzymes (a kinase and a phosphatase). but there are cases of neurologic deterioration in adult- This mitochondrial complex catalyzes the oxidative hood.182 It has been suggested that women with PKU start decarboxylation of branched chain ketoacids derived a phenylalanine-restricted diet before conception.183 from the transamination of the branched chain amino As discussed above on the section on pediatric neu- 172 acids, leucine, isoleucine, and valine. (see Fig. 15-11). rotransmitter disorders, hyperphenylalaninemia can have The defect results in the marked increase of these three other etiologies. Treatment the mainstay of treatment is essential amino acids in serum, urine, and CSF. The com- based on early detection with routine newborn screening mon neonatal form manifests with feeding difficulties, and prevention of neurologic consequences by early ini- decreased responsiveness, metabolic acidosis, seizures, an tiation of a phenylalanine-free diet. Recommendations abnormal odor of the urine, progressive coma, and cere- for treatment with BH4, available as sapropterin dihy- bral edema. Fluctuating ophthalmoplegia has also been drochloride, a formulation of natural BH4, and recom- 173 observed. Early recognition and treatment can result mendations for evaluating treatment responses in PKU in a normal neurologic outcome. Milder varients with have been published.184 later onset and greater levels of the branched-chain alpha- ketoacid dehydrogenase have been reported. In the “inter- Organic Acid Disorders mediate” form, symptoms begin in infancy or childhood; Organic acids are produced from the catabolism of amino there is a mild metabolic acidosis, anemia, and symptoms acids and are intermediates in metabolic pathways. They 174 of motor delay and mental retardation. contain one or more carboxylic acid or acid phenolic Phenylketonuria groups without basic amino groups. Organic acidurias are generally considered inborn errors of protein metabolism, Phenylketonuria (PKU) is an autosomal recessive dis- a defect in metabolism resulting in an elevation of the order caused by a deficiency of hepatic phenylalanine organic acid and an intoxication-like clinical presentation. hydroxylase, the enzyme required to metabolize pheny- There are multiple organic acidurias, many presenting lalanine to tyrosine (Fig. 15-9). Most cases are associated in the neonatal period with metabolic acidosis, but later- with mutations in the PAH gene located on chromosome onset forms also occur. Neurologic manifestations are extremely common in organic acid disorders and in some Phenylalanine hydroxylase can represent the presenting or primary feature. Phenylalanine Tyrosine Disorders of Lysine Catabolism BH4 Glutaric Aciduria Type 1 (Autosomal Recessive) Figure 15-9. Phenylalanine metabolism. Abbreviation: Glutaric aciduria type 1 is caused by a defect in the BH4, tetrahydrobiopterin. gene that codes for glutaryl-CoA dehydrogenase

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Lysine Hydroxylysine Glutaryl-CoA dehydrogenase Lysine CoA 2-Aminoadipic acid Glutaryl-CoA Crotonyl-CoA

Tryptophan

3-Hydroxy- Glutaric Acetoacetyl-CoA glutaric acid acid

D- and L-2-hydroxyglutamate dehydrogenase

Figure 15-10. Catabolism of lysine, hydroxylysine, and tryptophan.

(GCDH), which catalyzes the formation of crot- Neuroimaging studies show characteristic atrophy onyl-CoA from glutaryl-CoA (Fig. 15-10).185,186 of the frontotemporal cortex, enlarged subdural fluid Biochemically, deficiency of glutaryl-CoA dehydro- spaces, and delayed myelination. Additional findings genase activity results in the accumulation and excre- may include “bat-winged” dilation of the sylvian fissures, tion of glutaric acid and 3-hydroxyglutaric acid, bilateral symmetric hypodensities in the lenticular nuclei, detectable in the urine, blood, and CSF. The diag- caudate degeneration, bilateral temporal arachnoid cysts, nosis is confirmed by documentation of deficient and mild leukodystrophy that spares U-fibers. glutaryl-CoA dehydrogenase activity in cultured skin More than 100 mutations in the GCDH gene have fibroblasts. Glutarylcarnitine can be identified on been identified and no molecular basis differentiates newborn screen by tandem mass spectrometry, if car- the groups. Clinical variability does not appear to nitine is not significantly reduced. The disorder has a correlate with the extent of residual enzyme activity. predilection for the basal ganglia. The pathologic mechanism in glutaric aciduria is Clinically, there are several types of presentation, and unclear. Hypotheses include 3-hydroxyglutaric acid phenotypic heterogeneity occurs within families.187,188 stimulation of glutamatergic NMDA receptors causing In the majority, macrocephalus is present at or shortly excitatory neurotoxicity and an inhibitory effect of glu- after birth, with rapid changes in head circumference taric acid, glutaconic acid, and 3-hydroxyglutaric acid reaching a peak in the first 6 months. Most infants are on the inhibitory neurotransmitter GABA. hypotonic, irritable, jittery, and have feeding difficul- Treatment ties, although cognitive development may be appropriate. Others have global developmental delay and A low-protein diet (restriction of the glutarigenic progressive hyperkinetic movement problems. Typically amino acids [lysine, tryptophan, and hydroxylysine]) around 6 to 18 months of age, there is an acute dete- with riboflavin and l-carnitine has been utilized, but rioration of motor function in association with an appears to be of limited value, especially in patients infection, a minor head injury, or following an immuni- with striatal damage. Dystonia is treated empirically zation. Although the child appears to be alert, hypoto- with anticholinergics such as trihexyphenidyl,and nia, dystonia, choreoathetosis, and generalized seizures other agents. Pallidotomy has been tried in cases with may be present. Extrapyramidal movements are often severe striatal injury, with limited benefit. residual symptoms. Severe episodes of dystonia (“dys- Branched-Chain Organic Acidurias tonic storm” or “status dystonicus”) can be accompanied by hyperthermia and rhabdomyolysis. Other variants of Methylmalonic Acidemia (Autosomal Recessive) this disorder include normal development until about In genetic forms of methylmalonic acidemia (MMA), 2 years of age, a form that mimics the presentation of the conversion of methylmalonyl-CoA to succinyl- extrapyramidal cerebral palsy, and even single cases over CoA is impaired secondary to a genetic abnormality age 6 years without neurologic symptoms.189 Glutaric in the mitochondrial apoenzyme, methylmalonyl-CoA aciduria type 1 has manifested in adulthood with leuko- mutase, or its adenosylcobalamin cofactor (Fig. 15-11). encephalopathy.190 Infants are also prone to suffer acute Infants with absence of the apoenzyme (classic form) subdural hemorrhages after mild head injury.191 become symptomatic in the first week of life with

[email protected] 66485438-66485457 180 section 5 selected secondary movement disorders hypotonia, lethargy, respiratory distress, vomiting, Propionic Acidemia (Autosomal Recessive) metabolic acidosis, and ketosis. Laboratory tests show Propionic acidemia is caused by a deficiency of propionyl- metabolic acidosis and ketosis with many having hyper- CoA carboxylase, a mitochondrial biotin-dependent ammonemia and hypoglycemia. Diagnosis is made by enzyme, resulting in elevation of serum and urine analysis of urine organic acids, which show elevated propionic acid (see Fig. 15-11). There are several pre- methylmalonic acid; propionic acid may also be increased sentations including severe neonatal, chronic intermit- because of a secondary inhibition of propionyl-CoA tent, and gradually progressive.195 The presentation carboxylase. Enzyme assays can be performed on leu- of this disorder in early infancy mimics that of meth- kocytes and all cases should be tested for responsiveness ylmalonic aciduria—that is, recurrent episodes of to vitamin B12 (cobalamin). Survivors typically have ketoacidosis, hyperammonemia, hyperglycinemia, and severe residual neurologic impairments, including dys- hypoglycemia. Hypodense lesions in the cerebral white tonia.192 MRI studies show alterations in myelination matter and lenticular nuclei occur in both disorders. A and changes in the basal ganglia.193 Pathologically, there variant of this disorder has been reported with hypo- is necrosis of the putamen or globus pallidus. Less fre- tonia, spastic quadriparesis, and choreoathetosis, but quently, especially in those with cobalamin cofactor defi- lacking the typical metabolic crises.196 ciencies, onset is delayed to the late infantile or juvenile Diagnosis period. In general, the vitamin B12-responsive group has a milder course and better outcome. The disease course High levels of propionic acid and its derivatives may be characterized by recurrent episodes of ketoacido- (3-hydroxypropionate, propionylglycine, and tiglic acid) sis, hyperammonemia, leukopenia, thrombocytopenia, are excreted in the urine. Since propionate accumulates in and anemia, which can result in multiple organ failure propionic aciduria as well as MMA, the diagnosis should and even death.194 The enzymatic defect is treated with be confirmed by documentation of reduced activity of protein restriction, cobalamin supplementation, and propionyl-CoA carboxylase in fibroblasts or leukocytes. metronidazole to suppress microbial propionate pro- Treatment duction. Therapy directed toward extrapyramidal find- Long-term treatment includes a low-protein diet, ings generally has a limited response. supplementation with biotin and l-carnitine, and

Leucine Isoleucine Valine Branched-chain a-keto acid dehydrogenase

Isovaleryl-CoA 2-Methylbutyryl-CoA Isobutyryl-CoA

3-Methylglutaconyl-CoA 2-Methyl-3- hydroxybutyryl CoA 3-Methylglutaryl-CoA hydratase MHBD

3-OH-3- 2-Methyl-acetoacetyl- Methylmalonic Methyglutaryl-CoA CoA semialdehyde b-KT

Acetyl-CoA Propionyl-CoA

Propionyl-CoA carboxylase Methylmalonyl-CoA

Methylmalonyl-CoA B12 mutase Succinyl-CoA

Figure 15-11. Catabolism of branched-chain amino acids. Abbreviations: MHBD, 2-methyl-3-hydroxylbutyl-CoA- dehydrogenase; β-KT, beta-ketothiolase.

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the use of metronidazole to reduce the amount of reported with developmental delay and radiographic propionate in tissues. Orthotopic liver transplanta- abnormalities involving the putamen preceding the first tion has been used in patients with propionic aca- episode of ketoacidosis.205 A single case has occurred demia who fail maximum medical therapy.197 with generalized and intractable dystonia associated with a linear area of increased signal intensity on T2-weighted 3-Methylglutaconic Aciduria images in the globus pallidus bilaterally.206 3-Methylglutaconic acidemia is actually a group of metabolic disorders characterized by the increased Other Organic Acidurias urinary excretion of 3-methylglutaconic acid and Two different clinical entities, identified respectively by 198 3-methylglutaric acid. In 3-methylglutaconic aci- an increase in either the l or d isoform of hydroxyglu- demia type 1, the conversion of 3-methylglutaryl- taric acidemia, have been identified. The d-form pro- CoA to 3-OH-methylglutaryl-CoA is impaired duces a severe neonatal neurologic syndrome, whereas secondary to a defect of 3-methylglutaryl-CoA hydratase the l-form has a later onset and variable presentation. (see Fig. 15-11). Defective activity results in a wide A combined l and d form with neonatal onset repre- spectrum of clinical abnormalities ranging from mild sents an additional variant.207 speech delay to severe encephalopathy with basal ganglia involvement.199 Several other 3-methylglutaconic l-2-Hydroxyglutaric Aciduria disorders have been described, including type III l-2-hydroxyglutaric aciduria is a rare autosomal recessive (Costoff syndrome), mapped to chromosomal locus neurometabolic disorder of childhood (see Fig. 15-10). 19q13.2, with symptoms of bilateral optic atrophy, cho- Mutations have been identified in a gene called duranin, 200,201 rea, ataxia, spasticity, and cognitive effects. A mild localized on chromosome 14q22.1, encoding a mito- nonsyndromic form has been described associated with chondrial FAD-dependent l-2-hydroxyglutarate dehy- 202 psychomotor retardation, optic atrophy, and seizures. drogenase.208 Most patients appear normal until early Methylhydroxybutyryl-CoA Dehydrogenase childhood, when symptoms of cognitive deterioration, This is one of several inborn errors in the pathway of progressive truncal or gait ataxia, and mild extrapyramidal isoleucine degradation (see Fig. 15-11). 203 Deficiency (tremor or dystonic posturing) and pyramidal signs of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase become apparent. Seizures are often a presenting sign and 209–212 A child (MHBD) has a predominantly neurologic presentation macroencephaly is present in most cases. with migraine and no other manifestations except seizures ranging from a static encephalopathy to a progressive has been described.213 Neuroimaging shows a subcortical global neurodegenerative disorder. Normal develop- leukoencephalopathy, progressive loss of myelinated ment in the early months may be followed by regres- arcuate fibers, bilateral increased densities in the basal gan- sion and loss of previously acquired skills. Neurologic glia (globus pallidus more than caudate or putamen) and features have included ataxia, dystonia, choreoatheto- dentate nucleus, and progressive cerebellar atrophy.214–216 sis, spasticity, optic atrophy, and a retinopathy. MRIs The severity of symptoms may vary within families and have been variable, ranging from normal to cortical diagnosis may be delayed until adulthood because of mild atrophy with signal changes in the basal ganglia.204 clinical symptoms. Diagnosis is established by the iden- Methylacetoacetyl-CoA or Acetoacetyl-CoA Thiolase tification of elevated levels of l-2-hydroxyglutaric acid in (β-Ketothiolase) Deficiency urine, CSF, or plasma. It has been postulated that excess β-Ketothiolase deficiency, a second disorder of isoleucine l-2-hydroxyglutaric acid is toxic to neurons.211 Treatment and ketone body metabolism, typically manifests with includes a protein-restricted diet, riboflavin, carnitine an episode of ketoacidosis (see Fig. 15-11).203 2-Methyl- supplements, and symptomatic therapy. 3-hydroxybutyric acid is the characteristic metabolite in the urine, but additional metabolic complications may d-2-Hydroxyglutaric Acidemia include hyperammonemia and hyperglycinemia. The Patients with this variant exhibit a variable phenotype gene for the hepatic mitochondrial acetoacetyl-CoA thi- ranging from severely affected to having no or mini- olase has been mapped to 11q22.3-q23.1. The disorder mal symptoms. Severe cases have a neonatal onset with usually manifests in childhood with recurrent episodes intractable epilepsy, hypotonia, persistent involuntary of ketoacidosis, vomiting, and dehydration. Episodes movements including dystonia and choreoathetosis, usually resolve after symptomatic treatment with glucose cortical blindness, and profound developmental and bicarbonate and most patients recover fully. Some delay.217,218 Milder cases have developmental delay and patients, especially those with prolonged crises, have had delayed speech.218,219 Neuroimaging has shown delayed long-term neurologic sequelae. Four patients have been myelination and gyration, ventriculomegaly, and caudate

[email protected] 66485438-66485457 182 section 5 selected secondary movement disorders cysts. Diagnosis is confirmed by a large excretion of d-2- prolonged survival.231 Neuroradiographic findings include hydroxyglutaric acid in the urine and accumulation in periventricular leukomalacia, subcortical leukodystrophy, plasma and CSF. The molecular defect is a missense cystic brain degeneration, and delayed myelination.232 mutation in the gene for d-2-hydroxyglutarate Treatment is primarily symptomatic, although there are dehydrogenase.220 d-2-Hydroxyglutaric acid inhibits reports suggesting benefits from the use of various cofac- cytochrome c oxidase and ATP synthase activity and is tors including thiamine and lipoic acid.233 presumed to impair energy metabolism.221 Pyruvate Dehydrogenase Complex Deficiency Glycolysis, Pyruvate Metabolism, and The pyruvate dehydrogenase complex (PDH) is the Tricarboxylic Acid Cycle Disorders essential rate-limiting step connecting glycolysis with the TCA cycle. PDH deficiency is a commonly identi- Glycolysis is a sequence of reactions that convert glu- fied cause of lactic acidosis in children with metabolic cose into pyruvate. Pyruvate is a crucial metabolite in symptoms that vary from mild to severe. Most cases cells that is metabolized by four different enzymes: pyru- are secondary to mutations encoding the E1α-subunit vate carboxylase (PC), pyruvate dehydrogenase complex on chromosome Xp22. Neurol`ogic manifestations (PDH), lactate dehydrogenase (LDH), and alanine ami- include hypotonia, weakness, ataxia, spasticity, cerebel- notransferase (ALT). The tricarboxylic acid cycle (TCA, lar degeneration, seizures, and mental retardation.234 Krebs cycle) occurs in the matrix of the mitochondrion Ataxia can be intermittent with its median age at onset and converts acetyl-CoA to carbon dioxide and energy being about 18 months. Other motor symptoms can (GTP and reduced cofactors of nicotinamide adenine include recurrent acute dystonia,235 complex extrapyra- dinucleotide [NADH] and flavin adenine dinucleotide midal movements in adults,236 and episodic peripheral [FADH2]). These cofactors, in turn, feed into the electron weakness mimicking Guillain-Barré syndrome.237,238 transport chain to generate ATP (see mitochondria). Dysmorphisms, microcephaly, and agenesis of the cor- Triosephosphate Isomerase Deficiency pus callosum may be present.239 Laboratory studies show Triosephosphate isomerase (TPI) deficiency is an auto- elevated lactate and pyruvate levels in plasma and urine, somal recessive disorder of glycolysis. TPI catalyzes the although cases with normal blood, and even CSF, values 238,240 Definitive diagnosis requires interconversion of glyceraldehyde-3-phosphate and have been reported. documentation of diminished PDH activity in muscle, dihydroxyacetone phosphate, and its deficiency results white blood cells, cultured fibroblasts, and other tissue. in the accumulation of dihydroxyacetone phosphate, Treatments include addressing the acidosis, a ketogenic especially in red blood cells. This rare multisystem disease is characterized by a triad of symptoms including diet, thiamine supplementation, and dichloroacetate. A nonspherocytic hemolytic anemia, recurrent infections, combined therapeutic approach using self-complementary adeno-associated virus genotype-specific vectors for and progressive neurologic dysfunction with dystonia, 241 tremor, pyramidal tract signs, and evidence of spinal gene delivery and dichloroacetate has been suggested. motor neuron involvement.222–224 A patient with a TPI 2-Ketoglutarate Dehydrogenase Deficiency deficiency, resulting from a compound heterozygote 2-Ketodehydrogenase is a multienzyme complex consist- mutation, had a biopsy-proven chronic axonal neurop- ing of three protein subunits that catalyzes the oxidative athy.225 Most patients die within the first 6 years. decarboxylation of 2-ketoglutarate to succinyl-CoA. The onset of symptoms has varied from the neonatal period Pyruvate Carboxylase Deficiency to 16 months. Clinical presentation involves severe neu- Pyruvate carboxylase (PC) is a biotin-containing mito- rologic impairment with failure to thrive, hypotonia, chondrial enzyme that catalyzes the conversion of weakness, developmental delay, seizures, extrapyramidal pyruvate to oxaloacetate, controls the first step in symptoms, ataxia, and increased tone.242,243 Patients have hepatic gluconeogenesis, and is involved in lipogenesis elevated serum lactate levels, a high lactate/pyruvate ratio, 226,227 (Fig. 15-12). PC deficiency is an autosomal reces- ketoglutaric aciduria, and ketoacidosis. A 14-month-old sive disorder with a heterogeneous clinical presentation. child with intermittently normal excretion of 2-ketoglu- The type A group is characterized by infantile onset with tarate and mild clinical findings has been reported.243 mild to moderate lactic academia, hypoglycemia, and psychomotor retardation with early death.228 Group B Fumarase (Fumarate Hydratase) Deficiency has severe neonatal lactic acidosis, hypoglycemia, hyper- Fumarase deficiency is an autosomal recessive inborn ammonemia, hypercitrullinemia, and early death. Milder error of the Krebs cycle; fumarase catalyzes the variants with longer survivals comprise group C.229,230 reversible interconversion of fumarate and malate. Mosaicism in the PC gene appears to correlate with There are two isoforms of fumarase (coded on the

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Glycolysis Glucose

Fructose-1,6-bisphosphate

TPI Glyceraldehyde-3- Dihydroxyacetone- phosphate phosphate

LDH Lactate Pyruvate Phosphoenolpyruvate Pyruvate Alanine ALT

Pyruvate dehydrogenase complex (PDH) Pyruvate carboxylase (PC) Acetyl Co-A

TCA cycle Oxaloacetate Citrate

Malate Isocitrate

Fumerate hydratase

Fumarate a-Ketoglutarate

a-ketodehydrogenase Succinyl-CoA

Figure 15-12. Glycolysis, pyruvate metabolism, TCA cycle. Abbrevations: TPI, triosephosphate isomerase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase.

same region of chromosome 1), mitochondrial and Mitochondrial Disorders cytosolic, with similar structures except for the amino- terminal residue. Variable clinical presentations have Mitochondrial diseases represent a variety of inherited dis- been reported.244–246 Early-onset cases have a progres- orders of energy metabolism with a wide range of symp- sive encephalopathy with failure to thrive, microceph- toms and presentations. In a 20-year review,252 patients aly, hypotonia, seizures, and fumaric aciduria.247,248 fell into seven phenotypic categories: neonatal-onset lac- Some patients have craniofacial dysmorphism includ- tic acidosis (fulminant acidosis), Leigh syndrome, nonspe- ing microcephaly, frontal bossing, hypertelorism, and cific encephalopathy, mitochondrial (encephalo)myopathy a depressed nasal bridge.248 Other manifestations have (MERRF, MELAS, MNGIE, Kearne-Sayne), intermittent included muscular atrophy, pyramidal syndromes, dys- neurologic (ataxia or weakness), visceral (liver, cardiac), and tonia, and paralysis of upgaze.249 Cerebral malforma- Leber hereditary optic neuropathy. Disorders involve mito- tions have included agenesis of the corpus callosum chondrial abnormalities involving pyruvate metabolism and ventriculomegaly with polymicrogyria, hypomy- (discussed previously) and respiratory chain defects. elination, or periventricular cysts.250 Laboratory studies Components of oxidative phosphorylation (OXPHOS) show elevated plasma pyruvate and lactate and exces- include five protein-lipid enzyme complexes, desig- sive amounts of fumaric acid in the urine. There is no nated complex I, complex II, complex III, complex IV effective specific treatment. Heterozygote mutations of (cytochrome c oxidase), and complex V (ATP synthase), the fumarate hydratase gene are associated with renal which are located in the mitochondrial inner membrane cell cancer and hereditary leiomyomatosis.251 (Fig. 15-13). These enzymes contain flavins, coenzyme [email protected] 66485438-66485457 184 section 5 selected secondary movement disorders

H+ TCA cycle ADP ATP Fumarate Succinate

H+ H+ H+

O2 H2O Matrix ND2 Inner ND1 ND3 Cyt b COX I mitochondrial ND6 ND4 A8 A6 e– COX II membrane ND5 ND4L – – e e e– e– COX III

Intermembrane CoQ space Cyt e

Subunits Complex I Complex II Complex III Complex IV Complex V mtDNA-encoded: 7 0 1 3 2 nDNA-encoded: ~35 4 10 10 ~14

Figure 15-13. Respiratory chain. Abbreviations: ND1, NADH dehydrogenase 1; Cyt b, cytochrome b, COX 1, cytochrome C oxidase.

Q (ubiquinone), iron-sulfur clusters, hemes, and protein- 10 the pyruvate dehydrogenase complex (E1α subunit gene), bound copper. Complexes I and II collect electrons from pyruvate carboxylase, and deficiencies in respiratory the catabolism of fats, proteins, and carbohydrates and complexes I (nDNA-encoded NADH-Ubiquinone oxire- transfer them sequentially to coenzyme Q , complex III, 10 ductase Fe-S protein [NDUFS] gene subunit), II (nDNA and complex IV. Complexes I, III, and IV utilize the energy encoded flavoprotein subunit), IV (assembly protein), and in electron transfer to pump protons across the inner mito- V (mtDNA-encoded A6 subunit (see Fig. 15-13).254–256 chondrial membrane, producing a proton gradient that The most common defect, affecting about one quarter of is used by complex V to condense ADP and inorganic patients, involves cytochrome c oxidase or COX deficiency phosphate into ATP. Complexes I through V are unique (complex IV). In some cases the defect in COX-deficient enzymes in the body in that they are derived from genes Leigh disease has been mapped to chromosomal locus from both the nuclear DNA and from the mtDNA.253 9q34 with the putative candidate gene (SURF-1) shown Elevations of lactate, pyruvate, lactate/pyruvate ratio to encode an assembly or maintenance factor.257 All of (greater than 20), alanine, tricarboxylic acid cycle inter- the aforementioned defects impair brain metabolism, the mediates, dicarboxylic acids, and/or a generalized amino brain and brainstem being especially vulnerable. aciduria can be important diagnostic clues to the pres- Leigh syndrome usually manifests in infancy or early ence of an OXPHOS disease. Other metabolites that childhood with psychomotor delay and hypotonia. As may also be increased include tiglylglycine, ethylmalonic this multisystem disorder progresses, feeding and swal- acid, 3-methylglutaconic acid, 2-ethylhydracrylic acid, lowing defects, nystagmus, ophthalmoplegia, optic atro- 2-methylsuccinate, butyrylglycine, isovaleryl glycine, and phy, ataxia, pyramidal signs, and respiratory problems ammonia. Analysis of lactate, pyruvate, and amino acids become apparent.258,259 Movement disorders, such as in venous blood can be complicated by technical factors, dystonia, choreoathetosis, and myoclonus, have been such as duration of tourniquet application, recent sei- prominent in some cases and, at times, may be the ini- zures, vigorous crying and struggling that occurs during tial sign.260–262 Nineteen of 34 cases with Leigh syndrome venipuncture, and delays in sample processing. Further, had multifocal or generalized dystonia at presentation.261 isolated normal plasma lactate concentrations have been Leigh-like syndrome is the term applied to individuals with identified in subjects with chronic lactic acidemia. CSF an atypical neurologic or radiographic phenotype that is analysis (cell count, protein, glucose, lactate, pyruvate, suggestive of, but different from, Leigh syndrome.263-264 and amino acids) is less variable and very important in Non-neurologic features in Leigh syndrome can include patients with evidence of CNS involvement. short stature, dysmorphism, endocrine, gastrointestinal, Leigh Syndrome and cardiac problems.259 Pathologic findings include sym- Leigh syndrome (subacute necrotizing encephalomyelopa- metric necrotic lesions (spongy degeneration) with demy- thy) is a complex of progressive neurodegenerative disorders elination, vascular proliferation, and gliosis affecting the caused by several defects of energy metabolism, including basal ganglia, diencephalon, cerebellum, and brainstem. [email protected] 66485438-66485457 Chapter 15 Inherited Metabolic Disorders 185

Diagnosis is based on clinical features, the pres- the sudden onset of visual loss in a young adult, although ence of elevated arterial or CSF lactate levels, and cases as young as age 5 years have been reported. The T2-weighted MR images showing symmetric areas of spectrum of clinical findings is broad and includes indi- increased signal in the putamen, or occasionally the viduals with dystonia and MRI lesions similar to those caudate, globus pallidus, substantia nigra, thalamus, seen in Leigh syndrome.278,279 Gene therapy has been and brainstem.259,265 Additional helpful diagnostic test- used successfully in models to rescue the mitochondrial ing includes a muscle biopsy for the presence of ragged deficiency causing Leber hereditary optic neuropathy.280 red fibers and biochemical analysis, mitochondrial DNA analysis, magnetic resonance spectroscopy of Mohr-Tranebjaerg Syndrome the brain, and phosphorus magnetic resonance spec- Mohr-Tranebjaerg syndrome (MTS) is a mitochondrial troscopy of muscle. There is no specific therapy for disorder, but not one that is associated with a defect of mitochondrial diseases. Various therapies, including energy generation. Gene mutations are linked to a locus vitamins, coenzyme Q, and dichloroacetate, improve at Xq21.3-22 and assigned to the deafness-dystonia pep- metabolic indices, but have not been shown to signifi- tide (DDP1) gene.281,282 TIMM8a, a protein product of cantly improve clinical outcome.266 the DDP1 gene, is part of a multiprotein complex located in the intermembrane space of the mitochondrial inner Other Mitochondrial Syndromes membrane. Truncated peptides lead to impairment of The classic syndrome of mitochondrial encephalomyopathy, the import of nuclear-encoded proteins into the inner lactic acidosis, and stroke-like episodes (MELAS) is associ- membrane of carrier protein into the mitochondria and ated with a mitochondrial gene MTTL1 A3243G muta- insertion into the mitochondrial inner membrane.283 tion. Additional symptoms in MELAS include ataxia, Clinically, MTS is a rare neurodegenerative progressive external ophthalmoplegia, and seizures.267 The disorder. Symptoms are characterized by the childhood 3243 mutation is not specific for this disorder, since it has onset of sensorineural deafness and progressive been reported with a wide range of clinical phenotypes, dystonia beginning in adolescence.284–286 The dystonia including sensorineural hearing loss, diabetes, myopathy, ranges from being task specific to generalized and from and cardiomyop‑athy.268,269 Myoclonic epilepsy with ragged mild to severe. Other symptoms may include visual red fibers (MERRF) is associated with an mtDNA muta- loss, varying degrees of cognitive impairment, behav- tion at 8344. Clinical features include cortical myoclonus ioral problems, and spasticity. PET and MRI studies with or without epilepsy, myopathy, and encephalopathy. show hypometabolic areas in the striatum and cortex Ataxia is commonly present and is sometimes associated and atrophy of the occipital lobes.285 Dystonia has been with a photomyoclonic response. Multifocal dystonia was reported in female carriers of MTS.287 the presenting and salient feature in a patient with myopathy, ragged red fibers, progressive ophthalmoplegia, Disorders of Purine Metabolism and a sensorineural hearing loss but with a 3243 mtDNA mutation.270 Chorea, parkinsonism, and dystonia have Lesch-Nyhan Disease also been identified in other mitochondrial disorders. For Lesch-Nyhan disease (LND) is an X-linked reces- example, a patient with dementia, ataxia, and chorea had sive disorder associated with heterogeneous mutations a mutation in tRNA at position 5549.271 Mitochondrial (substitutions, deletions, early stops, insertions) in neurogastrointestinal encephalopathy (MNGIE) is a rare the gene for the enzyme hypoxanthine-guanine phos- autosomal recessive disorder caused by mutations in the phoribosyltransferase (HPRT) located on Xq26-27.288 thymidine phosphorylase (ECGF1) gene. Patients usu- A given mutation of the HRPT gene may lead to different ally have gastrointestinal problems (diarrhea, vomiting, phenotypes.289 The biochemical defect is a deficiency pseudo-obstruction), cachexia, ptosis, ophthalmoparesis, of HPRT, which converts the free purine bases hypox- myop‑athy, and sensorimotor neuropathy. MRI shows a anthine and guanine into their respective nucleotides leukoencephalopathy.272–274 (Fig. 15-14). In addition to this recycling defect, there is also a secondary increased activity in the de novo purine Leber Hereditary Optic Neuropathy Plus Dystonia synthesis pathway. Purines are important intermediaries Leber hereditary optic neuropathy (LHON) is an in energy-dependent reactions and cofactor-requiring X-linked inherited disorder associated with mitochon- reactions, and intercellular-intracellular signaling. drial DNA point mutations.275,276 In contrast, a patient In the absence of HPRT, hypoxanthine and guanine with LHON plus dystonia and a severe complex I respi- cannot be recycled and are degraded and excreted as uric ratory defect, but lacking a pathologic mtDNA muta- acid. HPRT activity in classic cases is less than 1% of tion, has suggested a mitochondrial abnormality of normal, but patients with partial syndromes with higher nuclear origin.277 The disorder is dominated clinically by levels of residual enzyme have been described.290 [email protected] 66485438-66485457 186 section 5 selected secondary movement disorders

Ribose-5-P PRPP PRPS1

SAICAR SAICA-ribose

ADSL

AICAR S-AMP S-Ado ADSL Inosine Guanosine monophosphate monophosphate AMP (IMP)

Hypoxanthine-guanine Guanosine phosphoribosyltransferase Inosine Adenosine (HPRT)

Guanine Phosphoribosyl Hypoxanthine Adenine + PRPP pyrophosphate

Xanthine

Uric acid

Figure 15-14. Disorders of purine metabolism. Abbreviations: PRPP, phosphoribosyl pyrophosphate; PRPS1, phosphoribosyl pyrophosphate synthetase 1; SAICAR, succinylaminoimidazolecarboxamide ribotide; AICAR, aminoimidazolecarboxamide ribotide; S-AMP, adenylosuccinate; S-Ado, succinyladenosine; AMP, adenosine monophosphate; ADSL, adenylosuccinate lyase.

Clinically, the three major features of LND are saccades preceded by head movement or eye blink) in hyperuricemia, self-injurious behaviors (SIBs), and patients with severe enzyme deficiency.295 neurological problems. Although the full syndrome Pathophysiologically, an abnormal dopaminergic is most typical, individual components may occur in system with reduced dopamine terminals has been isolation. Overproduction of uric acid leads to hyper proposed. CSF neurotransmitter studies have shown uricemia, and if not treated, to renal stones and gouty reduced levels of DA and HVA,296 as have direct mea- arthritis. SIBs (e.g., self-biting, head banging, eye surements of neurotransmitters in postmortem brain poking, arm flinging) are a hallmark, but nondiagnos- limbic and striatal regions.297 Dopamine D2-receptor tic, feature of this disorder. SIBs typically appear at immunoreactivity is increased in histochemical post- about age 2 to 3 years, although in some patients may mortem studies in putamen.298 PET scans have not emerge until the late teenage years. Neurologic reported reduced fluorodopa uptake and a reduction of abnormalities have been variably described in the [11C]WIN 35,428 binding to dopamine transporters. literature. In three older series, the cardinal features Despite the identified reductions of dopaminergic were described as mental retardation, choreoatheto- activity, patients with LND are hyperkinetic rather sis, and spasticity or dystonia with hypotonia.291–293 than parkinsonian. In a study of 17 patients (age range 8 to 38 years) Diagnosis with Lesch-Nyhan disease, performed with particular Diagnosis is made based on clinical presentation plus attention to motor features, dysfunction was best elevated urine uric acid. Since hyperuricemia may not described as severe dystonia superimposed on hypo- be present in all patients, measures of 24-hour urinary tonia.294 Dystonia, present in all subjects, was typi- uric acid excretion and genetic testing may be required cally absent at rest and increased with excitement for confirmation. or attempted purposeful movements. Choreiform movements were present in about half the subjects Treatment and ballismus of the upper extremity in about one Therapy is directed to reducing hyperuricemia (generous quarter. Pyramidal signs were observed in a minority hydration and allopurinol) and to preventing self-injury of cases. Ocular motility is grossly abnormal (fixation (protective measures, behavior modification therapy, interrupted by unwanted saccades and voluntary and possibly pharmacotherapy with benzodiazepines,

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neuroleptics, gabapentin, or carbamazepine). Although located on the X chromosome (Xq22-q24), is due to a no adequate controlled trials have been performed, avail- gene mutation causing an increase in PRPS1 reaction able reports suggest that extrapyramidal signs do not velocity.308,309 Affected males present in childhood with uniformly improve with levodopa, neuroleptics, or tet- neurodevelopmental impairment, hyperuricemia, gout, rabenazine. In investigations of levodopa therapy, some and sensorineural deafness.308–311 A later-onset form has patients failed, others had unacceptable side effects, and only gout and urolithiasis. Therapies designed to reduce a child with LND and low CSF HVA improved.299 uric acid production and incease its excretion have no beneficial effect on neurodevelopmental problems or deafness. Adenylosuccinate Lyase Deficiency Adenylosuccinate lyase (ADSL) catalyzes two steps Phosphoribosylpyrophosphate Synthase Deficiency in the synthesis of purine nucleotides: the conversion Two disorders identified with PRPS1 deficiency are as fol- of succinyl aminoimidazole carboxamide ribotide lows: (1) Arts syndrome with mental retardation, early- (SAICAR) into aminoimidazole carboxamide ribotide onset hypotonia, ataxia, delayed motor development, and (AICAR) along the de novo pathway of purine synthe- optic atrophy. A predisposure for infections can lead to sis and the conversion of adenylosuccinate (s-AMP) early death.312,313 (2) Charcot-Marie-Tooth disease–5 with a into AMP (see Fig. 15-14). The ADSL gene has been triad of optic atrophy, deafness, and polyneuropathy.314,315 mapped to chromosome region 22q13.1-q13.2.300 The disorder has a variable spectrum ranging from an Disorders of Creatine Metabolism acute presentation within the first several weeks of life The creatine phosphate system is involved in the storage and rapid demise to minimally delayed cognitive and and transmission of phosphate-bound energy. Creatine is 301–304 motor development. Common features include synthesized in the liver and pancreas, stored in the mus- psychomotor retardation, autistic features, hypotonia, cle and brain, and nonenzymatically converted to creati- epilepsy, and growth retardation. Affected individuals nine. There are three creatine deficiency disorders: two are not dysmorphic. Variability in enzyme loss and autosomal recessive disorders that affect the biosynthesis a nonparallel loss of both activities of ADSL likely of creatine (guanidinoacetate methyltransferase [GAMT] explain differences in phenotype. The pathogenesis of and arginine:glycine amidinotransferase [AGAT] defi- ADSL deficiency is unclear with hypotheses includ- ciency) and an X-linked creatine transporter defect. ing an impaired synthesis of purine nucleotides to toxic effects of accumulating succinyl purines.305 Guanidinoacetate Methyltransferase Deficiency (Creatine Deficiency Syndrome) Diagnosis Guanidinoacetate methyltransferase (GAMT) converts Diagnosis is made by documenting increased concen- guanidinoacetate to creatine and deficiency of this trations of succinyl adenosine (s-Ado) and SAICAR in enzyme results in creatine depletion and accumulation CSF and/or urine. Several methodologies are used for of guanidinoacetate (Fig. 15-15). The disorder, trans- detection, including high-performance liquid chroma- mitted in an autosomal recessive fashion, is localized to tography (HPLC) with ultraviolet detection and spec- mutations on chromosome 19p13.3. GAMT deficiency tral analysis305 and the modified Bratton-Marshall test.306 manifests in infancy after an unremarkable postnatal Patients with higher s-Ado/SAICA-riboside ratios tend period. Symptoms are characterized by developmental to do better and have survival into adulthood. arrest, epilepsy that may be resistant to medications, Treatment Glycine Arginine Treatment with adenine, with the goal of replacing deficient adenine nucleotides, and allopurinol, to avoid AGAT conversion into poorly soluble 2,8-dihydroxyadenine, has not been successful.301 Oral administration of Ornithine Guanidinoacetate D-ribose has been reported to reduce seizure frequency 307 SAM Guanidinoacetate and improve behavior. methyltransferase (GMAT) Phosphoribosylpyrophosphate Synthase Superactivity SAH Phosphoribosylpyrophosphate synthetase (PRPS1) cata- Creatine lyzes the phosphoribosylation of ribose 5-phosphate to Figure 15-15 GMAT-mediated reactions. Abbreviations: 5-phosphoribosyl-1-pyrophosphate (PRPP)—a necessary AGAT, l-Arginine:glycine amidinotransferase; SAM, step for the de novo and salvage pathways of purine S-adenosylmethionine; SAH, S-adenosylhomocysteine; and pyrimidine biosynthesis. Superactivity of PRPS1, THF, tetrahydrofolate.

[email protected] 66485438-66485457 188 section 5 selected secondary movement disorders severe speech impairment, progressive dystonia, Cofactor Disorders dyskinesias, hypotonia, and autistic-like behavior, although each can occur to a varying degree.316–319 MRI Molybdenum Cofactor (Sulfite Oxidase) Deficiency T2-weighted images may show high signal in the globus A molybdenum-containing pterin molecule is a cofactor pallidus bilaterally and the EEG often has multifocal for three mammalian enzymes; sulfite oxidase (essential spikes and slow waves. Brain spectroscopy is diagnostic for detoxifying sulfites), xanthine dehydrogenase (role with diminished creatine and phosphocreatine peaks. in purine metabolism and formation of uric acid from Diagnosis xanthine and hypoxanthine), and aldehyde dehydrogenase (catalyzes conversion of aldehydes to acids). Diagnosis of GAMT deficiency is established by detec- Molybdenum cofactor deficiency is a rare neurode- tion of a creatine deficiency (absence of creatine peak) generative condition that primarily affects the CNS by in the brain by magnetic resonance spectroscopy, the altering sulfite oxidase activity. Sulfite oxidase is a mito- measurement of guanidino compounds (decreased chondrial enzyme responsible for catalyzing the oxida- creatine and increased guanidinoacetate) in CSF and tion of sulfites; the latter are produced from metabolites urine, low plasma and urine creatinine, and defective of sulfur containing amino acids and sulfates. Deficit GAMT activity in fibroblasts or liver tissue. Neurologic enzyme activity can be secondary to a defect in the manifestations are believed to reflect a combination of enzyme (autosomal recessive) or secondary to defects in cerebral energy deficiency, due to a depletion of brain the production of its cofactor. Clinical manifestations creatine/phosphocreatine, and the neurotoxic effect of induced by cofactor deficiency are indistinguishable excess brain guanidinoacetate. Proposed mechanisms from those caused by an isolated sulfite oxidase enzyme for the effect of excess guanidinoacetate include Na+- deficiency. In both, the disorder starts in the neona- ATPase inhibition, decreased antioxidant capacity, and tal period with feeding difficulties, encephalopathy, activation of GABA-A receptors.320–323 and intractable seizures. Other manifestations include Treatment axial hypotonia, hypomotility, limb rigidity, dislocated Biochemical and neuroradiologic abnormalities respond lenses, and profound developmental delay.331 Dystonia to treatment with oral creatine supplementation and and bilateral basal ganglia changes have been reported the use of guanidine-lowering strategies, but clinical early in the presentation,332 and survivors have a vari- improvement may be incomplete.324 Dietary treatment ety of extrapyramidal movements. Brain imaging may with arginine restriction and ornithine supplementa- show multiple cystic white matter cavities in basal gan- tion has reduced EEG epileptogenic activity.325 glia, brainstem, and cerebellum, loss of brain volume, and cessation of myelination. Isolated sulfite oxidase Other Creatine Deficiency Syndromes deficiency has also manifested with a progressive leu- Brain creatine deficiency has also been reported in koencephalopathy and lactic academia.333 association with genetic alterations of arginine:glycine Diagnosis amidinotransferase (AGAT) and the sodium- and chlo- Diagnosis is suspected by excess urinary excretion ride-dependent creatine transporter.326–329 The transporter of sulfite (detectable by dipstick), thiosulfate, and is required to move creatine into the brain and muscle S-sulfocysteine (detectable by anion exchange chroma- against a high gradient. Both disorders are characterized tography). Plasma cystine and homocysteine levels are by mental retardation, macrocephaly, expressive dyspha- reduced due to sulfite conjugation with cystine, forming sia, and behavioral problems. Epilepsy is prominent in the sulfocysteine, and to homocysteine.333 False-negative X-linked creatine transporter syndrome. Brain MRI may urinary screens for sulfite can occur if the urine is not be normal or show hyperintense T2-weighted abnormal- fresh (sulfites converted to sulfates) and false-positive ities, especially in the periventricular region. Neither of results can be due to treatment with sulfur-containing these deficiency syndromes has extrapyramidal problems, medications. Enzymatic diagnosis can be confirmed in suggesting that basal ganglia involvement may arise from fibroblasts and liver. A short-term response to dietary the neurotoxic effect of guanidinoacetate rather than the methionine restriction with cysteine supplementation depletion of brain creatine. In AGAT, urine guanidino- has been reported.334 acetate concentration and the creatine/creatinine ratio is decreased, whereas in the transporter defect, urine guani- Other dinoacetate is normal and the creatine/creatinine ratio is increased. Brain spectroscopy is abnormal in both disor- Glucose Transport Defect (GLUT1 Deficiency) ders. Creatine supplementation in AGAT deficiency has The glucose transport defect (GLUT1) is an autosomal been beneficial,330 but treatment for the creatine trans- dominant disorder of glucose transport across the porter defect remains to be identified. blood-brain barrier.335–337 The affected gene, located [email protected] 66485438-66485457 Chapter 15 Inherited Metabolic Disorders 189

at 1p35-p31.3, solute carrier member 2, family 1 (SLC2A1), encodes a facilitator glucose transporter in the blood-brain barrier. Several clinical phenotypes have been described with the most common including infantile seizures, typically unresponsive to antiepileptic drugs, a developmental encephalopathy with mild to severe mental retardation, acquired microcephaly, ataxia, and spasticity.336 Atypical presentations have occurred without seizures, but with movement disorders. In children, movements were characterized by paroxysmal episodes of blinking and abnormal head and eye movements, facial and hand dystonia, and mild choreiform movements.336,338,339 Mutations in SLC2A1 have also been reported in older patients with paroxysmal movements (choreo athetosis and/or dystonia). Presentations have been consistent with paroxysmal exercise-induced dyskinesia (PKD) and paroxysmal nonkinesigenic dyskinesia (PNKD).340,341 In these patients, the median age of onset of PKD was 8 years, all had involvement of the lower extremity, and the median duration of movements was 15 minutes. In many cases the initial diag- Figure 15-16. Acanthocytes (Greek for “thorn,” deformed erythrocytes with spicules of varying sizes) are seen in the nosis was incorrectly identified as epileptic myoclonic peripheral smear in patients with at least three hereditary jerks. Individuals also had coexisting epilepsy, a reduced neurologic disorders labeled as neuroacanthocytoses: chorea- CSF/blood glucose ratio, reduced glucose uptake deter- acanthocytosis, McLeod syndrome, and abetalipoproteinemia. mined in oocytes, and altered glucose metab- Xenopus Acanthocytes are also found in PKAN and HARP syndrome. olism in corticostriate pathways on functional MRI (fMRI) studies.340 The pathogenesis of GLUT1 deficiency is believed to be due to decreased glucose in the brain, with glu- associated with seizures (about 50%), dementia, self- cose acting as both a source of energy and a signaling injurious behavior, impaired executive function skills, molecule.342 The ketogenic diet has been successfully cognitive decline, and psychiatric features. Childhood used to treat seizures in GLUT1 patients, as well as obsessive-compulsive disorder has preceded the devel- paroxysmal movement disorders.337,340 opment of this disorder.348 Muscle creatine kinase or liver transaminase levels are increased, muscle wast- Neuroacanthocytosis ing or weakness is common, and tendon reflexes are Acanthocytes (Greek for “thorn,” deformed erythrocytes reduced due to a sensorimotor polyneuropathy. Muscle with spicules of varying sizes) are seen in the periph- biopsies have shown signs of denervation and peripheral smear in patients with at least three hereditary eral nerve biopsies have shown depletion of large neurologic disorders labeled as neuroacanthocytoses: myelinated fibers.347,349 The mean age of onset is about chorea-acanthocytosis, McLeod syndrome, and abeta- 30 years, but the disorder has been reported in chil- lipoproteinemia. Acanthocytes are also found in dren less than 10 years old. The disorder is caused by PKAN and HARP syndrome (Fig. 15-16). mutations in the VPS13A gene that interfere with the Chorea-acanthocytosis is an autosomal recessive disor- production of chorein located in human brain and der characterized by progressive hyperkinetic movements erythrocytes.346,350,351 (orofacial dyskinesias, limb chorea, dystonia, motor and Pathologically, the caudate and putamen are atro- phonic tics), acanthocytosis, and the absence of any lipid phic with depletion of small and medium-sized spiny abnormality.343–346 Chorea is the most characteristic neurons.352 MRI has shown symmetric abnormalities in movement abnormality, primarily affecting the the basal ganglia, with increased signal on T2-weighted lower extremities. Dystonia is also common and may scans of the striatum and predilection to the head be the presenting symptom in some cases.347 The of the caudate.347,353–355 PET studies show a reduc- hyperkinetic state occasionally progresses to parkin- tion in blood flow and glucose utilization in frontal- sonism or akinetic mutism. Chorea-acanthocytosis is subcortical regions and dysfunction of dopaminergic

[email protected] 66485438-66485457 190 section 5 selected secondary movement disorders neurons projecting from the substantia nigra to the Leukoencephalopathies 353,356,357 striatum. Diagnosis depends on the presence Pelizaeus-Merzbacher Disease of acanthocytes, neurologic abnormalities, and chorein Pelizaeus-Merzbacher disease is an X-linked recessive assay in peripheral blood.358 disorder of CNS myelin caused by a mutation in the 371,372 McLeod Syndrome proteolipid protein (PLP) gene on Xq22. Gene duplication is the most common mutation with mis- This is an X-linked multisystem disorder caused by sense mutations, insertions, and deletions being less mutations of the XK gene encoding the XK pro- common. PLP is a major CNS myelin protein and its tein, the exact function of which is unknown.359,360 excessive production or conformational change can Hematologic findings include acanthocytes, compen- have a critical role in the maturation and maintenance sated hemolysis, the absence of red blood cell (RBC) of central myelin. Pelizaeus-Merzbacher disease has two Kx antigen, and weak expression of Kell RBC anti- clinical forms: type 1 begins in infancy with abnormal gens. Onset of neurologic signs is in the third to fourth eye movements (irregular oscillations, horizontal, or ver- decade. CNS phenotype is similar to Huntington’s tical nystagmus) and laryngeal stridor. Later, generally disease with choreic movements, neurobehavioral within the first 6 months, psychomotor development problems, psychiatric difficulties, and seizures.346 slows, with a greater involvement of motor function, Initial abnormal movements may be subtle and especially in the lower extremities due to progressive include increased restlessness, postural adjustments, spasticity.373 Choreiform movements of the limbs may or facial tic–like movements.361 Facial dyskineia, dys- be present, and seizures have been reported.372,374 MRI arthria, and involuntary vocalizations may also be scans typically show a lack of myelin with low intensity present. Affected individuals also have neuromus- on T1-weighted and high intensity on T2-weighted cular manifestations with myopathy, sensorimotor images. The proton MRS profile differs from other axonal neuropathy and cardiomyopathy. CT and commonly observed demyelinating disorders and can MRI show atrophy of the caudate nucleus and MRI aid in diagnosis.375 Females heterozygous for the muta- increased T2 intensity in the lateral putamen.362,363 tion have been reported with progressive pendular nys- 18F-fluorodeoxyglucose PET shows impaired glucose tagmus, athetosis, spastic gait, and dysarthria.376 Type 2 metabolism in the striatum.364 is an X-linked spastic paraplegia. Bassen-Kornzweig Syndrome Aicardi-Goutières Syndrome Abetalipoproteinemia is an autosomal recessive disorder characterized by acanthocytes, fat malabsorption, This is an autosomal recessive encephalopathy charac- hypocholesterolemia, ataxia, neuropathy, and pig- terized by the appearance of a severe neurologic dys- mentary retinal degeneration.365–367 Neurologic prob- function in infancy, although clinical heterogeneity lems manifest before age 20 years and often mimic with later onset and less severe involvement has been Friedreich ataxia. Serum apolipoprotein B containing reported.377–379 Severely affected individuals have pro- lipoproteins, low-density, and very-low-density lipo- found psychomotor developmental delay, spastic- proteins are absent, causing impaired fat absorption ity, progressive microcephaly, dystonic posturing, and and intestinal transport that, in turn, results in very death in early childhood. In this group, there is CSF low serum levels of cholesterol and triglycerides. The lymphocytososis and/or elevated interferon-alpha. disorder may manifest in early childhood with malab- Radiographic imaging shows intracranial calcifica- sorption or later in life with progressive ataxia, visual tions (especially basal ganglia), white matter hypoden- problems, and neuropathy. Neurologic symptoms are sities, and cerebral atrophy. The syndrome is caused by due to deficient absorption of fat-soluble vitamin E, mutations in the AGS1 gene encoding the exonuclease involve the posterior columns and spinocerebellar TREX1 or mutations in the AGS2, AGS3, or AGS4 tracts, and can be prevented or treated with vita- genes that encode subunits of the human ribonuclease min A and E administration.368 Retinal degenera- H2 complex. tion is due to a combined deficiency of vitamins A and E. Abetalipoproteinemia is caused by muta- Canavan, van Bogaert, Bertrand Disease tions in the gene encoding microsomal triglyceride Canavan disease is a progressive autosomal recessive transfer protein located on chromosome 4q22-24. leukodystrophy caused by a deficiency in aspartoacy- The protein functions in the assembly of apolipo- lase, localized in oligodendrocytes, which catalyzes the protein B containing low-density lipoproteins and deacetylation of N-acetyl-l-aspartate to form aspartate chylomicrons.369,370 and acetate. Various mutations in the asparto-acylase

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gene, localized on chromosome 17pter-p13, have been glycosylated. In order to become glycosylated, dur- identified. The classic form manifests in infancy with ing the process of protein translation, the N-terminal lethargy, hypotonia, head lag, and macrocephaly.380 portion of the protein is translocated from the outer Over time the child develops hyperextension of the to the inner side of the RER membrane, and, in lower extremities and spasticity. Increased irritabil- turn, a preassembled oligosaccharide is attached. The ity, optic atrophy, seizures, and cognitive symptoms oligosaccharide itself is a branched structure consist- are common, with death occurring within a few years ing of two N-acetyl-glucosamines, nine mannoses, of onset. Congenital and juvenile variants have been and three glucose residues (Fig. 15-17). In CDG I reported.381,382 Diagnosis is based on detection of ele- disorders, the defect resides in the assembly of the oli- vated levels of N-acetylaspartic acid (NAA) in urine, gosaccharide precursor, which results in partial or com- CSF, and brain (elevated NAA to creatine ratio on plete underglycosylation of proteins.386,387 magnetic resonance spectroscopy), and enzyme activity The clinical spectrum of CDG ranges from multi- measurement in fibroblasts. MRI shows decreased signal system disorders to those affecting specific organs.386–388 on T1-weighted and increased signal on T2-weighted CDG Ia is the most common clinical abnormality, images in white matter, primarily in cerebral hemi- accounting for 83% of cases of CDG I. It is charac- spheres, globus pallidus, and thalamus. Histology terized by a deficiency in the enzyme phosphomanno- demonstrates spongiform degeneration of the cortex mutase 2 (PMM2) and caused by a mutation in the and subcortical white matter. The pathophysiology of PMM2 gene located on chromosome 16.389 Canavan disease is unclear.383 Management is strictly In type 1a, the disease begins in the first year of life symptomatic. with two presentations including a neurologic pattern and a multisystem pattern with both neurologic and sys- 389–391 Congenital Disorders of Glycosylation temic manifestations. Typical neurologic features (Formerly Named Carbohydrate- include delayed development, hypotonia, strabismus/ other oculomotor abnormalities, ataxia, areflexia-poly- Deficient Glycoprotein Syndrome) neuropathy, and seizures. Some patients have feeding Congenital disorders of glycosylation (CDG) rep- problems, failure to thrive, dysmorphic facies (bilaterally resent an expanding group of inherited (autosomal inverted nipples and mild clinodactyly), and areas of recessive) disorders that are characterized by defects in lipohypertrophy and lipoatrophy on the buttocks and the N- and/or O-glycosylation of proteins and subse- arms. Retinitis pigmentosa, cardiomyopathy, hepatic quent aberrant formation of glycoproteins.384,385 CDG dysfunction, stroke-like episodes, and a coagulopa- is divided into two major groups, protein- and lipid- thy characterized by low levels of protein C, protein S, glycosylation disorders. antithrombin III, and factor XI may be present. MRI In brief, proteins synthesized in the rough endo- studies typically show hypoplasia of the vermis and cer- plasmic reticulum (RER) that are to be secreted or ebellar hemispheres. Other, less frequently appearing destined to become membrane proteins must be radiographic abnormalities include moderate global

Mannosyl- Mannosyl- Mannosyl- Mannosyl- Mannosyl- transferase I transferase II transferase III transferase IV transferase V Flipase β1,4 GDP- GDP GDP- GDP GDP- GDP GDP- GDP GDP- GDP β1,4 α1,3 α1,6 PMM -6-P -1-P α1,2 α1,2

CDG-Ia

Figure 15-17. Construction of the transferred oligosaccharide. Squares are n-acetylglucosamine residues. Circles are mannose. CDG-1a, congenital disorders of glycosylation-1a; GDP guanosine diphosphate. (From Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies, Eur J Pediatr 2003; 162:359-379.)

[email protected] 66485438-66485457 192 Section 5 Selected secondary movement disorders atrophy, olivopontocerebellar hypoplasia, and brainstem 8. Smith KJ, Hall SM, Schauf CL: Vesicular demyelina- hypoplasia. Diagnosis is based on electrophoretic mobil- tion induced by raised intracellular calcium, J Neurol Sci ity of the serum protein transferrin and the detection of 71:19–37, 1985. unusual isoforms. Abnormalities of transferring glyco- 9. Dudesek A, Roschinger W, Muntau AC, et al: Molecular sylation can also be detected using a mass spectroscopy analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase technique.392 Since mannose has been shown to cor- deficiency, Eur J Pediatr 160:267–276, 2001. rect the size of truncated lipid-laden oligosaccharides in 10. Niederwieser A, Shintaku H, Leimbacher W, et al: 393 CDG Ia fibroblasts, it has been tried in patients with “Peripheral” tetrahydrobiopterin deficiency with this disorder. Unfortunately, a course of intravenous and hyperphenylalaninaemia due to incomplete 6-pyruvoyl oral mannose failed to improve clinical findings or to tetrahydropterin synthase deficiency or heterozygosity, correct the hypoglycosylation of different proteins.394 Eur J Pediatr 146:228–232, 1987. 11. Larnaout A, Belal S, Miladi N, et al: Juvenile form of Cerebral folate deficiency dihydropteridine reductase deficiency in 2 Tunisian patients, Neuropediatrics 29:322–323, 1998. Cerebral folate deficiency syndrome is a rare but poten- 12. Blau N, Bonafe L, Thony B: Tetrahydrobiopterin tially treatable condition characterized by low levels deficiencies without hyperphenylalaninemia: diagnosis of 5-methyltetrahydrofolate (5-MTF) in the cerebro- and genetics of dopa-responsive dystonia and sepiap- spinal fluid with normal folate levels in the plasma terin reductase deficiency, Mol Genet Metab 74:172– and red blood cells.395,396 Typically symptoms include 185, 2001. developmental delay or regression, deceleration of 13. Ichinose H, Inagaki H, Suzuki T, et al: Molecular mech- head growth, hypotonia, ataxia, and seizures. About anisms of hereditary progressive dystonia with marked one-third have dyskinesias including choreoathetosis diurnal f luctuation, Segawa’s disease, Brain Dev 22(Suppl 1): and hemiballismus. MRI may be normal or in some S107–S110, 2000. show supra- or intratentorial atrophy or periventricular 14. 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Marquardt T, Denecke J: Congenital disorders of J Inherit Metab Dis 8(Suppl 1):88–92, 1985. glycosylation: review of their molecular bases, clini- 369. Shoulders CC, Brett DJ, Bayliss JD, et al: cal presentations and specific therapies, Eur J Pediatr Abetalipoproteinemia is caused by defects of the gene 162:359–379, 2003. encoding the 97 kda subunit of a microsomal triglyceride 388. Grunewald S: Congenital disorders of glycosylation: transfer protein, Hum Mol Genet 2:2109–2116, 1993. rapidly enlarging group of (neuro)metabolic disorders, 370. Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma Early Hum Dev 83:825–830, 2007. M, Wetterau JR: The role of the microsomal trigly- 389. Miossec-Chauvet E, Mikaeloff Y, Heron D, et al: geride transfer protein in abetalipoproteinemia, Annu Neurological presentation in pediatric patients Rev Nutr 20:663–697, 2000. with congenital disorders of glycosylation type Ia, 371. Garbern J, Cambi F, Shy M, Kamholz J: The molecu- Neuropediatrics 34:1–6, 2003. lar pathogenesis of Pelizaeus-Merzbacher disease, Arch 390. Jaeken J, Carchon H: What’s new in congenital disorders Neurol 56:1210–1214, 1999. of glycosylation? Eur J Paediatr Neurol 4:163–167, 2000.

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391. Enns GM, Steiner RD, Buist N, et al: Clinical and type I and phosphomannomutase deficiency, Eur J molecular features of congenital disorder of glycosy- Pediatr 157:605–606, 1998. lation in patients with type 1 sialotransferrin pattern 395. Bonkowsky JL, Ramaekers VT, Quadros EV, Lloyd M: and diverse ethnic origins, J Pediatr 141:695–700, Progressive encephalopathy in a child with cerebral 2002. folate deficiency syndrome, J Child Neurol 23:1460– 392. Lacey JM, Bergen HR, Magera MJ, et al: Rapid deter- 1463, 2008. mination of transferrin isoforms by immunoaffinity 396. Gordon N: Cerebral folate deficiency, Dev Med Child liquid chromatography and electrospray mass spec- Neurol 51:180–182, 2009. trometry, Clin Chem 47:513–518, 2001. 397. Ramaekers VT, Sequeira JM, Blau N, Quadros EV: 393. Panneerselvam K, Freeze HH: Mannose corrects altered A milk-free diet downregulates folate receptor auto- N-glycosylation in carbohydrate-deficient glycoprotein immunity in cerebral folate deficiency syndrome, Dev syndrome fibroblasts, J Clin Invest 97:1478–1487, Med Child Neurol 50:346–352, 2008. 1996. 398. Moretti P, Sahoo T, Hyland K, et al: Cerebral folate defi- 394. Mayatepek E, Kohlmuller D: Mannose supplementa- ciency with developmental delay, autism, and response tion in carbohydrate-deficient glycoprotein syndrome to folinic acid, Neurology 64:1088–1090, 2005.

[email protected] 66485438-66485457 Movements That Occur in Sleep O 16

O Sleep is a universal experience; infants spend more than movements, a low-amplitude mixed-frequency pattern half of their time sleeping and adults spend about one on electroencephalogram (EEG), and the absence of third of the day asleep. Sleep is an active process, not muscle tone in voluntary muscles. always restful, and frequently filled with various move- Normal sleep architecture in older children and adults ments, some of which are normal whereas others might consists of progressive cycles throughout the night. At have a more pathologic basis. Pediatric neurologists are the onset of sleep, the individual moves from drowsiness frequently confronted with interpreting descriptions of into the NREM phase stage 1, then progresses to stage movements that occur during sleep. Is the described 2, and subsequently into delta or slow-wave sleep (stages movement abnormal, a component of a sleep-related 3 and 4). After about 80 to 90 minutes, the first period

disorder, an extension of a preexisting movement disor- of REM sleep occurs, lasting about 5 to 10 minutes. O der, or a seizure? Physicians have long known that sleep The individual then typically returns to stage 1 or 2 disturbances could represent a sign of disease, but the sleep before again entering delta sleep. The next epi- recognition of the existence of primary sleep disorders sode of REM sleep occurs in about 60 to 90 minutes. first occurred in the 1950s. The discovery of rapid eye As the night progresses, NREM-REM cycles continue movement (REM) sleep and subsequently the nightly with fewer stages of 3 and 4 sleep. In the early-morn- repetitive cycles of non–rapid eye movement (NREM) ing hours, cycles alternate between stages 1 to 2 and and REM sleep led to the recognition that sleep is an REM. Most delta sleep occurs during the first third of active process with distinct neurophysiologic abnor- the night and most REM sleep occurs in the last third. malities. This chapter reviews various movements that Developmentally, sleep systems in children mature rap- occur as part of primary sleep disorders, movements idly: in the first year of life REM sleep predominates, that are present during the day and persist in sleep, and but in the preschool and school-age years NREM stages nocturnal seizures. Since the categorization of involun- 3 and 4 predominate, with longer periods of deeper tary movements that occur around the time of sleep stages of sleep. Normal sleep movements, such as posi- requires a working knowledge of sleep-wake cycles, a tion shifts, are common in infants and decrease with brief review of sleep physiology is provided. age.1 Infants also lack the typical REM motor inhibition seen in older children and adults.2 In adults, about one half of the sleep period is spent in stage 2 sleep, 20% in Overview of Sleep Physiology stage 3 and 4, and 25% in REM sleep (Fig. 16-1). The sleep-wake cycle is subdivided into three states: Regulation of the sleep-wake cycle is a complex wake, non–rapid eye movement (NREM), and rapid activity that requires a coordination of neuronal activity eye movement (REM) sleep. Each state has char- among the hypothalamus, brainstem, thalamus, and acteristic physiologic patterns or stages that can be cortex. The preoptic area of the hypothalamus appears recorded by polysomnographic techniques. NREM to be a major sleep-promoting area with neurons sleep is typically the state that initiates sleep, that is, in this region interacting with neurons in the brain- drowsiness merges with sleep. NREM is divided into stem that are involved with arousal, i.e., the inhibi- four stages: stage 1 has the loss of the posterior domi- tion of neurons in the pedunculopontine, laterodorsal nant rhythm, mild slowing of the background activity, tegmental nuclei, locus ceruleus, and dorsal raphe and the appearance of vertex sharp waves; stage 2 has promote sleep.3 Regulation of sleep wake cycles by distinctive features of sleep spindles or K complexes; the circadian system is related to but separate from stage 3 has the presence of 0 to 2 Hz, greater than 70 the promotion of sleep. The suprachiasmatic nucleus microvolt slow waves that occupy 20% to 50% of the (SCN), located in the anterior hypothalamus and the 30-second epoch; and stage 4 contains slow waves recipient of information on light via the retinohy- occupying more than 50% of the 30-second epoch. pothalamic tract, appears to be the major circadian REM sleep is characterized by intermittent rapid eye pacemaker (oscillator) for motor activity.4 Other 205 [email protected] 66485438-66485457 206 Section 5 Selected Secondary Movement Disorders factors mediating the SCN appear to include humoral Sleep-related myoclonic disorders factors,5 pathway mediators located in the subparaven- Hypnic Jerks (Sleep Starts; Hypnagogic Jerks) tricular zone of the hypothalamus,6 and “clock genes” such as the period gene rPer2.7 The transition between periods of wakefulness and NREM sleep may feature sleep starts, or hypnic jerks. Classification of Movements in Sleep These movements, often accompanied by an illusion of falling, a vivid dream, or some other sensation, is a sudden, Movements that occur in sleep, in general, can be abrupt myoclonic jerk of all or parts of the body, which classified on the basis of whether they are occasionally may wake the patient. Unless frequent,8 these I. Sleep-related movement disorders (involuntary movements are benign and associated with normal prog- movements that occur around the time of sleep) nosis. Excessive sleep starts have been reported in children A. Myoclonus with migraine9 and in neurologically impaired children.10 B. Movements associated with dyssomnias The electromyogram (EMG) shows brief (less than 250 1. Cataplexy milliseconds) complexes that may be simultaneous or 2. Periodic limb movements of sleep sequential. No treatment is necessary. Sensory (acoustic) C. Movements associated with parasomnias sleep starts are usually benign, although one case has been 1. NREM disorders of arousal associated with a brainstem lesion.11 2. Sleep-wake transition disorders Benign Neonatal Sleep Myoclonus 3. REM disorders D. Other In benign neonatal sleep myoclonus, movements are II. Hyperkinetic movement disorders that are pres- intermittent, repetitive, unilateral or bilateral, and 12–14 ent during the daytime and persist during sleep largely confined to sleep. Onset is usually in the first III. Seizures in and around the time of sleep month of life and myoclonus persists for several months, IV. Related to other factors: sleep apnea, gastrointes- but rarely into early childhood. Jerks may be triggered tinal reflux, panic attacks by noise and usually occur in brief clusters for several minutes before stopping spontaneously. The frequency Sleep-Related Movement Disorders of movement is about 1 per second with burst duration of 40 to 300 ms in clusters of four to five. Although Since the categorization of involuntary movements clusters may last for up to an hour,12 they typically do that occur around the time of sleep requires a working not arouse or wake the infant, and end with awaken- knowledge of sleep-wake cycles, a brief review of sleep ing.15,16 The jerks occur during all stages of sleep, most in physiology is provided. NREM sleep. Neurologic examination is normal, and

SLEEP PATTERNS DURING ONE NIGHT

Falling REM REM REM Waking up asleep sleep sleep sleep

4 Sleep stage (non-REM) Non-REM Non-REM Non-REM sleep sleep sleep Non-REM sleep

10 pm 12 am 2 am 4 am 6 am REM = rapid eye movement

Figure 16-1. In adults, about one half of the sleep period is spent in stage 2 sleep, 20% in stage 3 and 4, and 25% in REM sleep. NonREM is darker gray, REM is lighter gray. [email protected] 66485438-66485457 Chapter 16 Movements That Occur in Sleep 207

there is no association with developmental delay or sei- involuntary naps or “sleep attacks” while driving, walk- zures. Recognition of this condition is important, since ing, talking, and eating. Sleep attacks and episodes of it can avoid unnecessary and costly EEGs and neu- decreased vigilance may be mistaken for syncope or sei- roimaging testing. Anticonvulsants are not necessary zures. Cataplexy, often involving antigravity muscles, can or effective and may actually worsen the myoclonus.12 occur in various forms, including a simple buckling of the knees, head nodding, facial muscle flickering, weak- Propriospinal Myoclonus ness in the arms, or collapsing to the floor.29,30 In chil- Myoclonic jerks involving primarily the trunk, with pos- dren, knees, head and jaw are the most compromised sible extension into the limbs, occur in a small number of body regions with about one third having a semiperma- patients during the transition between wakefulness and nent state of eyelid and jaw weakness on which there is 17,18 drowsiness. In some patients, jerks may be confined a superimposed cataplectic attack.31 Events may occur to abdominal muscles or spread to involve muscles of the daily and their duration tends to be brief, lasting seconds 19 legs and neck, and occur during wakefulness. In oth- to a minute. Laughing is the most frequent emotional ers it may only be evident when the individual is drowsy, trigger, but excitement, surprise, tickling, fear, or anger 20,21 relaxed, or recumbent. Movements may produce dif- can also be precipitants. In children, typical triggers may ficulty with sleep induction but are relatively easily abol- be absent and cataplectic attacks may occur spontane- ished by light sleep. The mechanism appears to involve ously.31 Sleep hallucinations, or dream-like experiences, excitatory impulses that travel through relatively slowly may occur while the individual is falling asleep (hyp- conducting intersegmental propriospinal pathways. nagogic hallucinations) or while awakening (hypnopompic hallucinations). Hallucinations can be simple or Excessive Fragmentary Myoclonus in NREM Sleep complex and tend to be visual, but can include auditory, Fragmentary myoclonus, brief, asymmetric, focal jerks olfactory, gustatory, or somatosensory sensations. They 22 of the face and limbs, usually appears in NREM sleep, are reported in 15% to 66% of patients with narcolepsy. 23 but can also occur in REM sleep. Fragmentary myoclo- Sleep paralysis is the inability to move during REM sleep, nus may be associated with a variety of sleep disorders or sleep onset (hypnagogic sleep paralysis), or awaken- 22,24 occur in isolation. It is unclear whether this represents ing (hypnopompic sleep paralysis). Muscle atonia and an inadequate inhibitory drive failing to block descend- paralysis last for less than 10 minutes. Sleep paralysis is ing activation or a condition of excessive activation. reported by 17% to 80% of narcoleptic patients, but it 28 Idiopathic Myoclonus in the Oromandibular also occurs in normal individuals. Region during Sleep (Nocturnal Faciomandibular Narcolepsy is rare, with a prevalence of 20-30 per Myoclonus) 100,000 persons. It usually starts before the third This disorder consists of isolated or short runs of shock- decade and about 10% of narcoleptics have their onset 32 In children, cataplexy is present like jaw movements. It occurs predominantly in stages before age 10 years. in 15% to 80% of cases and may be the first symptom 1 and 2 NREM sleep and may be confused with brux- in 3% to 9%.31,33 Symptomatic cases in children have ism.25–27 A mother and son have been reported with tongue biting and bleeding during sleep attributed to been reported in association with Niemann-Pick disease type C, Norrie’s disease, Prader-Willi syndrome, and faciomandidular myoclonus.26 brainstem lesions.32,34,35

Movements associated with Dyssomnias Pathophysiology Dyssomnias are disorders that are characterized by The hypocretin (orexin) neuronal system is involved in excessive daytime sleepiness or complaints of difficulty narcolepsy.36,37 Hypocretins are peptides synthesized in a initiating or maintaining sleep. few thousand cell bodies located within the perifornical area of the posterior hypothalamus. These neurons proj- Narcolepsy ect widely in the central nervous system (CNS), includ- Clinical features ing to the limbic system, intrahypothalamic nuclei, The classic tetrad of symptoms including excessive day- periventricular areas, and monoaminergic cell groups time sleepiness (EDS), cataplexy (sudden episode of (locus ceruleus, raphe nuclei, ventral tegmental area, muscle weakness provoked by a strong emotion without substantia nigra, and tuberomamillary nuclei).38–41 The loss of consciousness), sleep hallucinations, and sleep potential role of hypocretin in the regulation of normal paralysis occurs in only 15% of narcoleptics.28 EDS is sleep continues to be defined.42 In studies of patients required for the diagnosis and consists of a continuous, with narcolepsy-cataplexy, reduced levels of CSF hypo- irresistible sleepiness that fluctuates and often includes cretin-1, less than 110 pg/mL, have been diagnostic.36,48

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Cataplexy, which is accompanied by reduced EMG tone Supportive clinical features include a positive fam- and areflexia, is proposed to be the result of disinhibi- ily history, the absence of any primary physical abnor- tion of a ponto-medullary-spinal pathway.28,43,44 mality that could cause the symptoms, improvement with dopaminergic therapy, and the presence of EDS. Diagnosis Periodic limb movements in sleep (PLMS) occur in Narcolepsy is a clinical diagnosis. Helpful diagnostic 80% or more of patients with RLS, but the absence of testing includes the Multiple Sleep Latency Test this problem does not exclude the diagnosis of RLS.58 (MSLT), a four- to five-nap test used for objective RLS is primarily a disorder of middle-aged and older documentation of daytime sleepiness and abnormal adults, but it has been reported in children with a prev- REM sleep transitions.45 The diagnostic specificity alence ranging from 2% to 5%.59,60 Definitive diag- of the MSLT, however, has been controversial.46 The nostic criteria for RLS in children include meeting all combination of a history of cataplexy and more than four essential adult criteria and either be able to relate two abnormal REM transitions during the MSLT is a description in his or her own words that is consistent typical for the diagnosis. Other diagnostic approaches with leg discomfort or have two out of three of the fol- include the presence of the HLA markers DQB1*0602 lowing supportive criteria: (a) sleep disturbance for age, and DQA1*0102, and the specific and sensitive measure (b) a biologic parent who has definite RLS, (c) polysom- of a low level of cerebrospinal fluid (CSF) hypocretin-1 nography documenting a PLMS index of greater than 61,62 (orexin) (e.g., less than 100 pg/mL).47,48 5/hour of sleep. In pediatric RLS, a clinical sleep disorder (trouble falling or staying asleep) often precedes the Treatment diagnosis. Common comorbidities include parasomnias, Treatment of narcolepsy includes education, good attention-deficit/hyperactivity disorder (ADHD), anxiety, sleep habits, daytime naps, counseling, and pharmaco- depression, and PLMS, and a history of “growing 62–66 therapy. Modafinil and stimulant medications (meth- pains” is common. The PLMS index is abnormal in 59 ylphenidate, amphetamines) are effective for EDS.49–51 about two thirds of cases. Family history is often positive Frequent or severe cataplexy is treated with tricyclic anti- in children with RLS and is more common in parents of depressants (imipramine, clomipramine) or serotonin children with ADHD as compared with those of control 62–64,66 specific reuptake inhibitors (fluoxetine, paroxetine), children. Serum ferritin (iron-storing protein) 66 venlafaxine, or sodium oxybate.52,53 Sodium oxybate is levels are low in most children with RLS. a formulation of gamma hydroxybuterate that has been Although there may be remissions, a progressive shown to be highly effective in reducing cataplexy and course is most common. Akathisia induced by neuro- at high doses reduce daytime sleepiness.54,55 leptics or associated with parkinsonism can be distinguished from RLS by its generation from an inner sense Restless Legs Syndrome of restlessness, failure to be relieved by activity, lack of localization to the extremities, and lack of diurnal fluc- Clinical features and Diagnosis tuation.67 Neurologic examination in the idiopathic or Restless legs syndrome (RLS) in adults is characterized familial forms of RLS is normal, but a peripheral neu- by four components: ropathy or radiculopathy may be present in “second- 1. Focal restlessness (akathisia) accompanied by dys- ary” forms. Secondary (symptomatic) RLS has been esthesias. Affected individuals have an irresistible found in individuals with renal insufficiency or failure, desire to move the extremities, particularly the and symptoms may be exacerbated by deficiencies of 56,68,69 lower extremities, accompanied by an uncomfort- iron, vitamin B12, or folate, and pregnancy. able, deep, distressing, crawling, creeping, jumping, Pathophysiology or jittery sensation localized in the body part with The primary form of RLS is believed to be genetic akathisia. and at least five gene loci have been identified.62,70 The 2. Motor restlessness. This is an irresistible desire to move pathophysiology of RLS is unclear and the location of accompanied by excessive movements. These move- the specific lesion is uncertain. Interactions between ments typically involve the legs, but can be more the dopaminergic system and CNS iron insufficiency generalized during the time of RLS symptoms. have been hypothesized.71 3. Quiescegenic. RLS symptoms are precipitated or exacerbated by long periods of remaining seated or lying Treatment and are temporarily relieved by walking or stretching. All pharmacotherapy, with the exception of iron, is 4. Circadian pattern. Symptoms are worse in the eve- symptomatic. Levodopa plus a decarboxylase inhibitor ning and night and better in the morning.56,57 has improved dysesthesias, PLMS, quality of sleep, and

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life quality measures.72 Long-term use, however, may hypothesized.80,81 Cerebral generator abnormalities have be complicated by rebound augmentation of symp- been proposed for the periodic limb movements seen in toms.73 Several dopaminergic agonists (pramipexole, RLS based on functional magnetic resonance imaging ropinirole, cabergoline, and pergolide) have been effec- (fMRI) activation of the red nucleus and brainstem.94 tive in improving RLS symptoms. Benzodiazepines, Treatment carbamazepine, and gabapentin have also been used The treatment of PLMS, especially in patients with with varying degrees of improvement, and opioids have 74 RLS, includes pharmacotherapy with dopaminergic been reserved for refractory cases. agonists, benzodiazepines, and opioids. Clonazepam is Periodic Limb Movements of Sleep generally the initial medication, and long-acting ben- Clinical features and Diagnosis zodiazepines are not recommended because they may 95–97 Periodic limb movements of sleep (PLMS; nocturnal myo- cause excessive sedation. clonus, periodic limb movement disorder) is a broad Movements associated with Parasomnias term used to include both periodic stereotypic leg move- Parasomnias are undesirable physical phenomena ments and the rare periodic arm movements of sleep. (motor, verbal, or behavioral) that occur during sleep The typical triple flexion-like leg movements consist of a but are not associated with complaints of excessive rapid partial flexion of the foot at the ankle, dorsiflexion 98,99 of the big toe with fanning of small toes, and partial daytime sleepiness (hypersomnia) or insomnia. They are thought to represent activation of the CNS flexion of the knee and hip followed by a slow recovery producing activity of skeletal muscles ranging from of the extended posture. The movements last from 0.5 violent activity to common behaviors. Parasomnias can to 5 seconds (too slow to be called myoclonus), with a be divided into several subgroups: (1) arousal disorders; periodicity of 20 to 40 seconds in a stereotyped fashion; (2) sleep-wake transition disorders; (3) disorders asso- clusters may be present for minutes to hours or can last ciated with REM sleep; and (4) others that could occur throughout the entire sleep period.75–77 PLMS are confirmed by surface EMG recordings from both anterior in either REM or NREM sleep. tibialis muscles and scored according to established crite- Disorders of Arousal ria. They occur most frequently during stages 1 and 2 of Arousal disorders are the most common childhood NREM sleep or even during the wake state and less fre- movement disorders in sleep; they tend to occur during 78 quently during deep sleep stages 3 and 4. The occurrence the first half of the sleep period, and arise during NREM of PLMS in repetitive periodic patterns is in distinct con- stages 3 and 4. These entities (sleepwalking, sleep terrors, trast to seizure activity. The periodic repetitive nature and and confusional arousals) are grouped together, because exacerbation in light NREM sleep are important compo- they possess common aspects including immaturity of nents of PLMS. The term periodic limb movement disor- arousal mechanisms, automatic behavior, altered per- der is used when PLMS are accompanied by fragmented ception of the environment, and varying degrees of 79 sleep, insomnia, and excessive daytime sleepiness. amnesia. Differences among the three types of parasom- PLMS has a prevalence of 4% to 11% in the general nias reflect varying degrees of emotional, autonomic, population, typically appears in middle age, and is more and motor activation. There is no known specific 82 common in the elderly. In a large sample of pediatric poly- pathophysiologic mechanism, and psychotropic medi- 81 somnographies the prevalence in childhood was 7.8%. cation and physiologic sleep disruptions have provoked Episodes can occur without any sleep disturbance as an episodes. Disorders of arousal are also seen as symptoms isolated condition or can be associated with sleep arousals, in individuals with obstructive sleep apnea syndrome, which can lead to excessive daytime sleepiness. In addition upper airway resistance syndrome, RLS, and PLMS.100 to RLS, PLMS may be associated with other sleep disor- Peak prevalence is between 4 and 8 years; episodes are 83,84 ders (e.g., narcolepsy, REM sleep behavioral disorder), infrequent and may last for minutes. Most disorders of with various neurologic disorders (e.g., dopa-respon- arousal improve when children reach preadolescence sive dystonia, Tourette syndrome, Huntington’s disease, and disappear after puberty or early adulthood.101,102 Parkinson’s disease, stiff-person syndrome, hyperekplexia, If present, treatment of the sleep-disordered breath- 63–65,85–89 ADHD, Williams syndrome), with other medi- ing (SDB), RLS, or PLMS results in disappearance of 90,91 cal conditions (childhood leukemia, uremia), and the parasomnias. Although rarely indicated, benzodiaz- 92,93 with the use of antidepressants and antipsychotics. epines (clonazepam and diazepam) can prevent recur- Pathophysiology rences. These medications reduce slow-wave sleep, but Little is known about the pathophysiology of PLMS their effectiveness may be due to a blunting of motor and, similar to RLS, a role for ferritin has been or autonomic susceptibility to arousal stimuli. Treating

[email protected] 66485438-66485457 210 Section 5 Selected Secondary Movement Disorders associated sleep disorders (SDB, RLS/PLMS) may also by the child’s inability to recall a dream and lack of remove triggers for sleepwalking or sleep terrors.100 memory of the event, although some children report vague recollections of threatening situations.100 Events Sleepwalking (Somnambulism) may also occur as symptoms of obstructive sleep apnea Clinical Features and PLMS, with or without RLS. Many patients also The prevalence of sleepwalking is up to 15% in chil- have sleepwalking. Precipitating factors are similar to dren age 5 to 12 years.101,103 There is no gender prefer- those causing somnambulism and treatment is similar ence. Onset typically appears 1 to 2 hours after sleep. to that for other arousal disorders. The child suddenly sits up, gets out of bed, and walks for 5 seconds to 30 minutes. During the event the child Confusional Arousals is difficult to arouse, and afterward, he usually has no Symptoms may occur in up to 25% of children, usually recall of the event. Sleepwalking events can be elabo- begin before age 5, and may persist into adulthood. rate and include leaving the house, dressing, opening These events typically occur in the first half of the locks, cooking, eating, and cleaning. Injuries may occur night, usually beginning less dramatically than sleep during this activity,104 but generally the individual can terrors, with moaning sounds gradually progressing negotiate around the house. Sleepwalking has a heri- to crying, sitting, and thrashing as if having a temper table predisposition, a higher concordance in monozy- tantrum. The child may appear frightened, confused, gotic than dizygotic twins, and a positive correlation or disoriented, but there are no autonomic responses. with the HLA-DQB1*05 subtype.105–107 Symptoms Duration may be from 5 to 15 minutes and picking usually begin between ages 4 and 12 years and lessen up the child does not help. Confusional arousals during and after the teenage years.106 Factors that may are more common when the individual is overtired, serve as precipitants include fatigue, sleep deprivation, there has been a disruption of the routine schedule, or concurrent illnesses, and medications (sedatives, desi after the use of alcohol.113 Occasional events require no pramine, lithium, paroxetine, olanzepine, thioridazine, treatment, but when frequent, small doses of benzodi- and others). An inability of the brain to awaken fully azepines at bedtime have been beneficial.114 from slow-wave sleep (disordered arousal mechanism) is thought to cause this disorder.108 A laboratory method Sleep-Wake Transition Disorders has been developed to trigger somnambulistic behaviors Rhythmic Movement Disorders by combining sleep deprivation and acoustic stimuli.109 Clinical features Treatment Rhythmic movement disorders (RMDs) are character- Therapy includes parent reassurance and safeguard- ized by repetitive stereotyped movements that define the ing the environment. Scheduled awakenings, routinely clinical pattern, for example, head banging, head roll- 115 awakening the child after several hours of sleep and just ing, body rocking, or leg banging. Head banging, or before the usual time of occurrence, have been moder- jactatio capitis nocturnal, refers to vigorous anteropos- ately successful.110 Other treatment includes avoiding terior movements of the head usually onto the pillow precipitating events and, if indicated, benzodiazepines or an adjacent object. Head rolling, in contrast, has or serotonin reuptake inhibitors.111,112 lateral rotation or rolling of the head and neck. In body rocking, the child rocks back and forth while Sleep Terrors (Night Terrors, Pavor Nocturnus) on hands and knees. Children do not recall the events Sleep terrors are more common in boys and the preva- and are unresponsive during the attack. Less common lence rate may be up to 3.5% of children.103 They consist RMDs include leg banging, kicking, and body rolling. of the sudden arousal from deep sleep with autonomic Vocalizations, such as humming or moaning, may activation. Onset typically appears 1 to 2 hours after accompany these activities. RMD is common in the sleep, the child abruptly screams out or cries piercingly, first year of life and seldom begins after 18 months.116 and develops intense motor symptoms. Patients are Prevalence in a Swedish population followed longi- agitated with a sense of intense terror and have a signif- tudinally ranged from 66% at 9 months to 6% at 5 icant autonomic response (tachycardia, tachypnea, dia- years of age.117 Movements typically occur in clusters, phoresis, hypertension, and mydriasis). The individual usually at a frequency of 0.5 to 2 Hz, and last up to 15 is difficult to arouse, appears not to recognize parents, minutes, although they can persist for hours. RMD usually and is inconsolable. The event may last for more than resolves between 2 to 5 years of age, but in a small number 30 minutes. Symptoms usually begin between ages 18 of individuals may persist into adolescence or rarely into months to 12 years with the peak onset between 5 to 7 adulthood.118,119 Rhythmic movements are seen in idio- years. They are typically differentiated from nightmares pathic REM sleep behavior disorder.120 Polysomnographic

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studies have shown that these behaviors arise most com- marked contrast to the lack of memory with sleep ter- monly in drowsiness and light NREM sleep stages 1 and rors. This disorder usually affects middle-aged or older 2 and can recur during the night. On only rare occasions men, but has been reported in children.131–133 RBD does RMD result in a serious injury.116,121,122 can occur as an idiopathic disease or appear as an early manifestation of a group of neurodegenerative diseases Pathophysiology (synucleinopathies) such as Parkinson’s disease, multiple The etiology of RMD is unknown. Most affected systems atrophy, or dementia with Lewy bodies.134–136 children are healthy, but RMD does occur in develop Transient forms have been precipitated by withdrawal 116 mentally delayed individuals. The etiology of from REM-suppressing medications (benzodiazepines), this condition is unknown and some authors have by withdrawal from drugs (fluoxetine, alcohol), or by postulated a form of self-stimulation or self-soothing intoxication with tricyclic antidepressants. RBD is 116,117 behaviors. Higher anxiety scores have been found also common in patients with narcolepsy.137 The mini- in children with RMD as compared to children without mal diagnostic criteria for RBD include a polysomno- 119 this disorder, but any association remains unproven. graphic abnormality during REM sleep (intermittent or It has been proposed that central pattern generators complete loss of REM sleep, muscle atonia, and exces- might account for the rhythmic movements in both sive phasic EMG activity), documentation of abnormal 123 physiologic and pathologic conditions. REM sleep behaviors, the history of injurious disrup- Diagnosis tive sleep behaviors, and the absence of EEG epilepti- The diagnosis of RMD is clinical, based on history. form activity during REM sleep. Polysomnography has been suggested for diagnosis An unusual feature of RBD is the absence of the clas- when the clinical history is insufficient to provide sic REM-associated skeletal muscle atonia that keeps 138 Normal a definitive diagnosis or movements are atypical or individuals from acting out their dreams. REM atonia is achieved through the actions of cen- violent.124,125 ters in the pontine region that inhibit motor activity. Treatment Magnetic resonance spectroscopy has failed, how- Reassurance generally is all that is needed. Helmets, ever, to demonstrate in REM patients either marked behavior modification, and aggressive management neuronal loss or metabolic problems within the upper of neuropsychologic difficulties may be beneficial. brainstem.139 Further, the loss of REM atonia alone Short-acting benzodiazepines, such as oxazepam and is not sufficient to generate RBD. A reduction of triazolam, or the tricyclic antidepressant imipramine dopaminergic terminals in the striatum140 and dimin- may transiently reduce rhythmic movements.126–128 ished dopamine transporter binding141 have suggested Controlled sleep restriction with hypnotic administra- the presence of a presynaptic dopaminergic defect in tion has been recommended.129 this disorder.

REM Sleep Disorders (Second Half of Night) Other Disorders Nightmares (Dream Anxiety Attacks) Paroxysmal Hypnogenic Dyskinesia Nightmares are frightening vivid dreams that are typi- (Nocturnal Paroxysmal Dystonia) cally visual but sometimes auditory. They usually begin Paroxysmal hypnogenic dyskinesia (nocturnal parox- between 3 and 6 years of age, occur in more than 50% ysmal dystonia) includes violent, dystonic stiffening, of children, are more common in females, and are pres- choreoathetoid, or hemiballismic movements occurring ent during REM sleep. Nightmares can be secondary primarily during NREM sleep. Movements last for sec- to pharmacotherapy, especially with beta-blockers, onds to hours and events are sometimes associated with anticholinergics, and dopamine agonists. somnambulism. There is no postevent confusion and the affected person usually returns to sleep. Attacks REM Sleep Behavioral Disorder (RBD) of different duration have been described: short-last- REM sleep behavioral disorder (RBD) is characterized ing attacks are often variants of frontal lobe epilepsy, by varied and violent behaviors that occur during REM whereas longer attacks represent a paroxysmal move- sleep.130 Patients may punch, kick, leap, or run while ment disorder occurring during non-REM sleep. actively participating in a dream. For example, persons Ictal single-photon emission computed tomography enacting dreams about sporting events have run into (SPECT) in a patient with epileptic seizures manifesting their bedroom wall or while dreaming about a physical as nocturnal paroxysmal dystonia showed hyperper- encounter, persons may actually punch their bedmate. fusion in the anterior part of the cingulate gyrus.142 The dream precipitating RBD is readily recalled, in Persons of all ages may be affected.

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Sleep Bruxism (Nocturnal Tooth Grinding) high arousal rates, parasomnias, periodic limb move- 159,160 Clinical Features ments, and increased general sleep movements. Movement disorders that typically persist during sleep This disorder is characterized by frequent and intense include myoclonus associated with lesions in the lower grinding or clenching of the teeth during sleep.143 brainstem or spinal cord,161 palatal tremor due to Bruxism often produces an unpleasant sound that is lesions in the Mollaret triangle,162 and individuals with disturbing to others, but usually not to the initiator. In hemifacial spasm. Tics seen in Tourette syndrome can severe cases it causes damage to the teeth, periodontal persist in both REM and non-REM sleep in up to 80% tissue, or jaw.144,145 Masseter muscle hypertrophy, of cases, although typically in a reduced form as com- morning muscle discomfort, temporomandidular sore- pared to those seen during the daytime.163–165 Chorea, ness, and temporal headache may also be present. Teeth dystonia, hemiballismus, and parkinsonian tremor are grinding may occur at any age and has been observed typically reduced during sleep, but studies have shown in up to 20% of children.119,146 There is no difference characteristic movements durning sleep.164,166 Patients in gender and the prevalence decreases with age. Most with dopa-responsive dystonia (Segawa’s disease) often of the oromotor activity associated with sleep bruxism have excessive movements and periodic limb move- appears during stages 1 and 2 of sleep.147 ments while sleeping.167 In Huntington’s disease, sleep Although observed in children with mental retarda- fragmentation is common and increases with the tion, sleep bruxism clearly occurs in normal individuals, severity of the disease.166 Only a few movement disor- and a familial tendency has been noted.148 Many causal ders, including tardive dyskinesias and essential pala- factors have been suggested, including malocclusion, tal tremor, show complete cessation of movements in psychologic, or developmental factors, but no patho- sleep.168,169 Tremors are uncommon during sleep, but logic lesion has been identified. Others have suggested two reports have described infantile tremors related that sleep bruxism represents an extreme manifesta- to sleep onset.170 Geniospasm is an inherited paroxys- tion of normal masticatory muscle activity associated mal tremulous movement of the mentalis muscle that with sleep microarousal.149,150 Its presence has also been begins in childhood and may be induced by emotional reported in individuals treated with selective serotonin stress.171 A patient with paroxysmal rhythmic move- reuptake inhibitors and certain street drugs such as ments of the chin during NREM stage 2 that ceased ecstasy.151 Bruxism should be distinguished from oro- with onset of REM has been described.172 mandibular dystonia or idiopathic myoclonus in the oromandibular region during sleep. Seizures In and Around the Time Treatment of Sleep Treatment is indicated when the condition affects the integrity of teeth. A variety of approaches have been advo- Movement abnormalities occurring during sleep can cated, ranging from stress management and hypnosis152 to be a manifestation of epilepsy and their differentiation the use of muscle relaxants (diazepam and centrally acting from a sleep disorder is essential for appropriate evalu- 173,174 methocarbamol) and injections of botulinum toxin into ation and treatment. Several epilepsy syndromes the masseter muscles.153–155 Dental mouth guards have occur predominantly during NREM sleep, a find- also been recommended to prevent the unpleasant sound ing attributed to NREM sleep being a period during and tooth destruction.156 Short-term trials have suggested which there is a coordination of synaptic activity that that catecholaminergic drugs, for example, levodopa in enhances the recruitment of a critical mass of neurons 175 combination with a decarboxylase inhibitor157 and pro- necessary to initiate and propagate a seizure. Some pranolol,158 may attenuate bruxism. investigators have noted that seizures are more common in NREM stages 1 and 2, despite NREM stages Hyperkinetic Movement Disorders 3 and 4 having the greatest activating influence on 176,177 That Are Present during the interictal epileptiform discharges. Several clinical characteristics are helpful in distin- Daytime and Persist during Sleep guishing seizures from a sleep movement abnormal- Although it is often stated that most movement disor- ity. These typically include a stereotyped appearance, ders are abolished by sleep, some movements typically random occurrence, brief duration, presence of gaze persist whereas others may involve brief remnants of deviation, incontinence, and a postictal period of con- abnormal activity, especially in transitions to light sleep fusion.127 Although nocturnal seizures may often be or wakefulness. One must also recognize that affected readily identifiable, at times a video EEG polysom- individuals can have co-occurring sleep fragmentation, nographic recording may be required for clarification.

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Thorpy MJ: Classification of sleep disorders, J Clin genetic susceptibility to sleepwalking, Mol Psychiatry Neurophysiol 7:67–81, 1990. 8:114–117, 2003. 127. Ambrogetti A, Olson LG, Saunders NA: Disorders 108. Broughton RJ: Sleep disorders: disorders of arousal? of movement and behaviour during sleep, Med J Aust Enuresis, somnambulism, and nightmares occur in 155:336–340, 1991. confusional states of arousal, not in “dreaming sleep”, 128. Alves RS, Aloe F, Silva AB, Tavares SM: Jactatio capitis Science 159:1070–1078, 1968. nocturna with persistence in adulthood. Case report, 109. Pilon M, Montplaisir J, Zadra A: Precipitating Arq Neuropsiquiatr 56:655–657, 1998. factors of somnambulism: impact of sleep deprivation 129. Etzioni T, Katz N, Hering E, et al: Controlled sleep and forced arousals, Neurology 70:2284–2290, 2008. restriction for rhythmic movement disorder, J Pediatr 110. Frank NC, Spirito A, Stark L, Owens-Stively J: 147:393–395, 2005. The use of scheduled awakenings to eliminate child- 130. Frauscher B, Gschliesser V, Brandauer E, et al: Video hood sleepwalking, J Pediatr Psychol 22:345–353, analysis of motor events in REM sleep behavior 1997. disorder, Mov Disord 22:1464–1470, 2007. 111. Crisp AH: The sleepwalking/night terrors syndrome in 131. Schenck CH, Bundlie SR, Ettinger MG, Mahowald adults, Postgrad Med J 72:599–604, 1996. MW: Chronic behavioral disorders of human REM sleep: 112. Schenck CH, Mahowald MW: Long-term, nightly a new category of parasomnia, Sleep 9:293–308, 1986. benzodiazepine treatment of injurious parasomnias 132. Herman JH, Blaw ME, Steinberg JB: REM behavior and other disorders of disrupted nocturnal sleep in 170 disorder in a two-year-old male with evidence of adults, Am J Med 100:333–337, 1996. brainstem pathology, Sleep Res 18:242, 1989. 113. Roth B, Nevsimalova S, Rechtschaffen A: Hypersomnia 133. Sheldon SH, Jacobsen J: REM-sleep motor disorder in with “sleep drunkenness”, Arch Gen Psychiatry 26: children, J Child Neurol 13:257–260, 1998. 456–462, 1972. 134. Boeve BF, Silber MH, Ferman TJ, et al: Association of 114. Rosen G, Mahowald MW, Ferber R: Sleepwalking, REM sleep behavior disorder and neurodegenerative confusional arousals, and sleep terrors in the child. disease may reflect an underlying synucleinopathy, Mov In Ferber R, et al: Principles and practice of sleep medi- Disord 16:622–630, 2001. cine in the child, Philadelphia, 1995, WB Saunders. 135. Boeve BF, Silber MH, Parisi JE, et al: Synucleinopathy 115. Sallustro F, Atwell CW: Body rocking, head bang- pathology and REM sleep behavior disorder plus ing, and head rolling in normal children, J Pediatr 93: dementia or parkinsonism, Neurology 61:40–45, 2003. 704–708, 1978. 136. Postuma RB, Lang AE, Massicotte-Marquez J, 116. 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138. Schenck CH, Mahowald MW: Polysomnographic, neu- 155. Tan EK, Jankovic J: Treating severe bruxism with botu- rologic, psychiatric, and clinical outcome report on 70 linum toxin, J Am Dent Assoc 131:211–216, 2000. consecutive cases, with the REM sleep behavior disorders 156. Dao TT, Lavigne GJ: Oral splints: the crutches for tem- (RBD): sustained clonazepam efficacy in 89.5% of 57 poromandibular disorders and bruxism?, Crit Rev Oral treated patients, Cleve Clin J Med 57:S10–S24, 1990. Biol Med 9:345–361, 1998. 139. Iranzo A, Santamaria J, Pujol J, et al: Brainstem proton 157. Lobbezoo F, Lavigne GJ, Tanguay R, Montplaisir JY: magnetic resonance spectroscopy in idopathic REM The effect of catecholamine precursor L-dopa on sleep sleep behavior disorder, Sleep 25:867–870, 2002. bruxism: a controlled clinical trial Mov Disord 12: 140. Albin RL, Koeppe RA, Chervin RD, et al: Decreased 73–78, 1997. striatal dopaminergic innervation in REM sleep behav- 158. Sjoholm TT, Lehtinen I, Piha SJ: The effect of ior disorder, Neurology 55:1410–1412, 2000. propranolol on sleep bruxism: hypothetical consider- 141. Eisensehr I, Linke R, Noachtar S, et al: Reduced stri- ations based on a case study, Clin Auton Res 6:37– atal dopamine transporters in idiopathic rapid eye 40, 1996. movement sleep behaviour disorder. Comparison with 159. Mahowald MW, Schenck CH: REM sleep parasomnias. Parkinson’s disease and controls, Brain 123(pt 6):1155– In Kryger MH, et al, editors: Principles and practice of 1160, 2000. sleep medicine, Philadelphia, 2000, WB Saunders. 142. Schindler K, Gast H, Bassetti C, et al: Hyperperfusion 160. Rothenberger A, Kostanecka T, Kinkelbur J, et al: Sleep of anterior cingulate gyrus in a case of paroxysmal and Tourette syndrome, Adv Neurol 85:245–259, 2001. nocturnal dystonia, Neurology 57:917–920, 2001. 161. Mano T, Shiozawa Z, Sobue I: Extrapyramidal invol- 143. Lavigne GJ, Rompre PH, Poirier G, et al: Rhythmic untary movements during sleep, Electroencephalogr Clin masticatory muscle activity during sleep in humans, Neurophysiol (Suppl) 35:431–442, 1982. J Dent Res 80:443–448, 2001. 162. Chokroverty S, Barron KD: Palatal myoclonus and 144. Bader G, Lavigne G: Sleep bruxism; an overview of an rhythmic ocular movements: a polygraphic study, oromandibular sleep movement disorder, Sleep Med Rev Neurology 19:975–982, 1969. 4:27–43, 2000. 163. Glaze DG, Frost JD Jr, Jankovic J: Sleep in Gilles de 145. De Laat A, Macaluso GM: Sleep bruxism as a motor la Tourette’s syndrome: disorder of arousal, Neurology disorder, Mov Disord 17(Suppl 2):S67–S69, 2002. 33:586–592, 1983. 146. Widmalm SE, Christiansen RL, Gunn SM, Hawley 164. Fish DR, Sawyers D, Allen PJ, et al: The effect of sleep LM: Prevalence of signs and symptoms of cranio- on the dyskinetic movements of Parkinson’s disease, mandibular disorders and orofacial parafunction in Gilles de la Tourette syndrome, Huntington’s disease, 4–6-year-old African-American and Caucasian chil- and torsion dystonia, Arch Neurol 48:210–214, 1991. dren, J Oral Rehabil 22:87–93, 1995. 165. Cohrs S, Rasch T, Altmeyer S, et al: Decreased sleep 147. Lavigne GJ, Rompre PH, Montplaisir JY: Sleep brux- quality and increased sleep related movements in ism: validity of clinical research diagnostic criteria in patients with Tourette’s syndrome, J Neurol Neurosurg a controlled polysomnographic study, J Dent Res 75: Psychiatry 70:192–197, 2001. 546–552, 1996. 166. Wiegand M, Moller AA, Lauer CJ, et al: Nocturnal sleep 148. Hublin C, Kaprio J, Partinen M, Koskenvuo M: Sleep in Huntington’s disease, J Neurol 238:203–208, 1991. bruxism based on self-report in a nationwide twin 167. Van Hove JL, Steyaert J, Matthijs G, et al: Expanded cohort, J Sleep Res 7:61–67, 1998. motor and psychiatric phenotype in autosomal 149. Kato T, Montplaisir JY, Guitard F, et al: Evidence that dominant Segawa syndrome due to GTP cyclohydro- experimentally induced sleep bruxism is a consequence lase deficiency, J Neurol Neurosurg Psychiatry 77:18–23, of transient arousal, J Dent Res 82:284–288, 2003. 2006. 150. Lavigne GJ, Kato T, Kolta A, Sessle BJ: Neurobiological 168. Yokota T, Atsumi Y, Uchiyama M, et al: Electro- mechanisms involved in sleep bruxism, Crit Rev Oral encephalographic activity related to palatal myoclonus Biol Med 14:30–46, 2003. in REM sleep, J Neurol 237:290–294, 1990. 151. Ellison JM, Stanziani P: SSRI-associated nocturnal brux- 169. Baca-Garcia E, Stanilla JK, Buchel C, et al: Diurnal ism in four patients, J Clin Psychiatry 54:432–434, 1993. variability of orofacial dyskinetic movements, 152. Clarke JH, Reynolds PJ: Suggestive hypnotherapy Pharmacopsychiatry 32:73–75, 1999. for nocturnal bruxism: a pilot study, Am J Clin Hypn 170. Singh K: Sleep related infantile tremors, Indian Pediatr 33:248–253, 1991. 38:1197–1198, 2001. 153. Chasins AI: Methocarbamol (robaxin) as an adjunct 171. Jarman PR, Wood NW, Davis MT, et al: Hereditary in the treatment of bruxism, J Dent Med 14:166–169, geniospasm: linkage to chromosome 9q13-q21 and 1959. evidence for genetic heterogeneity, Am J Hum Genet 154. Lavigne GJ, Montplaisir JV: Bruxism: epidemiology, 61:928–933, 1997. diagnosis, pathophysiology, and pharmacology. In 172. Kharraz B, Reilich P, Noachtar S, Danek A: An epi- Friction JR, et al, editors: Orofacial pain and temporo- sode of geniospasm in sleep: toward new insights into mandibular disorders, New York, 1995, Raven Press. pathophysiology? Mov Disord 23:274–276, 2008.

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173. Zucconi M, Ferini-Strambi L: NREM parasomnias: Epilepsy, sleep and sleep deprivation (epilepsy research sup- arousal disorders and differentiation from nocturnal frontal plement), ed 2, 73–81, 1991, New york. Elsevier. lobe epilepsy, Clin Neurophysiol 111:S129–S135, 2000. 179. Nobili L: Nocturnal frontal lobe epilepsy and non- 174. Malow BA, Vaughn BV: Treatment of sleep disorders in rapid eye movement sleep parasomnias: differences and epilepsy, Epilepsy Behav 3:35–37, 2002. similarities, Sleep Med Rev Paris 11:251–254, 2007. 175. Steriade M, McCormick DA, Sejnowski TJ: 180. Tinuper P, Provini F, Bisulli F, et al: Movement Thalamocortical oscillations in the sleeping and aroused disorders in sleep: guidelines for differentiating epileptic brain, Science 262:679–685, 1993. from non-epileptic motor phenomena arising from 176. Malow BA, Lin X, Kushwaha R, Aldrich MS: Interictal sleep, Sleep Med Rev 11:255–267, 2007. spiking increases with sleep depth in temporal lobe 181. Provini F, Montagna P, Plazzi G, Lugaresi E: Nocturnal epilepsy, Epilepsia 39:1309–1316, 1998. frontal lobe epilepsy: a wide spectrum of seizures, Mov 177. Minecan D, Natarajan A, Marzec M, Malow B: Disord 15(6):1264, 2000. Relationship of epileptic seizures to sleep stage and 182. Provini F, Plazzi G, Lugaresi E: From nocturnal sleep depth, Sleep 25:899–904, 2002. paroxysmal dystonia to nocturnal frontal lobe epilepsy, 178. Touchon J, Baldy-Moulinier M, Besset A, et al: Sleep Clin Neurophysiol 111 (Suppl) 2:S2–8, 2000. organization and epilepsy. In Degen R, Rodin E, editors:

[email protected] 66485438-66485457 Cerebral Palsy O 17 O Introduction chronic sleep disorders, and disorders of vision or hearing (10% to 30%).10–18 Use of the term cerebral Historically, the initial association among prematu- palsy has been controversial, considered by some to rity, birth injury, and perinatal asphyxia with cerebral be a nonspecific “wastebasket” and by others a valu- palsy is attributed to Dr. William John Little in a lec- able diagnostic tool.19 Most agree, however, that it does ture presented to the Obstetric Society of London in convey a nonprogressive nature and provides individu- 1861.1 Subsequent major contributions were made by als with greater access to medical care, rehabilitation, William Osler, who introduced the phrase “cerebral educational, and social services. palsy” to describe this nonprogressive disorder,2 and Sigmund Freud, who extended Little’s observations to O Epidemiology include factors in early pregnancy, as well as emphasizing the cerebral abnormality in spastic diplegia.3,4 The incidence of CP is about 1.5 to 2.5 per 1000 live Despite these early seminal contributions and the births, and the risk is higher in low birth weight (less efforts of multiple other investigators,5 the definition than 1500 grams) infants and in twin pregnancies.20,21 of cerebral palsy continues to evolve,6 the epidemiol- Improvements in obstetric and neonatal care have ogy of this disorder continues to be augmented,7 and reduced the incidence of CP in prematures,22,23 but its therapy remains a challenge. the overall prevalence has not changed due to a stable Cerebral palsy (CP) describes “a group of disorders rate in term infants, greater survival in preterm, and of the development of movement and posture, caus- extended longevity.7 Most cases of CP have no rela- ing activity limitation, that are attributed to nonpro- tionship to prematurity or asphyxia.25 The majority of gressive disturbances that occurred in the developing children affected with CP survive into adulthood, but fetal or infant brain. The motor disorders of cerebral life expectancy is negatively affected by the presence of palsy are often accompanied by disturbances of sensa- severe quadriplegia, profound retardation, and lack of tion, cognition, communication, perception, and/or appropriate medical care. behavior, and/or by a seizure disorder.”6 In addition to this formal definition, a new classification scheme Etiology has been recommended involving subdivision into unilateral or bilateral limb involvement, specific notation The etiology of CP is extensive, ranging from prenatal of each affected body region, description of anatomic and perinatal events to postnatal insults (Table 17-1).7,24–27 and radiographic findings, and causation and timing Hypoxic-ischemic encephalopathy represents only a small of the precipitating brain injury.6 Since specific sub- category within the neonatal encephalopathies and an classifications remain to be determined, for this chap- even smaller contributor to the causes of CP. Nonhypoxia/ ter we have retained the groupings spastic (hemiplegia, asphyxia causes of CP are numerous and include cere- diplegia, quadriplegia), dyskinetic, ataxic, and mixed. bral dysgenesis, intrauterine infection,28 intrauterine Despite the presence of underlying static brain lesions, growth restriction,29 preterm birth,30 coagulation disor- motor abnormalities are not fixed and often vary over ders, antepartum hemorrhage,31 multiple pregnancies, time.8,9 There is no consensus for a required etiology, abnormal presentations, neurometabolic diseases,32 chro- leading to the inclusion of subjects under this rubric mosomal anomalies,33 selected polymorphisms,34,35 con- who have diverse etiologies ranging from developmen- genital abnormalities, and many others affecting either tal malformations to metabolic disorders. In addition the mother or child.7 Despite the extensive list of potential to the defining motor disabilities, individuals with CP etiologies, it is not unusual to fail to identify a clear etiology. have a variety of nonmovement problems, including Criteria supporting an acute intrapartum hypoxic mental retardation (40% to 70%), epilepsy (35% to event sufficient to cause a CP event are presented in 60%), speech and language disorders (50% to 60%), Boxes 17-1 and 17-2.36,37 219 [email protected] 66485438-66485457 220 Section 5 Selected Secondary Movement Disorders

TABLE 17-1 etiologic Factors in CP BOX 17-2 other Criteria Suggesting Intrapartum Timing for the Occurrence Maternal Child of the Injury History of fetal loss Prematurity 1. A sentinel (signal) hypoxic event occurring Unusual menstrual Low birth weight immediately before or during labor periods Multiple births 2. A sudden sustained fetal bradycardia or the Thyroid disease Death in utero of a co-twin absence of fetal heart rate variability in the Estrogen Abnormal presentations presence of persistent late or persistent variable administration Growth retardation decelerations, usually after a hypoxic sentinel event when the pattern was previously normal Febrile urinary Nuchal cord tract infections 3. Apgar scores of 0 to 3 beyond 5 minutes Chorioamnionitis Thrombophilic 4. Onset of multisystem involvement within disorders Infections (uterine 72 hours after birth and neonatal) 5. An early imaging study showing evidence of Hemorrhage acute nonfocal cerebral edema (placental Developmental brain malformations separation) Adapted from MacLennan A: A template for defining a causal Toxic ingestion Thrombophilic disorders relation between acute intrapartum events and cerebral Toxemia Vascular malformations palsy: international consensus statement, BMJ 319(7216): 1054–1059, 1999. Low socioeconomic Congenital heart disease status Chromosomal abnormalities Neonatal encephalopathy (hypoxic ischemic) A National Institutes of Health (NIH)–sponsored task Metabolic disorders force has established a classification and definition of Endocrine disorder disorders causing hypertonia in children.38 The major Trauma causes for hypertonia include the following: Kernicterus Spasticity Intraventricular hemorrhage Hypertonia in which one or both of the following signs are present: BOX 17-1 Four Essential Criteria Required to 1. Resistance to externally imposed movement Define an Acute Intrapartum Hypoxic Event increases with increasing speed of stretch and Sufficient to Cause CP varies with the direction of joint movement. 1. Evidence of metabolic acidosis in fetal umbilical 2. Resistance to externally imposed movement rises arterial cord blood obtained at delivery rapidly above a threshold speed or joint angle. (e.g., pH < 7 and base deficit ≥ 12 mmol/L) 2. Early onset of severe or moderate neonatal Note: Spasticity is defined only in terms of properties encephalopathy in infants born at 34 or more of the joint being examined. It does not depend on weeks of gestation the presence of other positive (clonus, Babinski sign, 3. Cerebral palsy of the spastic quadriplegic hyperactive reflexes) or negative (weakness, poor coor- or dyskinetic type dination, loss of control) features, although these are 4. Exclusion of other identifiable etiologies 39 (e.g., trauma, coagulation defects, infectious frequently present. conditions, or genetic abnormalities) Dystonia Adapted from MacLennan A: A template for defining a causal relation between acute intrapartum events and cerebral A movement disorder in which involuntary sustained palsy: international consensus statement, BMJ 319(7216): or intermittent muscle contractions cause twisting and 1054–1059, 1999. repetitive movements, abnormal postures, or both.40 Note: Dystonia causes hypertonia only when there is co-contraction. Not all dystonia is hypertonic! Differentiating Hypertonia in Rigidity Children (Table 17-2) Hypertonia with all of the following: Hypertonia is defined as an abnormally increased resis- 1. The resistance to externally imposed joint move- tance, perceived by the examiner, to an externally ment is present at very low speeds of movement, imposed movement about a joint, while the patient is does not depend on imposed speed, and does attempting to maintain a relaxed state of muscle activity. not exhibit a speed or angle threshold.

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TABLE 17-2 differentiating Childhood Hypertonia Spasticity Dystonia Rigidity Velocity-dependent Sustained or intermittent Independent of both Summary resistance muscle contractions speed and posture Effect of increasing speed of passive Increases No effect No effect movement on resistance Effect of rapid reversal of direction on Delayed Immediate Immediate resistance Presence of a fixed posture Only in severe cases Yes No Effect of behavioral and emotional Minimal Yes Minimal state on pattern of activated muscles

Direction Unidirectional Bidirectional Bidirectional Presence of upper motor neuron Yes No No findings (clonus, hyperreflexia, + Babinski)

Adapted in part from Sanger TD, Delgado MR, Gaebler-Spira D, et al: Classification and definition of disorders causing hypertonia in childhood, Pediatrics 111(1):e89–e97, 2003.

2. Simultaneous co-contraction of agonists and (about 50%); dyskinetic (about 20%); ataxic (about antagonists may occur, and this is reflected in 10%); and mixed (about 20%). In actuality most cere- an immediate resistance to a reversal of the bral palsy patients are mixed in type to some degree, direction of movement about a joint. for example, mild dyskinetic signs are often present in 3. The limb does not tend to return toward a subtypes of spastic CP. particular fixed posture or extreme joint angle. Spastic Type 4. Voluntary activity in distant muscle groups does not lead to involuntary movements about the The spastic type of cerebral palsy is further divided rigid joints, although rigidity may worsen. into several subtypes on the basis of distribution of impairment: hemiplegia, with homolateral involvement of the arm and leg; with severe impairment Cerebral Palsy Syndromes quadriplegia, of all four extremities, usually the lower more than the Cerebral palsy is usually evident in the first 12 to 18 upper; tetraplegia, with involvement of all four extremi- months of life. The typical presentation is a delay in attain- ties, usually the upper greater than the lower; and diple- ing motor milestones, or findings of asymmetric motor gia, with milder impairment of all four extremities, but function or abnormalities of muscle tone. Serial neurode- with the arms relatively spared. Although the frequency velopmental evaluations are often required for proper clas- of types varies in different populations, a Scandinavian sification of the subtype, because findings on examination study reported that 33% of cases were hemiplegic, 6% may be affected by the state of alertness, emotional stress, quadriplegic, and 44% diplegic.45 All subtypes of spas- and irritability. Additionally, neurologic findings that are tic CP are associated with increased resistance to passive considered abnormal in adults may be physiologic during joint extension (hypertonia), hyperreflexia, clonus, and the first months of life (e.g., ankle clonus, brisk reflexes, abnormal plantar responses. Many infants with CP, how- and extensor plantar responses). Several early indicators of ever, pass through an initial hypotonic phase. In general, the presence of significant motor disability include delay neurologic abnormalities indicating spasticity are present in the appearance of motor milestones, early hand prefer- during quiet periods and sleep and do not change signif- ence, and exaggerated or persistent primitive reflexes.41,42 icantly with activity or emotional stress. Pseudobulbar Classification systems with prognostic implications for palsy, indicated by expressionless facies, and clonus may development and provisions for comparisons between be seen in both spastic and dyskinetic forms. The child centers have been published.43,44 with spastic CP is typically prone to develop earlier con- Cerebral palsy can be divided into four major types tractures and have more frequent orthopedic problems based on the predominant motor disability: spastic than does a child with choreoathetotic CP.

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The hemiplegic form has findings localized to one The quadriplegic subtype is the most severe extremity, usually with the upper extremity more form, with all four limbs significantly involved and involved then the lower. The appearance of hemiplegic considerable compromise of motor function. These CP in full-term infants is usually associated with pre- children have the early onset of motor delays and are natal circulatory disturbances (stroke) or, less com- at greater risk for severe mental retardation, epilepsy, monly, cerebral dysgenesis (schizencephaly).46,47 The dysarthria, microcephaly, and strabismus. etiologies of vascular occlusions include thrombophilic Spastic quadriplegia in the premature infant may be disorders (e.g., deficiencies of factor V Leiden, protein the result of severe PVL and in the full-term infant may C or S, and the presence of anticardiolipin antibod- be caused by prenatal insults, such as severe PVL, devel- ies), an infectious process, venous sinus thrombosis, opmental brain malformations (e.g., holoprosenceph- or congenital heart disease. The incidence of seizures aly, lissencephaly, and pachygyria), destructive brain approaches 70%, but cognitive capabilities are gener- lesions (e.g., intrauterine infections, infarction, hydro- ally spared. cephalus), or perinatal asphyxia. Neonatal hypoxic- The diplegic subtype has spasticity greater in the legs ischemic injury affects a variety of brain regions in the than in the arms. This form typically appears in infants prenatal and perinatal brain through multiple mecha- born prematurely and is associated with destruction of nisms including energy depletion, release of excitatory cerebral white matter adjacent to the lateral ventricles, amino acids, accumulation of reactive oxygen species, that is, periventricular leukomalacia (PVL). Preferential and initiation of apoptosis.55,56 Ischemic cell death is involvement of the corticostriatal fibers adjacent to the initiated by the decline of cerebral microcirculation and ventricle, which carry inputs to the lower extremities, inhibition of oxidative phosphorylation, which in turn explains the clinical presentation. causes a cascade of disturbances of intracellular homeo- The neurobiologic mechanism of PVL in the pre- stasis, for example, decreased pH, decreased adenos- mature infant involves several interacting factors.48,49 ine triphosphate (ATP), increased mitochondrial free Predisposing conditions for involvement of the cere- radical production via the mitochondrial redox chain, bral white matter include immature development diminished function of the Na+-K+ ATPase pump with of the vascular supply to this region and a matura- increased intracellular sodium and subsequently water, tion-dependent impairment of regulation of cerebral and membrane depolarization.57,58 These primary blood flow. Another major factor is the vulnerabil- events, in turn, lead to a secondary cascade including ity of the oligodendroglial precursor cell (pre-OL) the release of excitatory amino acids (e.g., glutamate), to attack by free radicals and glutamate generated by activation of NMDA receptors, influx of calcium, the ischemia-reperfusion. The pre-OL, in turn, under- formation of more reactive ion species that cause oxi- goes an apoptotic death.50 Severity of white matter dative damage to lipids, proteins, and other cell con- injury correlates with the distribution of pre-OLs.51 stituents, and ultimately to cell death.59 Other factors besides ischemia-reperfusion and exci- Dyskinetic (Choreoathetoid; totoxic agents may also be involved in causing damage to the immature oligodendrocyte. For example, Extrapyramidal) Type maternal or fetal infection, inflammation, cytokines, Dyskinetic CP syndromes are characterized by the and hyaluronic acid have been hypothesized to play presence of the involuntary movements of chorea, important contributory roles through their effect on athetosis, and dystonia. These movements typically either vascular hemodynamics, generation of reactive begin after the second year of life, may progress oxygen species, direct toxicity, or ability to block remy- slowly for several years, and persist into adulthood. elination. A study demonstrating distinct differences The time delay in the onset of dystonia following in inflammatory response and cytokine expression in perinatal asphyxia has ranged from 1 to 32 years.60 postmortem neonatal brains with and without PVL Abnormal movements usually involve all four provides support for involvement of an inflamma- extremities with the upper usually being functionally tory cytokine-mediated hypothesis.52 Hyaluronic acid more involved than the lower extremities. Dyskinetic blocks pre-OL differentiation into mature oligoden- CP is often misdiagnosed as a spastic form because droglia and, in turn, remyelination.53 The greater of the misinterpretation of clinical signs, for exam- predilection for PVL in the presence of intraventric- ple, spontaneous extensor plantar responses may rep- ular hemorrhage may be related to local increases resent dystonic posturing, rather than a traditional in iron concentration. Cystic PVL and concurrent Babinski sign. Furthermore, extrapyramidal hyperto- grade 3 germinal matrix hemorrhages are associated nicity is present throughout flexion and extension of with more severe CP.54 an extremity (lead pipe rigidity). Cogwheel rigidity is

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unusual in young children with cerebral palsy. Oral because of its sensitivity in identifying acquired lesions, motor dysfunction and tongue thrusting are common PVL, and congenital brain anomalies.72 MRI has dem- symptoms. Extrapyramidal movements show marked onstrated abnormal brain findings in about 80% or variability depending on the state of the individual; more of individuals with cerebral palsy.73–78 The scan they are decreased during relaxation and sleep and is helpful in determining the timing of the injury and increased by anxiety and stress. Dyskinetic forms of in some instances can provide important etiologic and CP, especially those associated with athetosis, tend to prognostic clues.79,80 Identification of a radiographic occur in term infants with severe perinatal asphyxia. abnormality may not, however, clarify the etiology of Pathophysiologically, extrapyramidal CP has been the motor deficit, for example, delayed myelination or localized within the basal ganglia (neostriatum and/ cortical atrophy. or globus pallidus) and/or thalamus, although more MRI in PVL shows either periventricular gliotic precise localization is lacking.61 Lesions in these scarring (T2-weighted scans) with moderate regions often appear at the end of a term gestation, ventricular enlargement or “squared-off” ventricu- usually after acute near total asphyxia.62 lar enlargement. Abnormal imaging is most promi- Since the etiology for dyskinetic CP may be heteroge- nent in the posterior ventricular system and tends neous and include metabolic or genetic components, it to be permanent. Diminished cortical and subcor- is important to follow the patient for progressive changes tical gray matter is not uncommon in the preterm and to consider a broader diagnostic evaluation. Other infant.81 Abnormal findings on MRI, measured at disorders to consider include kernicterus, mitochondrial term equivalent in very preterm infants, strongly abnormalities dopa-responsive dystonia, organic acidu- predict adverse neurodevelopmental outcome at 2 rias, Krebs cycle defects, creatine deficiency, succinic years of age.80 Others have reported that the extent semialdehyde dehydrogenase deficiency, Lesch-Nyhan of motor and cognitive impairment in children with syndrome, ataxia telangiectasia, and female carriers of PVL correlates with the degree of ventricular enlarge- ornithine transcarbamylase deficiency63–70 (see chapter 15 ment.82 In contrast, some have emphasized that the on metabolic disorders). sensitivity of lesion detection depends on the imaging modality.83 In term and near-term infants, focal arte- Ataxic (Cerebellar) Type rial infarction and brain malformation were the most The cerebellar or ataxic form represents a clinically and common neuroimaging abnormalities.84 In chil- etiologically heterogeneous group.71 Classic associated dren with dyskinetic CP, MRI often shows lesions findings include hypotonia, truncal titubation, dys- in the basal ganglia or thalamus.85,86 Lesions in both metria, cerebellar eye movements, and an ataxic gait. of these areas in term neonates have been identified Children with ataxic syndromes usually have a pre- as indicators of a hypoxic-ischemic sentinel event.87 natal etiology (e.g., developmental malformations of Neuroimaging in ataxic CP may be normal or show the cerebellum), but this can also be of heterogeneous either biparietal or infratentorial lesions.71 Several origin (e.g., mitochondrial disorder, carbohydrate studies show cerebellar injury in the extremely deficient glycoprotein disorder, Joubert’s syndrome). premature infant.88,89 Ultrasound evaluations in low Children with this type are generally born after a full- and extremely low birth weight infants have a poor term gestation and asphyxia is generally not a major predictive value, being normal in infants who devel- factor. oped adverse neurodevelopmental outcomes.90 Mixed Type Newer neuroimaging techniques have been applied to CP, including techniques that demonstrate Children with a combination of spastic and dyskinetic fiber tracts, areas of cortical activation, and concen- types are labeled as having a mixed type. trations of neurometabolites. Diffusion tensor imaging (DTI) is a magnetic imaging technique that Diagnostic Tests enables evaluation of white matter tracts in the brain and provides quantitative data on their physical Neuroimaging integrity.91 This approach is currently being used CP is a clinical diagnosis and a careful history and to examine white matter developmental changes in examination is necessary both to confirm the diagno- children with CP as compared to controls.92–94 In sis and to determine an etiology. A practice parameter one study, the degree of restricted water movement on the diagnostic assessment of the child with CP has (fractional anisotropy) was useful in predicting those recommended that the evaluation include neuroimag- cases with PVL who would develop significant motor ing, preferably magnetic resonance imaging (MRI), disabilities.93 Functional magnetic resonance imaging

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(fMRI), which identifies activated brain regions, has Physical Therapy shown that not all CP subjects with spastic quad- An important component of rehabilitation is occupa- riplegia have the same fiber track involvement.95 and tional and physical therapy. It is unclear, however, what that those with hemiplegia may have differences in type of therapy should be initiated, since proof of effi- sensory and motor organization.96 Studies with mag- cacy is often lacking. Traditionally, physical therapy is netic resonance spectroscopy have been limited, but designed to use passive positioning to inhibit the impact an analysis of the basal ganglia in children with CP of primitive reflexes, to facilitate the acquisition of gross showed that results failed to correlate with clinical and fine motor skills, and to prevent contractures,105 but severity.97 its effectiveness on functional motor outcome is contro- Other Laboratory Tests versial.106,107 Similarly, the use of neurodevelopmental treatments that emphasize specific handling techniques The diagnostic yields from metabolic and genetic (Bobath method) or conductive educational approaches evaluations are small, but testing should be has been questioned.108–110 Neuromuscular electri- considered in appropriate cases with dyskinetic and cal stimulation has been claimed to improve muscle ataxic CP, and in those individuals with specific strength, but the approach remains controversial.111–113 brain developmental malformations, for example, Constraint-induced movement therapy involves physical migrational defects, that are associated with specific constraint of the uninvolved or less affected extrem- chromosomal abnormalities. An electroencephalo- ity.114,115 Evidence for its beneficial effect is increasing, gram is not recommended unless seizures are part but additional studies are necessary to provide further of the clinical picture. support of efficacy and developmental appropriate- 116 Assessment Instruments ness. Muscle strengthening with the Adeli suit, which provides resistance to some movements, is claimed to Several instruments are available to monitor the devel- improve sensory feedback during movement and subse- opment of motor function in children with CP, includ- quent mechanical efficiency.117 Horseback riding ther- ing the Child Health Questionnaire,98 the Gross Motor apy, also known as hippotherapy, has also been shown Function Classification System for Cerebral Palsy,99 to be beneficial.118 One debate is whether outcomes of the Manual Ability Classification System,100 and the therapy should be based on improvement from a base- Functional Independence Measure.101 Two specific eval- line impairment level or evidence-based improvement uative assessment measures, the Gross Motor Function of functional capabilities and societal participation.119 Measure (GMFM) and the Pediatric Evaluation of Disability Inventory (PEDI), are reported to be reli- Spastic CP: Pharmacotherapy and able and valid measures for documenting change in Surgical Approaches motor ability over time.102 In a study comparing motor abilities of children with spastic CP receiving physical Spasticity can affect function, compromise comfort therapy that emphasizes practicing functional activi- and hygiene, and lead to musculoskeletal complica- ties versus therapy based on normalizing the quality of tions, including contractures, subluxation, and pain. movement, GMFM (an observational instrument mea- A variety of antispasticity interventions are available for suring gross motor function) did not change, whereas the treatment of children with CP, including physical PEDI (a judgment-based instrument based on parent therapy, oral medications, neurolytic blocking agents, reports) showed differences.103 intrathecal baclofen pumps, tendon-lengthening procedures, and selective dorsal rhizotomy.116,120,121 Management of Cerebral Palsy Oral Medications The management of cerebral palsy requires a compre Oral therapy is usually of greater relevance for indi- hensive multidisciplinary team approach that can deal viduals with diplegic or quadriplegic CP. Several agents with the numerous psychological, behavioral, and have been used with some benefit, including benzodi- physical needs of the child and family. Treatment should azepines, dantrolene, baclofen, and alpha-2-adrenergic- begin as early as possible, with the goal of therapy agonists.122 In general, these approaches help to reduce formulated to improve care, optimize motor function, spasticity, but have little beneficial effect on signs of prevent orthopedic deformities, and address associ- weakness and incoordination. ated impairments. Rehabilitative programs have direct Benzodiazepines (diazepam) are commonly used for benefit on parent-child relationships, socioemotional short- or long-term treatment of spasticity in children. status, confidence, and self-esteem.104 The benefit of diazepam, however, is limited by side

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effects, including sedation, weakness, memory distur- adults with spasticity.135 The combination of BTX-A bances, excess drooling, and a state of dependency.123 and serial casting has been used effectively in the man- Dantrolene sodium improves tone, range of motion, agement of equinus in children with CP.133,136 and reflexes, but its effectiveness is restricted by side effects such as weakness, drowsiness, lethargy, gastroin- Intrathecal Baclofen Pump testinal disturbances, and liver damage.124 Dantrolene Continuous intrathecal baclofen infusion through reduces muscle contractions by inhibiting the release of indwelling catheters and a programmable pump has calcium ions from the sarcoplasmic reticulum. been shown to reduce spasticity in the upper and lower Baclofen, an analog of gamma-aminobutyric acid extremities and improve function and activities of daily (GABA), binds to GABA receptors and impedes the living.137,138 Complications include infections, prob- release of the excitatory neurotransmitters glutamate lems with the catheter (kinking, migration), headaches, and aspartate. Its efficacy in treating spasticity is proba- nausea, and unresponsiveness or profound hypotonia bly based on its action at bicuculline-insensitive GABA caused by overdosing.139,140 Intrathecal baclofen has type B receptors located within the spinal cord. Oral been shown to be beneficial in dystonic CP, but not baclofen does have a mild effect on cerebral spasticity in other dyskinetic forms.141 Typical candidates for this but its use is limited by both poor lipid solubility and therapy include children with moderate to severe spas- side effects.125 tic quadriplegia who have failed oral therapy, respond Tizanidine is a central acting alpha-2-receptor ago- to a screening bolus of medication, and have adequate nist that primarily reduces polysynaptic spinal stretch body size for placement of the subcutaneous pump. reflexes.126 Its use in the treatment of spasticity has been largely focused on adult patients with multiple sclerosis Orthopedic Surgery and spinal cord injury.127 In a combined clinical anal- The role of the orthopedic surgeon is to maintain or ysis of control trials, it was suggested that tizanidine enhance motor abilities and to prevent deformities was similar in efficacy to baclofen and diazepam.126 through procedures such as tendonotomies, muscle Common side effects include dry mouth, somnolence, transfers, osteotomies, and arthrodeses. Aggressive asthenia, and dizziness. use of BTX-A, physical therapy, casting, and orthot- ics has effectively delayed the timing of surgical inter- Neurolytic Agents vention to later ages in childhood. There is also an Neuromuscular blocking agents, including alcohol, increasing trend toward single-event multilevel surgery aqueous phenol, local anesthetics, and botulinum A rather than sequential, more piecemeal, approaches.142 toxin, have been used to improve the balance between Computerized gait analysis for preoperative planning overly spastic agonist muscles and weakened antago- may be beneficial. nist muscles.128 Botulinum A toxin (BTX-A), the most One surgical procedure for spastic diplegia and widely used agent in this category, acts by blocking quadriplegia, which has recently been revived, is selec- acetylcholine release at the neuromuscular junction. tive functional dorsal (posterior) rhizotomy. In this Typically, the peak effect occurs at 2 to 4 weeks and procedure the posterior branches of the spinal nerves reinjection is necessary at 12 to 14 weeks. Side effects producing spasticity are sectioned in an attempt to include weakness or pain/bruising at the injection alter the modulating influence of the interneuron pool, site. Several studies in patients with CP have demon- which in turn controls the reactivity of alpha motor strated the value of BTX-A for equinus positioning of neurons. The use of intraoperative nerve stimulation the foot while walking129,130 or improved upper limb to determine which rootlets to cut is controversial. In movement and function.131 In contrast, other reports carefully selected patients with spastic diplegia this including a Cochrane Database review have suggested procedure has reduced spasticity, changed gait patterns, that data are insufficient to indicate its use to treat and improved the patient’s ability to deal with the envi- leg spasticity.132,133 A randomized double-masked pla- ronment or tasks of daily care.143 A comparative analy- cebo-controlled study in children with spastic diplegia sis and meta-analysis of three randomized clinical trials receiving 12 units/kg of BTX-A showed an excellent suggested that selective dorsal rhizotomy plus phys- safety profile, physiologic and mechanical benefits, iotherapy reduced spasticity in children with spastic but no significant differences from control in perfor- diplegia and had a small effect on gross motor func- mance goals achieved, energy expended, or Ashworth tion.144 Other reports, however, have suggested that scores.134 A subcommittee of the American Academy of there is no benefit from rhizotomy when compared Neurology has recommended that botulinum neuro- with intensive physical therapy.145 Hence, since this is toxin be offered as a treatment option in children and a major operative procedure, it remains controversial

[email protected] 66485438-66485457 226 Section 5 Selected Secondary Movement Disorders whether the functional outcomes outweigh potential 3. Longo LD, Ashwal S: William Osler, Sigmund Freud intraoperative and postoperative complications. and the evolution of ideas concerning cerebral palsy, J Hist Neurosci 2(4):255–282, 1993. Dyskinetic CP: Pharmacotherapy and 4. Accardo PJ: Freud on diplegia. Commentary and transla- Surgical Approaches tion, Am J Dis Child 136(5):452–456, 1982. 5. Raju TN: Historical perspectives on the etiology of cere- Oral Therapy bral palsy, Clin Perinatol 33(2):233–250, 2006. The treatment of dyskinetic CP is complicated, 6. Bax M, Goldstein M, Rosenbaum P, et al: Proposed def- because most individuals have mixed degrees of chorea, inition and classification of cerebral palsy, April 2005, athetosis, and dystonia. The general approach to Dev Med Child Neurol 47(8):571–576, 2005. therapy in the child with CP is to target the dyski- 7. Keogh JM, Badawi N: The origins of cerebral palsy, Curr Opin Neurol 19(2):129–134, 2006. netic movement that is causing the greatest difficulty. 8. Scott BL, Jankovic J: Delayed-onset progressive move- Therapeutic trials are largely empirical, and responses ment disorders after static brain lesions, Neurology 122 are often individualized. When the symptom is pri- 46(1):68–74, 1996. marily chorea or athetosis, benzodiazepines, valproate, 9. Saint Hilaire MH, Burke RE, Bressman SB, et al: carbamazepine, tetrabenazine, and neuroleptics are Delayed-onset dystonia due to perinatal or early child- often prescribed. In contrast, therapy for dystonic hood asphyxia, Neurology 41(2 pt 1):216–222, 1991. CP includes trials with anticholinergic medications 10. Guzzetta A, Mercuri E, Cioni G: Visual disorders in children (trihexyphenidyl),146 baclofen, anticonvulsants (car- with brain lesions: 2. 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95. Hoon AH Jr, Lawrie WT Jr, Melhem ER, et al: 111. Kerr C, McDowell B, Cosgrove A, et al: Electrical stim- Diffusion tensor imaging of periventricular leukomal- ulation in cerebral palsy: a randomized controlled trial, acia shows affected sensory cortex white matter path- Dev Med Child Neurol 48(11):870–876, 2006. ways, Neurology 59(5):752–756, 2002. 112. Stackhouse SK, Binder-Macleod SA, Stackhouse CA, 96. Thickbroom GW, Byrnes ML, Archer SA, et al: et al: Neuromuscular electrical stimulation versus voli- Differences in sensory and motor cortical organiza- tional isometric strength training in children with tion following brain injury early in life, Ann Neurol spastic diplegic cerebral palsy: a preliminary study, 49(3):320–327, 2001. Neurorehabil Neural Repair 21:475–485, 2007. 97. Kulak W, Sobaniec W, Smigielska-Kuzia J, et al: 113. Ozer K, Chesher SP, Scheker LR: Neuromuscular elec- Metabolite profile in the basal ganglia of children with trical stimulation and dynamic bracing for the man- cerebral palsy: a proton magnetic resonance spectros- agement of upper-extremity spasticity in children with copy study, Dev Med Child Neurol 48(4):285–289, cerebral palsy, Dev Med Child Neurol 48(7):559–563, 2006. 2006. 98. Vargus-Adams J: Longitudinal use of the Child Health 114. Charles JR, Wolf SL, Schneider JA, Gordon AM: Questionnaire in childhood cerebral palsy, Dev Med Efficacy of a child-friendly form of constraint-induced Child Neurol 48(5):343–347, 2006. movement therapy in hemiplegic cerebral palsy: a 99. Palisano RJ, Cameron D, Rosenbaum PL, et al: Stability randomized control trial, Dev Med Child Neurol of the gross motor function classification system, Dev 48(8):635–642, 2006. Med Child Neurol 48(6):424–428, 2006. 115. Naylor CE, Bower E: Modified constraint-induced 100. Eliasson AC, Krumlinde-Sundholm L, Rosblad B, et al: movement therapy for young children with hemiple- The Manual Ability Classification System (MACS) for gic cerebral palsy: a pilot study, Dev Med Child Neurol children with cerebral palsy: scale development and evi- 47(6):365–369, 2005. dence of validity and reliability, Dev Med Child Neurol 116. Papavasiliou AS: Management of motor problems in 48(7):549–554, 2006. cerebral palsy: a critical update for the clinician, Eur J 101. Krigger KW: Cerebral palsy: an overview, Am Fam Paediatr Neurol 13(5):387–96, 2009. Physician 73(1):91–100, 2006. 117. Bar-Haim S, Harries N, Belokopytov M, et al: 102. Vos-Vromans DC, Ketelaar M, Gorter JW: Comparison of efficacy of Adeli suit and neurodevelop- Responsiveness of evaluative measures for children with mental treatments in children with cerebral palsy, Dev cerebral palsy: the Gross Motor Function Measure and Med Child Neurol 48(5):325–330, 2006. the Pediatric Evaluation of Disability Inventory, Disabil 118. Sterba JA: Does horseback riding therapy or therapist- Rehabil 27(20):1245–1252, 2005. directed hippotherapy rehabilitate children with cerebral 103. Ketelaar M, Vermeer A, Hart H, et al: Effects of a func- palsy? Dev Med Child Neurol 49(1): 68–73, 2007. tional therapy program on motor abilities of children 119. Mayston M: Evidence-based physical therapy for the with cerebral palsy, Phys Ther 81(9):1534–1545, 2001. management of children with cerebral palsy, Dev Med 104. Parry TS: The effectiveness of early intervention: a crit- Child Neurol 47(12):795, 2005. ical review, J Paediatr Child Health 28(5):343–346, 120. Verrotti A, Greco R, Spalice A, et al: Pharmacotherapy 1992. of spasticity in children with cerebral palsy, Pediatr 105. Barry MJ: Physical therapy interventions for patients Neurol 34(1):1–6, 2006. with movement disorders due to cerebral palsy, J Child 121. Sanger TD: Hypertonia in children: how and when to Neurol 11(Suppl 1):S51–S60, 1996. treat, Curr Treat Options Neurol 7(6):427–439, 2005. 106. Palmer FB, Shapiro BK, Wachtel RC, et al: The effects 122. Pranzatelli MR: Oral pharmacotherapy for the move‑ of physical therapy on cerebral palsy. A controlled ment disorders of cerebral palsy, J Child Neurol 11 trial in infants with spastic diplegia, N Engl J Med (Suppl 1):S13–S22, 1996. 318(13):803–808, 1988. 123. Denhoff E: Cerebral palsy—a pharmacologic approach, 107. Turnbull JD: Early intervention for children with or Clin Pharmacol Ther 5(6):947–954, 1964. at risk of cerebral palsy, Am J Dis Child 147(1):54–59, 124. Glenn M, Whyte J, editors: The practical management 1993. of spasticity in children and adults, Philadelphia, 1990, 108. Butler C, Darrah J: Effects of neurodevelopmental treat- Lea & Febiger. ment (NDT) for cerebral palsy: an AACPDM evidence 125. Scheinberg A, Hall K, Lam LT, O’Flaherty S: Oral report, Dev Med Child Neurol 43(11):778–790, 2001. baclofen in children with cerebral palsy: a double- 109. Darrah J, Watkins B, Chen L, Bonin C: Conductive blind cross-over pilot study, J Paediatr Child Health education intervention for children with cerebral palsy: 42(11):715–720, 2006. an AACPDM evidence report, Dev Med Child Neurol 126. Wallace JD: Summary of combined clinical analysis 46(3):187–203, 2004. of controlled clinical trials with tizanidine, Neurology 110. Odman PE, Oberg BE: Effectiveness and expectations 44(11 Suppl 9):S60–S68, discussion S8–S9, 1994. of intensive training: a comparison between child and 127. Lataste X, Emre M, Davis C, Groves L: Comparative youth rehabilitation and conductive education, Disabil profile of tizanidine in the management of spasticity, Rehabil 28(9):561–570, 2006. Neurology 44(11 Suppl 9):S53–S59, 1994.

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128. Koman LA, Mooney JF 3rd, Smith BP: Neuromuscular staged operations, J Pediatr Orthop B 8(1):33–38, blockade in the management of cerebral palsy, J Child 1999. Neurol 11(Suppl 1):S23–S28, 1996. 143. Steinbok P: Outcomes after selective dorsal rhizotomy 129. Baker R, Jasinski M, Maciag-Tymecka I, et al: Botulinum for spastic cerebral palsy, Childs Nerv Syst 17(1–2): toxin treatment of spasticity in diplegic cerebral palsy: a 1–18, 2001. randomized, double-blind, placebo-controlled, dose-rang- 144. McLaughlin J, Bjornson K, Temkin N, et al: Selective ing study, Dev Med Child Neurol 44(10):666–675, 2002. dorsal rhizotomy: meta-analysis of three randomized 130. Reddihough DS, King JA, Coleman GJ, et al: controlled trials, Dev Med Child Neurol 44(1):17–25, Functional outcome of botulinum toxin A injections to 2002. the lower limbs in cerebral palsy, Dev Med Child Neurol 145. Graubert C, Song KM, McLaughlin JF, Bjornson 44(12):820–827, 2002. KF: Changes in gait at 1 year post-selective dorsal 131. Lowe K, Novak I, Cusick A: Low-dose/high- rhizotomy: results of a prospective randomized study, concentration localized botulinum toxin A improves J Pediatr Orthop 20(4):496–500, 2000. upper limb movement and function in children with 146. Hoon AH Jr, Freese PO, Reinhardt EM, et al: Age- hemiplegic cerebral palsy, Dev Med Child Neurol dependent effects of trihexyphenidyl in extrapyramidal 48(3):170–175, 2006. cerebral palsy, Pediatr Neurol 25(1):55–58, 2001. 132. Ade-Hall RA, Moore AP: Botulinum toxin type A in 147. Greene P: Baclofen in the treatment of dystonia, Clin the treatment of lower limb spasticity in cerebral palsy, Neuropharmacol 15(4):276–288, 1992. Cochrane Database Syst Rev (2):CD001408, 2000. 148. Fletcher NA, Thompson PD, Scadding JW, Marsden 133. Ackman JD, Russman BS, Thomas SS, et al: Comparing CD: Successful treatment of childhood onset symp- botulinum toxin A with casting for treatment of tomatic dystonia with levodopa, J Neurol Neurosurg dynamic equinus in children with cerebral palsy, Dev Psychiatry 56(8):865–867, 1993. Med Child Neurol 47(9):620–627, 2005. 149. Brunstrom JE, Bastian AJ, Wong M, Mink JW: Motor 134. Bjornson K, Hays R, Graubert C, et al: Botulinum toxin benefit from levodopa in spastic quadriplegic cerebral for spasticity in children with cerebral palsy: a compre- palsy, Ann Neurol 47(5):662–665, 2000. hensive evaluation, Pediatrics 120(1):49–58, 2007. 150. Nygaard TG, Waran SP, Levine RA, et al: Dopa- 135. Simpson DM, Gracies JM, Graham HK, et al: responsive dystonia simulating cerebral palsy, Pediatr Assessment: botulinum neurotoxin for the treat- Neurol 11(3):236–240, 1994. ment of spasticity (an evidence-based review): report 151. Rosenthal RK, McDowell FH, Cooper W: Levodopa of the Therapeutics and Technology Assessment therapy in athetoid cerebral palsy. A preliminary report, Subcommittee of the American Academy of Neurology, Neurology 22(1):1–11, 1972. Neurology 70(19):1691–1698, 2008. 152. Penn RD, Gianino JM, York MM: Intrathecal baclofen 136. Flett PJ, Stern LM, Waddy H, et al: Botulinum toxin for motor disorders, Mov Disord 10(5):675–677, A versus fixed cast stretching for dynamic calf tightness 1995. in cerebral palsy, J Paediatr Child Health 35(1):71–77, 153. Cif L, El Fertit H, Vayssiere N, et al: Treatment of dys- 1999. tonic syndromes by chronic electrical stimulation of the 137. Gilmartin R, Bruce D, Storrs BB, et al: Intrathecal internal globus pallidus, J Neurosurg Sci 47(1):52–55, baclofen for management of spastic cerebral palsy: mul- 2003. ticenter trial, J Child Neurol 15(2):71–77, 2000. 154. Thompson TP, Kondziolka D, Albright AL: Thalamic 138. Latash ML, Penn RD: Changes in voluntary motor stimulation for choreiform movement disorders in chil- control induced by intrathecal baclofen in patients dren. Report of two cases, J Neurosurg 92(4):718–721, with spasticity of different etiology, Physiother Res Int 2000. 1(4):229–246, 1996. 155. Kupsch A, Kuehn A, Klaffke S, et al: Deep brain stim- 139. Anderson KJ, Farmer JP, Brown K: Reversible coma ulation in dystonia, J Neurol 250(Suppl 1):I47–I52, in children after improper baclofen pump insertion, 2003. Paediatr Anaesth 12(5):454–460, 2002. 156. Bronte-Stewart H: Surgical therapy for dystonia, Curr 140. Butler C, Campbell S: Evidence of the effects of Neurol Neurosci Rep 3(4):296–305, 2003. intrathecal baclofen for spastic and dystonic cerebral 157. Krauss JK, Loher TJ, Weigel R, et al: Chronic stimu- palsy. AACPDM Treatment Outcomes Committee lation of the globus pallidus internus for treatment of Review Panel, Dev Med Child Neurol 42(9):634–645, non-dYT1 generalized dystonia and choreoathetosis: 2000. 2-year follow up, J Neurosurg 98(4):785–792, 2003. 141. Albright AL: Intrathecal baclofen in cerebral palsy move- 158. Vidailhet M, Yelnik J, Lagrange C, et al: Bilateral ment disorders, J Child Neurol 11(Suppl 1):S29–S35, pallidal deep brain stimulation for the treatment of 1996. patients with dystonia-choreoathetosis cerebral palsy: 142. Fabry G, Liu XC, Molenaers G: Gait pattern in patients a prospective pilot study, Lancet Neurol 8:709–717, with spastic diplegic cerebral palsy who underwent 2009.

[email protected] 66485438-66485457 Drug-Induced Movement Disorders inO Children 18 O

Introduction and Overview data for making clinical decisions for children is unsat- isfactory, for complex reasons. These include the scien- Recognizing and managing drug-induced movement tific and statistical difficulties arising from ill-defined disorders (DIMDs) in children poses many challenges. behavioral symptoms and diagnoses, inconvenience As is the case for adults, agents that modulate dopamine or impracticality for families of intensive placebo- are the most common causes of DIMDs. Because such controlled trials, ethical issues of clinical trials in spe-

medications are widely used in children, and in the cial populations, high costs of clinical trials, and lack O United States are increasingly used in preschool chil- of commercial interest. Third, there are inherent risks dren, these agents will receive special emphasis in this in medical treatments of all kinds, and psychiatric chapter. disorders are no different. Fourth, in many cases, even The problem of pediatric DIMDs has received with better knowledge of iatrogenic risks than we have increased attention in the last several years. Unfor- now, the benefit/risk ratio might still favor treatment. tunately, most systematic reviews, including those from Fifth, medication use in pediatric psychiatric disorders the Cochrane Collaboration, address adults but not should be part of a comprehensive treatment plan that children. A large proportion of publications are small includes appropriate therapy. However, access to com- case series or short-term randomized controlled trials. prehensive mental health care in many places is limited This chapter also attempts to provide appropriate by costs, insurance coverage, and access. caution and discuss the limitations of what we know. Last, although long-term adverse neurologic or psy- From an epidemiologic perspective, it is important chiatric effects of medications are unknown, in the to point out that the utilization of psychiatric drugs in short term, it appears that most DIMDs are reversible children has grown rapidly in the past 15 years.1–6 Since in children. 2006, the U.S. Food and Drug Administration (FDA) has approved the atypical antipsychotic risperidone for Definition of Drug-Induced several pediatric indications: symptomatic treatment of Movement Disorders irritability in autism, and schizophrenia in adolescents and for the short-term treatment of manic or Iatrogenic movement disorders, or drug-induced move- mixed episodes of bipolar I disorder in children and ment disorders (DIMDs), are conditions where the adolescents. Risperidone has high potency for D2 onset of abnormal movements is related to the use of receptors and, although classified as an “atypical” antip- medication. Several time courses may occur, as detailed sychotic, it shares similar pharmacologic properties and in Table 18-1. adverse event profile to the traditional, “typical,” neuroleptics. DIMDs have been reported most often in Clinical Characteristics— children prescribed this atypical antipsychotic. Other Phenomenology of Drug-Induced atypical antipsychotics, although not FDA approved Movement Disorders in Children for children, are widely prescribed. Thus the incidence of DIMDs in children is likely to increase further. Common DIMDs in children vary widely and include Iatrogenic conditions are a sensitive topic, and in hyperkinetic and hypokinetic syndromes: Hypokinetic/ this case some additional background is needed. First, rigid syndrome (parkinsonism), dystonia, chorea, tremor, much child psychiatric prescribing is necessarily off- ataxia, tics, stereotypies, and poorly specified dyskinesias. label, that is, done outside the approved indications. Akathisia is generally discussed as a drug induced Second, the availability of high-quality, clinical trial movement disorder because of the phenomenology of

231 [email protected] 66485438-66485457 232 Section 5 Selected Secondary Movement Disorders

TABLE 18-1 Forms of Drug-Induced cerns about metabolic consequences of the atypical Movement Disorders antipsychotics, including weight gain and increased risk of type 2 diabetes.15 However, most of the Type of DIMD Time Course increase in prescribing in the past 15 years is of the Acute Abnormal movements occur at atypical antipsychotics for off-label use in children. treatment onset, within a short The use of these agents for their original indications time interval, or at the time of for psychotic disorders is vastly outpaced in children a dose increase by use for anger, mood stabilization, aggression, and Chronic Abnormal movements occur early autistic spectrum disorder behaviors. The potential or insidiously during treatment relevance to public health of the practice of prescrib- and persist, e.g., mild enhanced ing atypical antipsychotics as mood stabilizer is clear physiologic tremor when placed in context of the stunning increase in Tardive Abnormal movements emerge the diagnosis of childhood bipolar disorder. Based on after a prolonged treatment the National Medical Ambulatory Care Survey for Withdrawal Abnormal movements occur children and youths ages 0 to 19 years, an estimated after dose decreases or 25 per 100,000 office visits involved a diagnosis of discontinuations bipolar disorder in 1994–1995. This skyrocketed to 1003 visits per 100,000 in 2002–2003.16 Critics of current psychiatric practices in the United States have restlessness. This is primarily sensory and secondarily suggested that pharmaceutical companies’ aggressive there is restless movement. Tremor is one of the most marketing has influenced both the rising prevalence common drug induced movement disorders (see of these diagnoses and the rising utilization of these Chapter 12). This chapter will be organized according medications.17 to drug class, rather than based on the type of movement Many case reports describe DIMDs in children disorder. treated with neuroleptics and atypical antipsychotics. Most acute DIMDs are transient and subside after Drug-Induced Movement Disorders withdrawal of the offending medication. Vastly different estimates of risks of acute, chronic, and tardive In general, for each drug class, epidemiology, clinical DIMDs are obtained depending on the sample size and features, pathophysiology, diagnostic approach, treat- study design. Table 18-2 shows typical neuroleptic and ment, and outcome will be discussed. atypical antipsychotic medications widely used in chil- DIMDs Associated with Dopamine dren, the FDA indications, common off-label uses, and Receptor Blockade: Typical Antipsychotics, estimates of risk of neurologic side effects, as reported Atypical Antipsychotics in the Web-based Micromedex.18 Two recent systematic studies with different meth- Epidemiology ods have generated widely disparate estimates of risks Conventional low- and high-potency neuroleptics have of DIMDs in children exposed to dopamine recep- been prescribed in children for decades. These agents tor blocking agents. The first, a meta-analysis, identi- were used to reduce aggressive behavior, particularly in fied 10 open-label and controlled studies of atypical children with mental retardation. Pimozide and halo- antipsychotics with duration of 12 months or more, peridol, the only two drugs currently approved by the involving 783 children and adolescents.19,20 Most were FDA for the treatment of Tourette syndrome, have studies of risperidone. Eighty percent of patients were been found to be effective in tic suppression, although white. Adequate data were available on fewer than side effects and discontinuation rates were high.7–11 In half of patients. The authors reported that extrapy- addition, the dopamine receptor blockers metoclo- ramidal symptoms occurred in 16%, with three pramide and prochlorperazine have been used in chil- cases of tardive dyskinesia, two on risperidone, one dren as antiemetics and for migraine-associated nausea on olanzapine. Although this study is important in for many years. providing a pediatric estimate across clinical trials, Studies in the United States of prescribing prac- as the authors acknowledged, a number of limita- tices since the marketing of risperidone in 1993 tions might have led to underestimates of the popu- show dramatic increases in the use of antipsychotics lation prevalence of tardive dyskinesia. These include for behavior problems in children of all ages.4,6,12–14 the use of different raters, different scales or no Conventional neuroleptics are still prescribed because scale reported, and no consistent diagnostic criteria. of their effectiveness, relatively lower cost, and con- In addition, exclusion criteria employed for reasons of [email protected] 66485438-66485457 Chapter 18 drug-Induced Movement Disorders in Children 233

TABLE 18-2 typical Neuroleptic and Atypical Antipsychotic Medications Used in Children FDA-Labeled Non–FDA- Common Adverse Indications for Labeled Events: Movement Severe Neurologic Medication Children Indications Disorders Adverse Events Typical Antipsychotics Chlorpromazine Nausea and None Akathisia Ineffective vomiting Dizziness thermoregulation Problem behavior Parkinsonism Heatstroke or Tetanus adjunct Somnolence hypothermia (rare) Tardive movement Neuroleptic malignant disorders syndrome (rare) Seizure (rare)

Fluphenazine None None As for chlorpromazine Haloperidol Tourette syndrome Delirium As for chlorpromazine Severe refractory hyperactive behavior (short-term treatment) Severe refractory problematic behavior in children Psychotic disorder Schizophrenia

Metoclopramide Intestinal diseases None Dystonia, Neuroleptic malignant somnolence syndrome Tremor

Pimozide Tourette Chronic Akathisia Ineffective syndrome schizophrenia Dizziness thermoregulation Dystonia heatstroke or Parkinsonism hypothermia (rare) Somnolence neuroleptic malignant Tardive movement syndrome (rare) disorders seizure (rare) Prochlorperazine Severe nausea and None Akathisia Ineffective vomiting Dizziness thermoregulation Schizophrenia Dystonia Heatstroke or Parkinsonism hypothermia (rare) Somnolence Neuroleptic malignant Tardive movement syndrome (rare) disorders Seizure (rare) Atypical Antipsychotics Aripiprazole Schizophrenia None Akathisia Neuroleptic Headache malignant syndrome Insomnia (rare) Somnolence seizure (rare) Olanzapine None Major depressive Impaired cognition Dyskinesia; seizure disorder Tourette syndrome Quetiapine None Delirium Dizziness (6%), Neuroleptic malignant Tourette somnolence syndrome (rare) syndrome seizure (rare) tardive dyskinesia (rare)

(Continued) [email protected] 66485438-66485457 234 Section 5 Selected Secondary Movement Disorders

TABLE 18-2 typical Neuroleptic and Atypical Antipsychotic Medications Used in Children—Cont’d

FDA-Labeled Non–FDA- Common Adverse Indications for Labeled Events: Movement Severe Neurologic Medication Children Indications Disorders Adverse Events Risperidone Bipolar disorder, Behavioral Akathisia Neuroleptic malignant schizophrenia syndrome, Parkinsonism syndrome Irritability in autism mental Somnolence Seizure retardation Tardive dyskinesia Bipolar disorder Tourette syndrome Obsessive- compulsive disorder, refractory; stuttering Tardive dyskinesia Ziprasidone None Schizo-affective Akathisia Neuroleptic malignant disorder Dizziness syndrome (rare) Tourette Somnolence Seizure syndrome Tardive dyskinesia scientific validity in controlled clinical trials can result Involuntary Movement scale (AIMS),24 but is in nonrepresentative samples.21 highly correlated with it. In the second study, researchers at the Maryland • Raters using the AIMS were trained to a high inter- Psychiatric Research Center studied 424 pediatric psy- rater reliability level of 0.80 (intraclass correlation chiatry patients over a 3-year period and reported long- coefficient). term-use neurologic complications in 118 children ages • Raters were blinded to treatment group and 5 to 18 treated for 6 or more months with typical or diagnosis. atypical antipsychotics.22 This study represents a model • The AIMS positive diagnostic threshold (cutoff for for studying risks of DIMDs and can serve as a basis for abnormal) was set based specifically on the pediatric future critical research in this area. Key features of this examination, to avoid classifying age-appropriate study may make the results more generalizable than the restlessness or involuntary movements such as tics meta-analysis of clinical trial data. as being drug induced. Randomized controlled trials are the standard for The findings of this study are extremely important. validity in assessing treatment effects. However, in this First, over 80% of the prescriptions of antipsychotics case, the clinic-based, nonrandomized, observational were for youths with no psychotic symptoms. Most study is more informative. The study methods are patients in both psychiatric groups were diagnosed with worth emphasizing: mood disorders and attention-deficit/hyperactivity dis- • The real-world, ethnically diverse patient sample. order (ADHD). Second, a total of 9% (11 of 118) The authors had a 90% capture rate of the children antipsychotic-treated children showed tardive DIMDs, in the psychiatric facilities involved. Polypharmacy, compared to none in the antipsychotic-naïve group. including exposure to multiple antipsychotics, and This risk appears to be much higher than the risk in multiple concurrent diagnoses were common. the meta-analysis of clinical trials. Third, the serious • The use of two comparator groups: 80 neurolep- tardive dyskinesias appeared to be reversible, although tic-naïve, age- and gender-matched youths with long-term follow-up is still needed. Information on psychiatric disorders and 35 healthy children with withdrawal dyskinesias also was not provided. no psychiatric disorders. Several factors appeared to affect the risk of tardive • Standardized use of a structured and validated DIMDs. The risk increased with duration of antipsy- assessment of extrapyramidal side effects, the chotic treatment, ranging from 3% at 6 to 12 months, Involuntary Movement Scale.23 This scale is to 14% at greater than 2 years. Ethnicity was also more anatomically specific than the Abnormal important, with higher risks in African-American than

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European children. For type of agent, the risk was 6% dopamine receptor blocker–related DIMDs occur more (5 of 81) for atypicals only, versus 27% (11 of 37) for commonly in children on the autistic spectrum. combined atypical and typical antipsychotics. Note that The pathophysiology of the risk for DIMDs may the real-world treatment description does not allow for have an identifiable genetic component, although at a valid estimate of relative risk of DIMDs for atypical this time most research is in adults and most promising versus typical antipsychotics. The effects of concomi- candidates have been negative or inconclusive. A study tant medications were also assessed. Over half of the of over 600 European white schizophrenics found no antipsychotic-exposed patients were treated with mood evidence that dopamine D2 receptor polymorphisms stabilizers (75%), antidepressants (75%), and psycho- influence DIMDs.37 Studies of other dopamine recep- stimulants (68%). The rates of concurrent medications tors38,39 and drug metabolizing enzymes, such as cyto- in the antipsychotic-naïve group were lower. chrome P450,40 do not demonstrate significant genetic Clinical Features prediction. Other recent studies suggest that genes involved in GABAergic pathways raise the risk for As in adults, dopamine receptor blocking agents, tardive dyskinesia.41 Based on views that susceptibility both conventional neuroleptics and the atypical to oxidative stress might be important, researchers antipsychotics, are prone to produce parkinsonism, assessed glutathione-S-transferase polymorphisms, dystonia, tics, tremor, oculogyric movements, oro- but found no association.42 Several small studies lingual and other dyskinesias, and akathisia.19,22,25 have suggested genetic polymorphisms in serotonin Symptoms may occur at any time after treatment receptors 2A or 2C increase risk for DIMDs antip- onset. Acute DIMDs, especially dystonia, oculogyric sychotic-treated adult schizophrenics.38,43 On a cellu- crises, and akathisia, are common in the first days of lar basis, mechanisms may include long term effects treatment. Chronic DIMDs may take the form of on dopamine receptor density and function, damage more subtle dystonia, tremor, and rigidity. Tardive to GABAergic striatal neurons, damage to cholinergic DIMDs include dyskinesias, stereotypies, tics, dystonia, interneurons.44 and oculogyric crises. These symptoms may also develop as withdrawal DIMDs. Development of a tardive Diagnosis orofacial lingual stereotypy has been described in an Diagnosis of an acute DIMD is usually straightforward, infant treated with metoclopramide for gastroesophageal when the dopamine receptor blocking medication has reflux.26 been prescribed as an antipsychotic or antiemetic and the Pathophysiology phenomenology is characteristic. In the case of accidental Much remains to be learned about the pathophysiology ingestion, the acute onset of an involuntary movement of DIMDs associated with dopamine receptor blocker disorder in a toddler should raise the diagnostic possibil- use and how to predict and prevent them. Effects on ity of ingestion of a dopamine receptor blocking agent. striatal dopamine receptor blockade and imbalance in Sources of possible exposure should be sought. striatum of dopamine and acetylcholine levels play a Diagnosis of a chronic or tardive DIMD in chil- role, but an individual’s vulnerability or susceptibility dren should be considered based on the phenomenol- to DIMDs remains an area of active research. ogy and time course of the movement disorder. This The susceptibility to DIMDs may relate to a diath- diagnosis can be more challenging than acute DIMDs. esis, or proneness to develop movement disorders, in Often, at the time of the first neurologic consulta- individuals with particular neurodevelopmental or psy- tion, the documentation of the pretreatment neuro- chiatric diagnoses treated with these agents. For exam- logic examination is inadequate. Phenomenologically, ple, in adults, tardive DIMDs have been reported in the diagnosis should be suspected when hypokinetic, young adults with schizophrenia for decades.27,28 In con- rigid symptoms or dystonia occur in children pre- trast, there are few reports of tardive dyskinesia in young scribed antipsychotics, because of the low prevalence adults with Tourette syndrome. It is unclear biologically of these symptoms from other causes. Stereotypies and why this might be, but it is worth noting that abnormal especially tics are less straightforward because they are involuntary movements are more prevalent in neurolep- common and tendency to tic may have been present tic-naïve adults with schizophrenia than in adults with before drug treatment. Thus, the emergence of these other psychiatric disorders.29,30 Similarly, tics, stereotyp- symptoms later in childhood may be misattributed to ies, and other movement disorders are more common medication. When a new movement disorder occurs at in children with neurodevelopmental or psychiatric the time of medication tapering or discontinuation, a disorders, including autistic spectrum disorders.31–36 withdrawal movement disorder should be considered Clinical experience with DIMDs in children shows that as a possibility. However, the differential diagnosis

[email protected] 66485438-66485457 236 Section 5 Selected Secondary Movement Disorders includes hyperkinetic movements that may have been and creatine kinase), and cognitive (confusion). masked during treatment with the dopamine receptor Treatment is emergent and may include general sup- blocker. Resuming the prior medication and dose and portive care (hydration, fever reduction) and specific reducing medications at a slower rate can help clarify interventions (withdrawing the offending medication, the diagnosis. bromocryptine, and dantrolene). Treatment Several other serious reactions including malignant hyperthermia (hyperpyrexia, muscle contractions Few rigorous studies in adults and especially in chil- due to general anesthesia) and anticholinergic or dren guide the clinician in this area. Anticholinergic sympathomimetic poisoning are in the differential. agents such as diphenhydramine and benztro- In addition, serotonin syndrome may occasionally be pine remain the mainstay of treatment for acute confused. In serotonin syndrome, described later, DIMDs caused by dopamine receptor blockade.45 rigidity is less prominent, but hyperreflexia, clonus, The alpha -adrenergic agonist clonidine, anti- 2 tremor, myoclonus, and shivering occur. cholinergics, and beta-blockers such as propranolol may be helpful for akathisia.46–48 For chronic DIMDs Associated with ADHD DIMDs that cause functionally impairing rigidity or Treatment tremor, anticholinergics are also used. In chronic and tardive DIMDs, when dyskinesias are mild, withdraw- Epidemiology of Psychostimulant Use in Children ing the offending agent may be sufficient to reverse the Like dopamine receptor blockers, the use of symptoms,19 although systematic data on this approach stimulants in children has increased markedly in the are also quite scarce.49 Ongoing collaboration with the last 20 years in the United States.1,58 Use of these prescribing psychiatrist is often needed because the agents among preschool children may also increase, mental illness or aggression may be severe. based on results of a large randomized controlled For tardive dyskinesia or dystonia, use of alpha- trial.59,60 Nonstimulant ADHD medications are also methyl-para-tyrosine (AMPT), an inhibitor of tyrosine increasingly used, including atomoxetine, a selective hydroxylase, the rate-limiting enzyme in dopamine bio- norepinephrine reuptake inhibitor marketed for synthesis, has been described.50 Reserpine, a dopamine ADHD treatment.61 depletor, is sometimes used. Clozapine is sometimes Clinical Features used as an alternate agent, due to its more selective D4 Stimulants, prescribed at reasonably appropriate doses, receptor effects. Tetrabenazine, which blocks D2 recep- rarely induce clinically significant movement disor- tors and depletes dopamine, has been recently approved ders. Methylphenidate, dextroamphetamine products, by the FDA for the treatment of chorea associated with and nonstimulants used for ADHD affect dopamine Huntington’s disease and has been used safely off-label and norepinephrine and thereby the most common for the treatment of tardive dyskinesia, as well as other DIMDs, if any occur, are hyperkinetic disorders such as hyperkinetic movement disorders, including tics.51,52 tics, stereotypies, or chorea. The prevalence of DIMDs Depression is often noted as a side effect.53,54 Vitamin with stimulants is higher in children with obsessive- E has been studied more extensively, but appears to be compulsive disorder (OCD) or autism spectrum disor- no better than placebo in improving tardive dyskinesia. ders (ASDs),62 or mild features of these disorders. Such It may reduce neurologic deterioration if neuroleptic children may experience new or increased repetitive treatment is continued.55 Calcium channel blockers are behaviors, including tics, compulsions, or repetitive not currently considered effective.56 picking behaviors. They may also become hyperfo- Neuroleptic Malignant Syndrome cused or have personality changes parents describe as a An additional severe, and potentially life-threatening, “zombie” or “robot” effect. DIMD is neuroleptic malignant syndrome (NMS), A major clinical issue is the possibility of induction although it is rare in children.57 This most commonly or exacerbation of tics. The concern about induction occurs after initiation or dose increases, has been of tics on stimulant medication was based on clini- mainly described after taking antipsychotics (including cian observations and case reports from over 25 years the atypicals), but occasionally has been reported after ago.63 FDA-mandated labeling in the United States other psychiatric medications. NMS can also occur as since those reports includes the advisory that stimulant a withdrawal phenomenon after chronic dopaminer- medications are contraindicated in individuals with gic therapy. The main manifestations are autonomic Tourette syndrome or any family history of tics. This (fever, tachycardia/tachypnea, diaphoresis), motoric warning has been largely discarded by experienced cli- (rigidity/bradykinesia with elevated rhabdomyolysis nicians and the Tourette Syndrome Medical Advisory

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Board.64 Rigorous randomized controlled trials support prevalence of these movement disorders is increased in that stimulants reduce ADHD symptoms for most children with a wide variety of neurologic, developmen- children, irrespective of the presence of a tic disorder, tal, and psychiatric diagnoses.34,35,77–79 A genetic influ- and that worsening of tics is uncommon, usually tran- ence has been suggested through genotyping data from sient, usually mild, and always reversible. In the case of the Preschool ADHD Treatment Study (PATS). In that new tics after starting stimulants, research suggests that study, 183 preschoolers were treated with methylpheni- in most cases tics would have occurred eventually, even date at several doses or placebo. Several modestly statis- in the absence of any psychostimulant treatment.65–67 tically significant associations were identified, including The most rigorous clinical assessment of the relation- polymorphisms in synaptosomal-associated protein 25 ship between stimulants and tics is the Treatment of (SNAP25) associated with tics, buccal-lingual move- ADHD in Children with Tics (TACT) study.68 In ments, and irritability and variants of dopamine recep- that study, children with comorbid tics and ADHD tor 4 (DRD4) associated with picking.80 were randomized to treatment with methylphenidate, Diagnosis clonidine, both, or double placebo. Tics improved by study’s end in all treated groups, compared to placebo. The diagnosis of a DIMD in a child treated for ADHD That is, even the group treated with methylphenidate should be suspected if the movements have the typical alone had improved tics, compared to placebo. Even hyperkinetic phenomenology and the onset is within in cases where tics consistently worsen on stimulant a week or two of treatment onset or a dose increase. medication, some individuals and families choose to Stimulants are short acting and readily discontinued or continue stimulant medication if the benefits warrant. restarted, allowing for a plan of stopping and restarting Atomoxetine has been reported in a few cases to medications to clarify cause and effect. 69 apparently induce tics. However, in a randomized, Treatment placebo-controlled trial of atomoxetine treatment for There are few helpful studies in this regard. It is most ADHD in 148 children with tics, atomoxetine tended to often not necessary to discontinue stimulants when mild reduce tic severity.70 Other dyskinesias and tremor have tics emerge. If the stimulant dose exceeds 1 mg/kg/day, been reported with atomoxetine, but this occurred in it is generally beneficial to reduce the dose, which also the context of rapid dose changes and polypharmacy.71 often helps with appetite and sleep along with reduc- Pathophysiology ing tics or tremor. In cases where stimulants do induce tics, stereotypies, and DIMDs Associated with Other chorea, there may be some pre-existing susceptibility in Medications individuals due to dopaminergic action in fronto-striatal circuits that ordinarily produce and regulate vol- Serotonin Reuptake Inhibitors untary movements. Although dopamine receptors in Selective serotonin reuptake inhibitors (SSRIs) are the striatum have been considered the likely anatomic widely prescribed in children with mood disorders origin for these DIMDs, dopamine receptors in cortex and OCD. This class of medication is generally at least may also influence hyperkinetic movement disorders.72 somewhat effective alone or combined with cognitive The net effects of both stimulants and norepinephrine behavioral therapy. Serotonin syndrome due to excess reuptake inhibitors on motor cortex can reduce inhibi- SSRI exposure involves neuromuscular excitation (man- tory interneuronal function,73 and this effect can vary ifest by clonus, hyperreflexia, myoclonus, tremor, shiv- related to both genetic factors and by presence of a tic ering), autonomic stimulation (hyperthermia, diarrhea, disorder phenotype.74 tachycardia, diaphoresis, tremor, flushing) and changed The susceptibility to DIMDs may relate to a diathesis, mental state (anxiety, agitation, confusion).81 The full or proneness to develop movement disorders, in individ- syndrome is rare in children. More commonly, treat- uals with neurodevelopmental or psychiatric diagnoses ment with an SSRI results in a mild degree of hyperre- treated with these agents. In the absence of known diath- flexia and tremor. The development of hyperreflexia on esis, there may still be a subtle predisposition to develop an SSRI is an indication that toxicity is more likely if the hyperkinetic movements during ADHD treatment. dose is increased. Such patients bear close clinical obser- Overflow and choreiform movements and other sub- vation. Physicians who are unaware of the SSRI-induced tle neurologic signs are found in children with ADHD tremor and hyperreflexia may order unnecessary brain or more than in typical children.75,76 Stereotypies and tics, spine magnetic resonance imaging (MRI) scans. seen in autism and Tourette syndrome, may be more In some cases, more significant problems with general markers of perturbed neurodevelopment, as the tremor or an exacerbation of tics may occur. In a few

[email protected] 66485438-66485457 238 Section 5 Selected Secondary Movement Disorders cases, what appears to be an exacerbation of tics is actu- a sensory ataxia, along with dysarthria and tremor.94 ally myoclonus. The myoclonus, in distinction to tics, Aggressive therapies such as autologous bone marrow is involuntary and does not diminish during voluntary rescue may be associated with acute neurologic symp- movements to the same degree that tics do. This is gen- toms such as headaches, confusion, and seizures, but erally an indication to reduce or eliminate the SSRI. may also be associated with tremor, ataxia, dysarthria, Most cases of SSRI-induced movement disorders and parkinsonism.94 are reported in adults,82 although a few pediatric cases have also been described.83,84 Treatment is reduction or Conclusion elimination of the medication. In some cases, cognitive 85 Children are vulnerable to the development of acute, behavioral therapies are an effective alternative. chronic, tardive, and withdrawal DIMDs. Factors Antiseizure Medications influencing vulnerability remain largely unknown. Antiseizure medications are used to prevent seizures Clinicians need to be aware of spectrum, time course, and migraines, and are increasingly prescribed to stabi- and treatment strategies for DIMDs in children. lize mood and reduce aggression. Numerous case reports describe acute and chronic REFERENCES DIMDs in children caused by antiseizure medications. The most common clinical features are acute 1. Cox ER, Motheral BR, Henderson RR, Mager D: Geographic variation in the prevalence of stimulant ataxia and nystagmus. Phenytoin and carbamazepine medication use among children 5 to 14 years old: results are most commonly identified. 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75. Denckla MB, Rudel RG: Anomalies of motor development combination for children and adolescents with obses- in hyperactive boys, Ann Neurol 3(3):231–233, 1978. sive-compulsive disorder: the Pediatric OCD Treatment 76. Mostofsky SH, Newschaffer CJ, Denckla MB: Overflow Study (POTS) randomized controlled trial, JAMA movements predict impaired response inhibition in 292(16):1969–1976, 2004. children with ADHD, Percept Motor Skills 97(3 pt 2): 86. Murphy JM, Motiwala R, Devinsky O: Phenytoin intox- 1315–1331, 2003. ication, South Med J 84(10):1199–1204, 1991. 77. Bodfish JW, Newell KM, Sprague RL, et al: Dyskinetic 87. Orth M, Amann B, Ratnaraj N, et al: Caffeine has no effect movement disorder among adults with mental retarda- on measures of cortical excitability, Clin Neurophysiol tion: phenomenology and co-occurrence with stereotypy, 116(2):308–314, 2005. Am J Ment Retard 101(2):118–129, 1996. 88. Chalhub EG, Devivo DC, Volpe JJ: Phenytoin- 78. Eapen V, Robertson MM, Zeitlin H, Kurlan R: Gilles de la induced dystonia and choreoathetosis in two retarded Tourette’s syndrome in special education schools: a United epileptic children, Neurology 26(5):494–498, 1976. Kingdom study, J Neurol 244(6):378–382, 1997. 89. Koukkari MW, Vanefsky MA, Steinberg GK, Hahn 79. Mahone EM, Bridges D, Prahme C, Singer HS: Repetitive JS: Phenytoin-related chorea in children with deep arm and hand movements (complex motor stereotypies) hemispheric vascular malformations, J Child Neurol in children, J Pediatr 145(3):391–395, 2004. 11(6):490–491, 1996. 80. McGough J, McCracken J, Swanson J, et al: Pharma 90. Lancman ME, Asconape JJ, Penry JK: Choreiform move- cogenetics of methylphenidate response in preschoolers ments associated with the use of valproate, Arch Neurol with ADHD, J Am Acad Child Adolesc Psychiatry 51(7):702–704, 1994. 45(11):1314–1322, 2006. 91. Weaver DF, Camfield P, Fraser A: Massive carbamazepine 81. Boyer EW, Shannon M: The serotonin syndrome, N Engl overdose: clinical and pharmacologic observations in five J Med 352(11):1112–1120, 2005. episodes, Neurology 38(5):755–759, 1988. 82. McKeon A, Pittock SJ, Glass GA, et al: Whole-body 92. Ma SdM, Rho JM, Murphy P, Cheyette S: Lamotrigine- tremulousness: isolated generalized polymyoclonus, induced tic disorder: report of five pediatric cases, Epilepsia Arch Neurol 64(9):1318–1322, 2007. 41(7):862–867, 2000. 83. Sokolski KN, Chicz-Demet A, Demet EM: Selective sero- 93. Giles LL, Delbello MP, Gilbert DL, et al: Cerebellar tonin reuptake inhibitor–related extrapyramidal symp- ataxia in youth at risk for bipolar disorder, Bipolar Disord toms in autistic children: a case series [see comment], 10(6):733–737, 2008. J Child Adolesc Psychopharmacol 14(1):143–147, 2004. 94. Kramer ED, Packer RJ, Ginsberg J, et al: Acute 84. Spirko BA, Wiley JF 2nd: Serotonin syndrome: a neurologic dysfunction associated with high-dose che- new pediatric intoxication, Pediatr Emerg Care 15(6): motherapy and autologous bone marrow rescue for 440–443, 1999. primary malignant brain tumors, Pediatr Neurosurg 85. Pediatric OCD Treatment Study (POTS) Team: 27(5):230–237, 1997. Cognitive-behavior therapy, sertraline, and their

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Introduction Common psychogenic movement disorders (PMDs) include dystonia, tremor, myoclonus, tics, A common problem in neurology is the existence of hemiballismus, chorea, parkinsonism, and gait disor- disorders that cause neurologic symptoms, but do not ders. Although there are few data on these disorders have an identifiable neurologic basis. Many differ- in children, it has been estimated that 2% to 4% of ent terms have been used to describe these disorders, children treated at movement disorder clinics have a including “hysterical, functional, conversion disorder, PMD.8–10 Conversion disorder has been reported in and psychogenic.”1 These terms reflect the concept that children as young as 4 years, but most often occurs an organic basis will not be found for the symptoms or during the peripubertal years.2,7 For PMDs in children, that a psychiatric disorder is the primary substrate from the average age of onset is 12 to 14 years, with a range Owhich the atypical symptoms blossom. of 7 to 18 years.8–10 No children under age 7 years were The concept of hysteria has been present in Western reported in those three series. PMDs affect girls more medicine for over 2000 years. Briquet in the 1850s and than boys in a 3:1 to 4:1 ratio.8–10 One report indicated Charcot in the 1880s are generally recognized for their a 1:1 ratio of boys to girls in children 12 years of age early work on disorders on the border between neurol- or younger.9 ogy and psychiatry and guiding them into modern medicine.2 The term conversion was first used by Breuer and Freud to describe the transformation of unresolved psy- Clinical Features of Psychogenic chologic conflicts and unassimilated emotions into physi- Movement Disorders 2 cal manifestations. Conversion disorders fall under the In adults, the nondominant side of the body is more broader heading of somatoform disorders in the American commonly affected, leading to theories of symptom Psychiatric Association’s Diagnostic and Statistical Manual origins in the right cerebral hemisphere.2 However, in 3 of Mental Disorders, Fourth Edition, Text Revision. children the dominant extremities are more likely to Diagnostic criteria for conversion disorder involve symp- be involved. It has been speculated that this difference toms affecting voluntary motor or sensory functions sug- may be due to incomplete hemispheric lateralization gesting a neurologic condition that are judged to be caused in children.11 Regardless of underlying mechanism, the by psychological factors. These symptoms cause impaired preferential involvement of the dominant extremities is function, are not intentionally produced, and cannot be a consistent finding in children with PMDs.9,10 3 explained after a thorough medical evaluation. The typical course of conversion symptoms in children is for the symptoms to resolve within 3 months from the time of diagnosis.12 The great majority of chil- Epidemiology dren have complete resolution of symptoms and recur- The first U.S. description of conversion disorder in chil- rence of symptoms appears to be rare.13,14 Outcome dren consisted of 98 cases.4 Despite continued study, of PMDs specifically has not been studied; long-term few data exist to estimate the population prevalence of outcome is good in the majority of cases,10,15 but may conversion disorder in children in the United States. be less good than for childhood conversion disorders Prevalence of conversion disorder among children has more generally.10 However, these reports from specialty been estimated at 2 to 4 per 100,000.5 Conversion dis- clinics may reflect an ascertainment bias. order is a relatively common reason for presentation to It is often possible to identify a specific precipi- movement disorders clinics. Among adults, estimates tant for the conversion symptoms in children.13 In a vary from 2% to 9% of patients.6,7 study of 47 Israeli children with conversion disorder, 242 [email protected] 66485438-66485457 Chapter 19 Psychogenic Movement Disorders 243

a specific reason for the conversion was discovered BOX 19-1 Useful Clues for Diagnosing in 40.16 Among children with PMD, antecedent his- Psychogenic Movement Disorders in Children tory of physical or emotional stressors is common, being reported in 53% to 69% of cases.9,10,15 Children Historical Clues 1.O Abrupt onset with PMD commonly have coexisting impairment of 2. Static course mood, especially anxiety, depressed mood, or irritabil- 3. Spontaneous remission or inconsistency over ity,9,10 and “perfectionistic” tendencies are common.9,13 time 4. Remission when the child is not aware of being Pathophysiology observed O 5. Presence of secondary gain There is emerging evidence that conversion disorders Clinical Clues have a basis in altered brain function. One of the first 1. Inconsistent character of the movement studies to demonstrate this was a single-photon emis- (amplitude, frequency, distribution, selective sion computed tomography (SPECT) study showing disability) 2. Paroxysmal movement disorder decreased regional cerebral blood flow in the thalamus 3. Movements increase with attention to the and basal ganglia contralateral to psychogenic senso- movement, or decrease with distraction rimotor deficits in adults.17 An important finding of 4. Ability to trigger or relieve the abnormal that study was that the contralateral basal ganglia and movements with unusual or nonphysiologic thalamic hypoactivation resolved after recovery. In adult interventions (e.g., body trigger points) 5. False weakness or sensory findings subjects with conversion hemiparesis, cerebral blood 6. Deliberate slowness of movements flow responses in a motor imagery task were abnor- 7. Entrainment mally increased in the ventromedial prefrontal cortex 8. Functional disability out of proportion to and superior temporal cortex despite normal task per- examination findings formance.18 These studies and several other small stud- Therapeutic Responses ies using electroencephalogram (EEG), functional 1. Unresponsiveness to appropriate medications magnetic resonance imaging (fMRI), positron emis- 2. Response to placebos sion tomography (PET), or SPECT have suggested 3. Remission with psychotherapy that conversion disorders are associated with abnormal modulation of motor and sensory representations by Certain features appear to be consistent across the affective or stress-related factors.19 To date, physiologic range of patients with PMD7,21 (Box 19-1). These clues or imaging studies have directly investigated PMDs and to making the diagnosis of a PMD may be present in no studies have included children. Nonetheless, these the history, in the physical examination, or in thera- data can be taken as strong evidence for a neurobio- peutic trials. Although suggestive of a PMD, presence logic basis for conversion disorders including PMDs. of these features alone does not confirm the diagnosis. Some of these features may be present in organic move- Diagnosis ment disorders, so care and further evidence is required At first glance, some organic movement disorders for diagnosis.7 may appear to be psychogenic in origin. Historically, A thorough medical history including family his- many physicians believed that Tourette syndrome and tory, physical examination, and in some cases diag- task-specific focal dystonias, such as writer’s cramp, nostic testing is necessary to arrive at a confirmed were “hysterical.” Some movements related to organic diagnosis of a psychogenic movement disorder. movement disorders can be suppressed, including tics, Conversion disorders and organic neurologic disease tardive dyskinesia, parkinsonian rest tremor, and some can coexist, most commonly in chronic relapsing dis- choreas. Hemiballismus, brought on by brain injury or eases such as epilepsy. However, fewer than 10% of stroke, can begin precipitously and follow a static or children diagnosed with conversion disorder have a diminishing course. Organic paroxysmal dyskinesias, preexisting physical disease.16 In adults, once a diag- by definition, occur and remit abruptly, and may be nosis of a functional, non-organic neurological dis- misdiagnosed as psychogenic. Rapid-onset dystonia order is made, new organic diagnoses rarely emerge, parkinsonism may have abrupt onset and reach a stable even when symptoms persist. A recent study in over severe plateau within days.20 Psychiatric dysfunction 1000 adults judged by neurologists as having symp- may be the initial presentation for diseases containing toms “unexplained by organic disease” found fewer abnormal movements, such as Huntington’s disease than 1% had acquired a new organic disease diagnosis and Wilson’s disease. 18 months later.35

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Diagnostic Criteria for Psychogenic disorder, but without the additional evidence required Movement Disorders for clinically established PMD. Many physicians are reluctant to make the diagnosis Possible PMD of a conversion disorder. This also appears to be true This least stringent category consists of abnormal of PMDs. The average time from onset of symptoms movements that are consistent with the classic defi- to diagnosis has been reported to range from several nition of an organic movement disorder, but that are days to as long as 21 years.9,10,15 Accurate diagnosis accompanied by an obvious psychiatric disturbance. is crucial since children may undergo invasive test- It must be remembered that psychiatric symptoms ing and surgical procedures before diagnosis. In one commonly accompany some organic movement dis- series, 22% of children underwent unnecessary sur- orders, such as Sydenham chorea, Huntington’s dis- gery before accurate diagnosis for symptoms related ease, Wilson’s disease, and Tourette syndrome. In other to the PMD.9 cases, psychiatric symptoms may be secondary to hav- Fahn and Williams22 have described criteria to cate- ing a prominent or disabling illness. Thus this category gorize the degree of diagnostic uncertainty with regard has limited usefulness. to dystonia, but this classification system can be applied to all psychogenic disorders. Among the assumptions Aids in Diagnosing Psychogenic underlying these criteria is that spontaneous remission of dystonia of organic etiology is uncommon. In other Movement Disorders movement disorders, such as chorea, tremor, or ataxia, Testing beyond the scope of the neurologic exam- spontaneous remission can occur, making diagnosis of ination can occasionally be helpful in support- a PMD by the following criteria less secure. These cri- ing a diagnosis of PMDs. Suggestion and placebo teria have not been validated in children nor are they challenge have been used by physicians to obtain necessarily useful in clinical practice. a clearer picture of a patient’s symptoms, and can help distinguish organic from psychogenic dis- Documented PMD ease. Placebos, including intravenous (IV) injections This most stringent category requires that the and mild skin irritants, are controversial because of abnormal movement be persistently relieved through the possibility of disturbing the trust implicit in the psychotherapy with or without psychotropic medi- doctor-patient relationship. They are even more con- cations. Adjunctive therapies include use of placebos troversial in young children because of informed and psychologic suggestion; however, placebo response consent concerns. However, in select circumstances has not been studied in children and placebo trials they may play a role in diagnosis and treatment when may not be reliable. Definitive diagnosis can also be used in a supportive environment as part of a compre- made if psychiatric intervention is refused or nonthera- hensive treatment plan and when the use of placebo is 22 peutic, but the patient is noted to have symptomatic fully disclosed in the course of the evaluation. improvement when unaware of observation. Diagnosis of certain PMDs may be aided by electrophysiologic studies although many movement Clinically Established PMD disorder specialists with access to neurophysiological studies rarely use them.36 Differentiation of psy- This category requires inconsistency of symptoms over chogenic jerks from myoclonus or tics may be done time or incongruence with the classic clinical presen- through electromyography (EMG). EMG bursts less tation of an organic movement disorder. It should be than 70 ms in duration are most likely organic in noted that some organic movement disorders have fluc- nature. Longer bursts with a well-organized tripha- tuation of symptom severity over time (e.g., Sydenham sic pattern of activation of opposing muscle groups chorea) and others, such as tic disorders, have a chang- may represent psychogenic or volitional movements. ing phenotype over time. Thus additional evidence in Combined application of EEG and EMG provides a the form of other physical signs that are definitely psy- more sensitive test. The poststimulus latency of reflex chogenic, multiple somatizations, or obvious psychiat- or stimulus-sensitive myoclonus can be examined. ric disturbance is necessary for this diagnosis. Latencies greater than 100 ms from the stimulus to the onset of movement suggest that the movement is Probable PMD voluntary.23 This category is defined as movements that are incon- Tremor occurring at different frequencies in differ- sistent or incongruent with a classic organic movement ent muscle groups usually indicates an organic etiology.

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Frequency variability can be seen in psychogenic in young women, these disorders occurred as painful tremor, but there is enough overlap between organic dystonias inconsistent with established organic dysto- and nonorganic tremor frequency variation to pre- nias and had associated nonanatomic sensory changes vent diagnosis based on frequency variability alone.24,25 and false weakness.29 Simultaneous activity in agonists and antagonists has As noted, organic dystonia can be misdiagnosed as been associated with psychogenic tremor. Tremors psychogenic. Misdiagnosis is most likely due to the faster than 11 Hz are likely beyond the upper fre- varied presentation and protean findings in dystonia. quency limit of voluntary tremor, and are likely of Clinical features that may appear psychogenic but are organic etiology.23 Entrainment of tremor with volun- organic include varied movements (writhing, jerking, tary rapid alternative movements of different frequen- spasms, and tremors), spontaneous remission, task-spec- cies supports the diagnosis of psychogenic tremor. ificity or action induction, normal neurologic examination, relief through geste antagoniste (sensory trick), Specific Movement Disorder worsening with increased stress and relief by relaxation, Types in Psychogenic Movement and paroxysmal appearance or diurnal variation.22 In Disorders addition, dystonias of sudden onset and remission can occur with medication ingestion, particularly dop- The most commonly reported movement disorders amine blocking agents such as phenothiazines. among children with PMD are tremor (26% to 65%), dystonia (34% to 47%), myoclonus (4% to 37%), Myoclonus 8–10 and gait disorders (13% to 30%). In two series, tics In a report of 18 cases of psychogenic myoclonus, 15,37 were reported as a common manifestation of PMD. movements were predominantly segmental in char- These relative proportions are comparable to what has acter, occurred at rest, and were often exacerbated 26,27 been reported in adults with PMDs. by voluntary movement. The psychogenic nature of Tremor these cases was suggested by “the inconsistent character of the movements, associated psychiatric symp- In a report of 24 adolescent and adult patients with tomatology, reduction in myoclonus with distraction, clinically established or documented psychogenic exacerbation and relief with placebo and sugges- tremor, subjects ranged in age from 15 to 78 years with tion, spontaneous periods of remission, acute onset 28 15 women and 9 men. Variability in tremor char- and sudden resolution, and evidence of underlying acteristics (e.g., tremor direction) was seen in greater psychopathology.”30 than 90% of patients and variable tremor amplitude and frequency was observed in all patients. Unusual characteristics of these tremors included abrupt onset, Treatment and Outcome bilateral involvement, distractibility, and a nonprogres- For patients with mild symptoms, a clear diagno- sive course with fluctuating severity.25 These psychosis given in a non-judgmental manner, in a way that genic tremors often consisted of resting, postural, and makes sense, and reassurance may be sufficient.36,38 As kinetic components and were associated with selective, for more significant symptoms, a multi-discplinary but not task-specific, disabilities. Neurologic exami- approach with an ongoing alliance between the neurol- nation often revealed other inconsistencies, and drug ogist and the patient is an important component of the treatment was usually ineffective. Children with psy- treatment process. Insight into the psychologic roots chogenic tremor may be more likely to be diagnosed of the conversion disorder may necessitate the involve- with a PMD based on clinical grounds and without ment of a psychiatrist or psychologist.31 Some patients, extensive laboratory or imaging investigations.9 their families, or other physicians may be resistant to the idea of a psychiatric or psychologic consultation. In Dystonia that case, it is often helpful to emphasize the neurobi- Fahn and Williams22 defined the features of psycho- ology of the disorder. It may be helpful to recommend genic dystonia in 39 patients, who were mostly female, that evaluation of the disorder should occur from dif- had symptoms lasting between 1 month and 15 years, ferent specialties simultaneously.22 Identification of the and ranged in age between 8 and 56 years old. Eighty- precipitating stressor, which may include psychological five percent of these patients had movements that were conflict, environmental stress, or trauma, and perpetu- incongruous or inconsistent with those of dystonia, ating factors is essential to guide treatment strategy.32 but most had other clues including false weakness, Physical therapy and positive reinforcement to pain, and multiple somatizations.7 Occurring mostly psychotherapy appear to reduce or abolish symptoms

[email protected] 66485438-66485457 246 section 5 selected secondary movement disorders in many cases. As discussed earlier, placebo testing REFERENCES may have a role in both diagnosis and treatment of symptoms, but it must be used in a supportive set- 1. Marjama J, Troster A, Koller W: Psychogenic movement ting. Anxiolytics and antidepressant medications disorders, Neurol Clin 13:283–297, 1995. may prove useful if mood disorders appear to be play- 2. Putnam F: Conversion symptoms. In Joseph A, Young R, editors: Movement disorders in neurology and neuropsychi- ing a primary role in the etiology of the abnormal 1 atry, Boston, 1992, Blackwell Scientific. movements. Biofeedback via EMG may be useful 3. American Psychiatric Association: Diagnostic and statisti- 32 in some cases. cal manual of mental disorders, Washington, DC, 2000, Characteristics of patients with better progno- American Psychiatric Association. sis include “acute onset, short duration of symp- 4. Sheffield HB: A contribution to the study of hysteria in toms, healthy premorbid functioning, absence of childhood as it occurs in the United States of America, coexisting organic psychopathology, and presence of N Y State J Med 68:412–436, 1898. an identifiable stressor.”1 Symptom duration of less 5. Kozlowska K, Nunn KP, Rose D, et al: Conversion dis- than 2 weeks was strongly correlated with a good order in Australian pediatric practice, J Am Acad Child outcome in psychogenic disorders.6 Of patients who Adolesc Psychiatry 46:68–75, 2007. had symptomatic improvement while in the hospi- 6. Lempert T, Dietrich M, Huppert D, Brandt T: Psychogenic disorders in neurology: frequency and clin- tal, 96% had good long-term outcome.33 Conversion ical spectrum, Acta Neurol Scand 82:335–340, 1990. symptoms following mechanical trauma may have a 7. Williams D, Ford B, Fahn S: Phenomenology and psy- better prognosis than those arising from severe emo- chopathology related to psychogenic movement disor- tional trauma. It has been postulated that mechanical ders, Adv Neurol 65:231–257, 1995. trauma may provoke a simple shock reaction, whereas 8. Fernandez-Alvarez E: Movement disorders of functional emotional trauma is more likely to elicit psychologi- origin (psychogenic) in children, Rev Neurol 40(Suppl cal defenses.34 1):S75–S77, 2005. 9. Ferrara J, Jankovic J: Psychogenic movement disorders in Conclusion children, Mov Disord 23:1875–1881, 2008. 10. Schwingenschuh P, Pont-Sunyer C, Surtees R, et al: Psychogenic movement disorders are an important Psychogenic movement disorders in children: a report form of conversion disorder that may cause substan- of 15 cases and a review of the literature, Mov Disord tial morbidity and are associated with a risk of unnec- 23:1882–1888, 2008. essary procedures. Their incidence in movement 11. Regan J, LaBarbera J: Lateralization of conversion disorder clinics has gradually been increasing as neu- symptoms in children and adolescents, Am J Psychiatr rologists recognize typical movement disorders and 141:1279–1280, 1984. refer the more atypical disorders, many of which are 12. Fritz G, Fritsch S, Hagino O: Somatoform disorders in PMDs, to specialists. They may be difficult to distin- children and adolescents: a review in the past 10 years, guish from organic neurologic conditions, but with a J Am Acad Child Adolesc Psychiatry 36:1329–1338, 1997. 13. Grattan-Smith P, Fairley M, Procopis P: Clinical features of careful history and neurologic examination in addi- conversion disorder, Arch Dis Child 63:408–414, 1988. tion to knowledge of diagnostic clues, a firm diagnosis 14. Turgay A: Treatment outcome for children and adole can be made. The diagnosis should not be based on scents with conversion disorder, Can J Psychiatry 35: merely excluding organic causes, but on specific diag- 585–589, 1990. nostic criteria. There have been relatively few series of 15. Ahmed MA, Martinez A, Yee A, et al: Psychogenic and children with psychogenic movements, but those that organic movement disorders in children, Dev Med Child do exist are relatively consistent across studies. Clearly, Neurol 50:300–304, 2008. differences between adults and children with PMDs 16. Zeharia A, Mukamel M, Carel C, et al: Conversion reac- exist; however, many elements are similar. Treatment tion: management by the paediatrician, Eur J Pediatr of conversion disorders, such as PMDs, often requires 158:160–164, 1999. a multifaceted approach, including behavioral, psy- 17. Vuilleumier P, Chicherio C, Assal F, et al: Functional neuroanatomical correlates of hysterical sensorimotor chological, physical, and pharmacologic therapies. loss, Brain 124:1077–1090, 2001. Children with acute onset and short duration of dis- 18. de Lange FP, Roelofs K, Toni I: Increased self-monitor- ease appear to have the best prognosis for recovery. ing during imagined movements in conversion paralysis, Acceptance of the diagnosis by the child and family is Neuropsychologia 45:2051–2058, 2007. probably important. An ongoing relationship with the 19. Vuilleumier P: Hysterical conversion and brain function, neurologist is important. Prog Brain Res 150:309–329, 2005.

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20. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al: In Hallett M, et al: Psychogenic movement disorders: The phenotypic spectrum of rapid-onset dystonia-par- neurology and neuropsychiatry, Philadelphia, 2006, AAN kinsonism (RDP) and mutations in the ATP1A3 gene, Enterprises and Lippincott Williams & Wilkins. Brain 130:828–835, 2007. 32. Ford C: Conversion disorder and somatoform disorder 21. Schrag A, Lang AE: Psychogenic movement disorders, not otherwise specified. In Gabbard G, editor: Treatment Curr Opin Neurol 18:399–404, 2005. of psychiatric disorders, Washington, DC, 1984, American 22. Fahn S, Williams D: Psychogenic dystonia, Adv Neurol Psychiatric Publishing. 50:431–455, 1988. 33. Couprie W, Wijdicks EFM, Roojmans HGM, vanGijn J: 23. Brown P, Thompson P: Electrophysiological aids to the Outcome in conversion disorder: a follow up study, diagnosis of psychogenic jerks, spasms, and tremor, Mov J Neurol Neurosurg Psychiatry 58:750–752, 1995. Disord 16:595–599, 2001. 34. Krull F, Schifferdecker M: Inpatient treatment of con- 24. McAuley JH, Rothwell JC, Marsden CD, Findley LJ: version disorder: a clinical investigation of outcome, Electrophysiological aids in distinguishing organic from Psychother Psychosom 53:161–165, 1990. psychogenic tremor, Neurology 50:1882–1884, 1998. 35. Stone J, Carson A, Duncan R, et al: Symptoms ‘unex- 25. Kenney C, Diamond A, Mejia N, et al: Distinguishing plained by organic disease’ in 1144 new neurology psychogenic and essential tremor, J Neurol Sci 263: out-patients: how often does the diagnosis change at fol- 94–99, 2007. low-up?, Brain EPUB 2009. 26. Factor S, Podskalny G, Molho E: Psychogenic movement 36. Espay AJ, Goldenhar LM, Voon V, et al: Opinions and disorders: frequency, clinical profile, and characteristics, clinical practices related to diagnosing and manag- J Neurol Neurosurg Psychiatry 59:406–412, 1995. ing patients with psychogenic movement disorders: 27. Thomas M, Vuong KD, Jankovic J: Long-term prog- An international survey of movement disorder society nosis of patients with psychogenic movement disorders, members, Mov Disord 24:1366–1374, 2009. Parkinsonism Relat Disord 12:382–387, 2006. 37. Gilbert DL, Isaacs KM: Phenomenology and clinical 28. Koller W, Lang AE, Vetere-Overfield B, et al: Psychogenic characteristics of pediatric patients diagnosed with a tremors, Neurology 39:1094–1099, 1989. psychogenic movement disorder. Presented at the Second 29. Lang AE: Psychogenic dystonia: a review of 18 cases, International Conference on Psychogenic Movement Can J Neurol Sci 22:136–143, 1995. Disorders and Other Conversion Disorders, Washington 30. Monday K, Jankovic J: Psychogenic myoclonus, DC, April 245:2–4, 2009. Neurology 43:349–352, 1993. 38. Stone J, Carson A, Sharpe M: Functional symptoms in 31. Jankovic J, Cloninger CR, Fahn S, et al: Therapeutic neurology: management, J Neurol Neurosurg Psychiatry approaches to psychogenic movement disorders. Mar 2005; 76 Suppl 1:i13-21.

[email protected] 66485438-66485457 [email protected] 66485438-66485457 Drug Appendix O A O Acetazolamide Dosages in small double-blind, placebo-controlled trials in adults range from 200–400 mg/day typically Actions: A weak diuretic and carbonic anhydrase administered in 100 mg increments. A liquid formula- inhibitor. tion (50 mg/5 mL) is available. Standard dose: Initial dose of 125–250 mg/day, Contraindications: Hypersensitivity. Use with with gradual titration as tolerated. Daily doses may caution in patients with congestive heart failure. Since range from 1000–2000 mg/day divided into two to cleared by the kidneys, renal insufficiency will increase four daily doses. the risk of side effects. Relative contraindications Contraindications: Hyponatremia, hyopokalemia, include dementia, psychosis, enlarged prostate, neuro- O a history of allergy to sulfa drugs (a sulfonamide deriva- genic bladder, and glaucoma. tive), and significant renal or hepatic dysfunction. Main drug interactions: Concurrent use with other Main drug interactions: Increases the serum levels anticholinergic medications may augment anticholin- of primidone, pseudoephedrine, quinidine, and lith- ergic side effects. Caution is advised when coadminis- ium. Increased risk of nephrolithiasis, especially when tered with central nervous system (CNS) stimulants. used in combination with topiramate. Main side effects: Primarily anticholinergic-type Main side effects: Drowsiness, dizziness, fatigue, side effects, including dry mouth, nose, and throat, paresthesias of extremities and face, tinnitus, taste blurred vision, nausea, light-headedness, urinary fre- changes, polyuria, muscle weakness, delirium, anorexia, quency or retention, constipation, sedation, disturbed nausea, vomiting, and diarrhea. Less common but sleep, memory difficulties, confusion, psychosis, pedal potentially serious side effects include metabolic aci- edema, and livido reticularis. Abrupt withdrawal can dosis, electrolyte imbalance, nephrolithiasis, hepato- lead to delirium. toxicity, Stevens-Johnson syndrome, bone marrow Special points: Effective in treating symptoms of suppression, and hypersensitivity reactions. early stages of Parkinson’s disease and may be effective for Special points: Successful in controlling paroxys- treating levodopa-induced dyskinesias. Refractoriness mal conditions such as periodic paralysis, ataxia and to therapy may develop, but can be restored after a brief vertigo in episodic ataxia types 1 and 2 and in spinocer- drug holiday. The dose should be tapered over weeks to ebellar ataxia type 6 with episodic features. Treatment avoid inducing a neuroleptic malignant syndrome, seen of paroxysmal dyskinesias has been less beneficial and with abrupt withdrawal. Limited studies exist assess- only a few case reports suggest that it may be helpful ing its efficacy in the treatment of movement disorders in action myoclonus. Obtaining a renal ultrasound has (chorea) in the pediatric population. been suggested when patients take acetazolamide for longer than 6 months. Aripiprazole

Amantadine Actions: Functions as a partial agonist at the D2 and 5-HT1A receptors, and as an antagonist at the Actions: An antiviral agent that modestly increases 5-HT2A receptor. dopamine release, inhibits dopamine reuptake, has Standard dose: 10 years and older: start 2 mg every N-methyl-d-aspartate receptor antagonist properties, day for 3 days, then if needed 5 mg once a day. Titrate and possibly central anticholinergic effects. in 5 mg intervals with typical dose of 10–30 mg/day. Standard dose: Children should receive about half Contraindication: Hypersensitivity. the adult dose and increasing more slowly, e.g., starting Drug interactions: Benzodiazepines increase risk with 50 mg/day and increasing to 50 mg twice a day for orthostatic hypertension and sedation. Carba- after 1–2 weeks, then 50 mg two to three times/day. mazepine, ketoconazole, quinidine.

249 [email protected] 66485438-66485457 250 Appendix A drug Appendix

Side effects: Suicidal ideation and behavior, wors- Benztropine ening depression, hypotension, hyperglycemia, weight gain, prolonged Q-T, gastrointestinal issues, akath- Actions: Centrally acting anticholinergic also increases isia, tardive dyskinesia, headache, insomnia, sedation, dopamine effect by inhibiting presynaptic reuptake. fatigue, anxiety, and restlessness. Standard dose: Usual dosage is 0.5–2 mg twice daily. Special points: Preliminary data suggest a tic-sup- Contraindications: Use with caution in patients pressing effect. taking other drugs with anticholinergic activity, such as antihistamines, tricyclic antidepressants, or amantadine, since these medications may cause increased con- Baclofen fusion or side effects. Benztropine can reduce plasma Actions: Acts at gamma-aminobutyric acid (GABA) levels of antipsychotic medications. type B receptors in the spinal cord. Main drug interactions: Dry mouth, sedation, Standard dosage: Start with 5–10 mg at bedtime. pupil dilation, blurred vision, constipation, urinary Titrate slowly until desired therapeutic response or side hesitancy or retention, fatigue, confusion, hallucina- effects. Usual maintenance dose is 10–60 mg per day tions, weakness, tachycardia, increased intraocular pres- in three divided doses, lower dose in children ages 2–7 sure, precipitation of narrow-angle glaucoma, impaired years. concentration and memory, delirium, and anhidrosis Contraindications: Children under 2 years. with susceptibility to hyperthermia. Other side effects Medication may exacerbate absence seizures. Use with include dizziness, nausea, vomiting, and anxiety. caution in patients with diabetes, renal insufficiency, Patients may develop tolerance to some of these effects seizure disorders, stroke, severe psychiatric distur- with continued low-dose treatment. bances, or confusional states. Special points: May be more effective and better Main drug interactions: Synergistic effect with tolerated in children. No evidence that one drug in other CNS depressants. this medication class (benztropine, trihexyphenidyl) Main side effects: Sedation, dizziness, weakness, is superior to another. Increase dosage very slowly to hallucinations, confusion, headache, nausea, consti- avoid side effects; relatively low doses may be helpful. pation, hypotonia, paresthesias, ataxia; may increase Anticholinergics can exacerbate tardive dyskinesias and serum glucose. chorea, but may be helpful for tardive dystonia. Rapid Special points: Sudden cessation can cause seizures taper can cause malignant hyperthermia, worsening and psychosis. May be helpful in dystonia. dystonia, or cholinergic symptoms.

Baclofen Intrathecal Pump (ITB) Botox Actions: Administered via continuous infusion via Actions: Botulinum toxin is a neurotoxin produced a catheter placed within the spinal dura. Treatment by Clostridia. The toxin exerts its effect by inhibiting requires surgery for catheter placement, implantation the release of acetylcholine from the presynaptic site at of a small pump and reservoir in the abdomen. the muscle-nerve junction. Two serotypes, botulinum Standard dosage: Variable; dose starts at about 100 toxin type A and type B, are available. µg/day; but some individuals may require as much as Standard dose: Intramuscular dose is highly depen- 1000 µg/day. dent on the muscle group injected and botulinum toxin Contraindications: Infusion system should not be serotype. Botulinum toxin A is given in dosages of 50–400 implanted in a child whose weight is less than 14 kilo- units per injection session. Botulinum toxin B is given in grams nor in the presence of infection. dosages of 5000–25,000 units per injection session. Main drug interactions: Synergistic effect with Contraindications: Myasthenia gravis and other other CNS depressants. neuromuscular conditions. Patients receiving high Main side effects (see Baclofen): Abrupt drug with- doses of aminoglycosides or with bleeding risks should drawal is associated with hallucinations and seizures. be treated with caution. Infection at the proposed Infusion system–related side effects include infection, injection site(s). catheter breakage, or persistent fistula. Main drug interactions: Botox may be potentiated Special points: Safety and effectiveness in children by aminoglycoside antibiotics or other drugs that inter- less than age 4 years have not been established. Surgery fere with neuromuscular transmission. is costly and use as a treatment for generalized dystonia Main side effects: Local side effects at the injec- is controversial. tion site include pain, erythema, ecchymoses, and rash.

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Excessive weakness of injected or neighboring muscles. Main drug interactions: Central nervous system Generalized side effects can include malaise, headache, depressant action may be potentiated by other sedative/ nausea, and flu-like symptoms. hypnotic drugs (e.g., alcohol, narcotics, barbiturates, Special points: The onset of benefit generally takes monoamine oxidase inhibitors, anxiolytic, antipsy- several days; symptomatic improvement may last for chotic, anticonvulsant or antidepressant drugs). as long as 2–4 months. Patients may develop antibod- Main side effects: Sedation, somnolence, fatigue, ies to botulinum toxin, resulting in lack of efficacy of confusion, dizziness, hyperactivity, and ataxia. Serious future injections. To minimize the risk of antibody for- side effects include hypotension and respiratory depres- mation, at least 3 months should elapse before injec- sion. Medication may cause a paradoxical change in tions are repeated. Botox injections have been used in behavior with increased aggression, hyperexcitability, the treatment of dystonia, blepharospasm, tremors, and irritability. spasticity, and tics. Special points: Clonazepam is a controlled substance with the potential for psychological and physi- Carbamazepine cal dependence. Abrupt discontinuation of clonazepam may precipitate withdrawal symptoms, including sei- Actions: Anticonvulsant zures. Tolerance is common, and dose escalation with Standard dose: Typical pediatric dose is 10–20 mg/ prolonged use may be needed. Useful in treating most kg per day, divided three times per day. To improve types of myoclonus. tolerance, a dose of 7–10 mg/kg divided twice per day should be initiated for the first week. Contraindications: History of bone mar- Clonidine row suppression or known sensitivity to tricyclic Actions: alpha-adrenergic agonist. antidepressants. Standard dose: Start with 0.05 mg orally at bed- Main drug interactions: Carbamazepine is a CYP- time. Increase the dosage as needed, every 3–7 days by 450-3A4 inducer. Phenytoin and phenobarbital may 0.05 mg/day. Use in divided doses. Twice-a-day dos- decrease its effect and valproic acid and erythromycin ing is often adequate for treating tics, but three to four may increase its effect. times per day is required for other usages (half-life is Main side effects: Dizziness, nausea, drowsi- approximately 6 hours). The usual maximum dosage is ness, unsteadiness, hepatotoxicity, and hyponatremia. 0.3–0.4 mg/day. Clonidine is also available as a trans- Serious side effects include bone marrow suppression dermal patch that can be used as a once-weekly patch. and Stevens-Johnson syndrome. Patches are formulated to deliver 0.1, 0.2, or 0.3 mg Special points: Paroxysmal dyskinesias typically per day. The usual patch dose is 0.2 mg. respond to doses that are less than those necessary to Contraindications: Documented hypersensitivity, control seizures. Carbamazepine may be as effective pregnant and breast-feeding individuals. Use with as valproic acid in managing chorea. Need to monitor caution if there is impaired liver or renal function. blood counts. Main drug interactions: Sedation is increased when clonidine is used in combination with CNS-depressing Clonazepam agents. The hypotensive effects of clonidine are enhanced Actions: Long-acting benzodiazepine with mecha- by narcotic analgesics and inhibited by tricyclic antide- nism of action through enhancement of GABA-ergic pressants. Beta-blockers may potentiate bradycardia and transmission (primarily at the GABA-A receptor) in enhance rebound hypertension associated with abrupt the CNS. withdrawal. Clonidine may enhance the CNS-depressive Standard dose: Start with 0.25–0.5 mg at bedtime effects of alcohol, barbiturates, or other sedating drugs. and titrate slowly as tolerated. An amount of 0.05 mg/ Main side effects: Sedation is the most common kg per dose has been advocated (0.01 mg/kg per day in adverse effect. Other side effects include orthostatic children less than age 10). Usual maintenance dose is hypotension, headache, dizziness, fatigue, bradycar- 1–4 mg per day divided three times daily, although some dia, insomnia, irritability, dysphoria, dry mouth, and patients require considerably more. Weekly dose esca- nightmares. Do not discontinue suddenly because of lation is recommended to allow for patients to become risk of rebound hypertension and symptoms of sympa- tolerant to the sedating effects of this medication. thetic hyperactivity. Local dermatitis is common with Contraindications: Contraindicated in patients the transdermal patch. with significant hepatic dysfunction, respiratory Special points: Considered first-line therapy for depression, or acute narrow-angle glaucoma. tics and is effective for attention-deficit/hyperactivity

[email protected] 66485438-66485457 252 Appendix A drug Appendix disorder (ADHD) symptoms. Combination with Main side effects: Liver failure, seizures, fatigue, methylphenidate has been shown to be more effective weakness, and ataxia. than monotherapy for children with tics and ADHD. Special points: Liver function tests should be Tolerance can develop. checked before starting and periodically while on treatment. Treatment may facilitate conversion of muscles Clozapine to a type 2 fiber predominance, which can adversely affect weight bearing. It may be prudent to use only Actions: An atypical neuroleptic that affects D , 4 in children who are expected to remain wheelchair 5-HT , muscarinic and □-1 antagonist receptors; is a 2 dependent. relatively weak blocker of D2 receptors. Standard dose: In adults, start with 25 mg/day and Fluphenazine increase by 25 mg/day every several days according to clinical response and as tolerated. Typical dose is 50–75 Actions: Dopamine D1 and D2 receptor antagonist. mg/day. Standard dose: Start at 0.5–1 mg at bedtime. Contraindications: Myeloproliferative disorder, Increase gradually up to 3–5 mg/day, divided two previous bone marrow suppression, and uncontrolled times daily. seizure disorder. Contraindication: Documented hypersensitivity Main drug interactions: Not to be used concom- (also see pimozide and haloperidol). itantly with other drugs that suppress bone marrow Main drug interactions: Caution with simulta- function. May potentiate the hypotensive effect of anti- neous use of compounds that prolong the QT inter- hypertensive drugs and enhance the atropine effect of val, cause sedation, or have an anticholinergic effect. anticholinergic drugs. Use with caution together with Fluphenazine may increase serum concentrations of other drugs that prolong the QTc interval. Clozapine tricyclic antidepressants and the hypotensive action in combination with lithium has been reported to cause of antihypertensive agents. Concomitant lithium may severe encephalopathy. cause an encephalopathy-like syndrome. Main side effects: Agranulocytosis, orthostatic Main side effects: Extrapyramidal reactions, neu- hypotension, sedation, dizziness, vertigo, salivation, roleptic malignant syndrome, parkinsonism, tardive sweating, dry mouth, constipation, tachycardia, syn- dyskinesia, drowsiness, restlessness, anxiety, agitation, cope, seizures, nausea, constipation, hyperglycemia, euphoria, insomnia, confusion, weight gain, head- fever, weight gain. Rare but serious side effects of clo- ache, seizures, tachycardia, galactorrhea, gynecomas- zapine include agranulocytosis, eosinophilia, respiratory tia, hyperglycemia, hypoglycemia, sexual dysfunction, insufficiency, cardiac arrest, myocarditis, cardiomyopa- blurred vision, retinopathy, and visual disturbances. thy, hyperglycemia, neuroleptic malignant syndrome, Special points: Fluphenazine has been well toler- pulmonary embolism, and hepatitis. Tardive dyskinesia ated and effective in treating tics. Use smallest dose and has been reported in clozapine-treated patients. shortest duration possible; evaluate continued need Special points: Because of the risk of agranulocyto- periodically. sis, weekly blood counts are required. Drug is available through a distribution system to ensure compliance Guanfacine with the required leukocyte monitoring. Clozapine is Actions: alpha 2a-adrenergic agonist in prefrontal generally used to treat levodopa-induced hallucinations cortex. and dyskinesias, and parkinsonian rest tremor. Standard dose: Guanfacine 1 mg should be administered at bedtime and should be increased by one-half Dantrolene to one tablet every 5–7 days, if necessary, to a dosage of Actions: Acts directly on muscle by inhibiting cal- one to three tablets given once or twice a day. cium release from sarcoplasmic reticulum causing the Contraindications: Hypersensitivity. Caution uncoupling of electrical excitation from contraction. should be used in patients with cerebrovascular disease Standard dose: Start at 0.5 mg/kg once/day and and cardiac, renal, or hepatic insufficiency. increase gradually over 3–4 weeks to a target dose of Main drug interactions: May potentiate the CNS- 2 mg/kg three times/day. depressive effects of alcohol, barbiturates, or other sedat- Contraindications: Active hepatic disease. ing drugs. Increases effect of other hypotensive agents. Main drug interactions: Drugs with probable Main side effects: Dizziness, drowsiness, confusion, interaction include codeine, fentanyl, meperidine, fatigue, headache, hypotension, and mental depression. morphine, and verapamil. Constipation and dry mouth are common.

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Special points: Less sedating and less hypoten- meningitis, acute respiratory distress syndrome, acute sive than clonidine. Abrupt withdrawal may cause renal failure, and anaphylaxis. rebound effects (increased blood pressure, headaches, Special points: Risk of anaphylaxis is increased and tics). Guanfacine is helpful in reducing tics and with IgA deficiency. Check IgA levels before initiation ADHD. of therapy. Generally considered investigational for the treatment of movement disorders, although some evi- Haloperidol dence suggests that IVIG may be as effective as oral Actions: Dopamine receptor antagonist. prednisone in decreasing the severity of chorea in SC. Standard dose: Start with 0.25–0.5 mg/day in the evening; if tolerated and symptoms warrant, can Levetiracetam increase dose in 0.25–0.5 mg increments on weekly Actions: Anticonvulsant; binds to SV2A, a synaptic bases, administered once or twice a day. Total daily vesicle protein. dose ranges from 0.75–5 mg. Standard dose: Starting dose of 250–500 mg/day, Contraindications: Hypersensitive reaction to this divided into two daily doses, and increasing as toler- class of medications, prolonged QT syndrome, nar- ated by 250–500 mg/week. Anticonvulsant dosages in row-angle glaucoma, parkinsonism, severe cardiac or children range from 20–40 mg/kg/day. liver disease, or history of an acute extrapyramidal syn- Contraindications: Lower doses should be used in drome including acute dystonia and neuroleptic malig- patients with impaired renal function. nant syndrome. Main drug interactions: No significant drug inter- Main drug interactions: Caution with the simul- actions have been identified. taneous use of compounds that prolong the QT inter- Main side effects: Common side effects are som- val, cause sedation, or have an anticholinergic effect. nolence, dizziness, headache, ataxia, fatigue, and Haloperidol may increase serum concentrations of emotional lability. Uncommon, but potentially seri- tricyclic antidepressants and the hypotensive action ous, side effects include depression and/or suicidality, of antihypertensive agents. Concomitant use of lith- psychosis, pancreatitis, and pancytopenia. ium may cause an encephalopathy-like syndrome. Special points: Helpful for action-induced and Fluoxetine may inhibit metabolism and increase the stimulus-induced cortical myoclonus, controversial effect of haloperidol. benefit for tics. Main side effects: Extrapyramidal reactions, neuroleptic malignant syndrome, parkinsonism, tardive Levodopa/Carbidopa dyskinesia, drowsiness, restlessness, anxiety, agitation, Actions: Levodopa is converted to l-dopa by dopa euphoria, insomnia, confusion, weight gain, head- decarboxylase; carbidopa is a peripheral dopa decar- ache, seizures, tachycardia, galactorrhea, gynecomas- boxylase inhibitor and blocks the peripheral conversion tia, hyperglycemia, hypoglycemia, sexual dysfunction, of levodopa to dopamine. blurred vision, retinopathy, and visual disturbances. Standard dose: Levodopa is commonly available in Rarely causes photosensitivity reactions. the United States as a combination of carbidopa plus Special points: Although other typical neuroleptics levodopa (10/100, 25/100, and 25/250 mg). Initial tend to have a slightly better patient tolerance, dosage of levodopa in children is 1 mg/kg per day, haloperidol remains a useful medication for some divided into three doses. Dose is determined by the hyperkinetic movement disorders. levodopa component, and the use of 25/100 tablets is recommended in children. Medication should be grad- Intravenous Immune Globulin (ivig) ually titrated based on efficacy or adverse effects. The Actions: Impedes ability of pathologic antibodies to target dosage is usually 4–5 mg/kg per day, although bind to their epitope. some have suggested doses up to 10 mg/kg/day. When Standard dose: 2 g/kg administered intravenously peripheral side effects are disturbing (nausea, vomit- over 2–5 days, redosing monthly as needed. ing, hypotension), additional carbidopa can be admin- Contraindication: Hypersensitivity, immunoglob- istered 30 minutes before the levodopa. Carbidopa/ ulin A (IgA) deficiency. levodopa should be taken at least 30 minutes before or Main side effects: Common side effects are site 60 minutes after meals to avoid competition with other pain/reaction, nausea, headache, and vasomotor symp- amino acids for gastrointestinal absorption. Tablets can toms. Serious complications include myocardial infarc- be crushed and dissolved in an ascorbic acid solution or tion, congestive heart failure, rash, thromboses, aseptic in orange juice and used within 24 hours.

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Contraindications: Hypersensitivity, the use of Penicillamine monoamine oxidase inhibitors, narrow-angle glaucoma, and melanoma. Use with caution in patients Actions: Chelator that increases the excretion of with orthostatic hypotension, psychosis, and asthma. copper. Main drug interactions: Use with caution with Standard dose: 250 mg four times a day at least 30 antihypertensive agents. Beneficial effect is reduced minutes before or 2 hours after meals. with simultaneous use of dopamine receptor block- Contraindications: Hypersensitivity to pen- ers (e.g., antipsychotic agents and metoclopramide). icillamine; can usually be overcome by concomitant Pyridoxine increases the peripheral metabolism of use of steroids, by lowering the dose, or by stopping l-dopa, if it is administered in absence of carbidopa. the drug for a period of time. Main side effects: Nausea/vomiting, confu- Main drug interactions: Interacts with zinc, ren- sion, dizziness, somnolence, hallucinations, depres- dering both drugs less effective. Interferes with the sion, headache, dry mouth, insomnia, fatigue, muscle action of vitamin B6. cramps, and constipation. Motor complications include Main side effects: Penicillamine has a long list dyskinesia, dystonia, myoclonus, and the end-of-dose of side effects, including an initial hypersensitivity wearing-off effect. syndrome, subacute effects (e.g., bone marrow sup- Special points: Patients with dopa-responsive dys- pression, proteinuria), and chronic side effects (e.g., tonia ( DRD) show a marked response at relatively low wrinkling, abnormal scar formation, elastosis perforans doses of carbidopa/levodopa compared with doses used serpiginosa). Penicillamine also produces autoimmune in Parkinson’s disease. If dyskinesia occurs with the ini- disorders such as systemic lupus erythematosus and tiation of therapy for DRD, dose should be reduced Goodpasture’s syndrome. In animals, medication is and then gradually increased. Neuroleptic malignant associated with weakening of blood vessel collagen and syndrome has been reported on withdrawal in patients elastin. with Parkinson’s disease, especially after long-term use. Special points: Associated with a high risk of Studies have suggested that l-dopa does not cause neu- developing initial neurologic worsening in patients ronal death in animal models of parkinsonism and with Wilson’s disease who have neurologic symp- chronic administration of l-dopa does not exacerbate toms. Vitamin B6 should be given as a 25 mg daily the degenerative process in Parkinson’s disease. supplement. Penicillamine is associated with a significant list of acute, subacute, and chronic toxicities and Olanzapine teratogenicity.

Actions: Atypical neuroleptic. Pimozide Standard dose: Start with 2.5 mg orally every evening, and then escalate gradually as necessary up to Actions: Dopamine receptor antagonist. 5–10 mg/day in divided doses. Standard dose: Start with 0.5–1 mg preferably in Contraindication: Hypersensitivity. Caution is rec- the evening; may be increased every 5–7 days. Usual ommended when there is concern regarding hypergly- range: 2–4 mg/day; in divided doses. Do not exceed cemia and diabetes. 10 mg/day. Main drug interactions: Use with caution in the Contraindications: Documented hypersensitiv- presence of other CNS depressants because there may ity, history of cardiac arrhythmias and prolonged QT be an additive effect. The simultaneous use of olan- syndrome. Prior history of neuroleptic malignant syn- zapine with dopamine agonists may decrease its ther- drome, tardive dyskinesia, or Parkinson’s disease. apeutic effects and olanzapine with antihypertensive Main drug interactions: Use with caution in com- medications may increase the risk of hypotension. bination with QTc-prolonging agents and those with Main side effects: Hypotension, somnolence, anticholinergic side effects. Increases the toxicity of weight gain, hyperglycemia, akathisia, parkinsonism, monoamine oxidase inhibitors and CNS depressants. or tardive syndromes, hyperprolactinemia, dysregu- Concurrent use of macrolide antibiotics or azole anti- lation of body temperature, neuroleptic malignant fungals increases the risk of cardiotoxicity and sudden syndrome, seizures. cardiac death. Concurrent use of sertraline is contrain- Special points: Case reports and very small series dicated, since it may produce increased toxicity or have reported a beneficial effect in the treatment of attenuate therapeutic response. tics and tardive dystonia. The risk of tardive syndromes Main side effects: Sedation, dysphoria, cognitive with atypical antipsychotics is less than that with blunting, school refusal, acute anxiety with somatiza- traditional antipsychotics, but nevertheless exists. tions, personality change, weight gain, gynecomastia,

[email protected] 66485438-66485457 Appendix A drug Appendix 255 or lactation, orthostatic hypotension, and blurred Main drug interactions: Decreased clearance of vision. Extrapyramidal reactions include akathisia, pramipexole may occur with cimetidine, ranitidine, oculogyric crisis, drug-induced parkinsonism, and a verapamil, and quinine. risk of tardive dyskinesia. Rare, but potentially serious, Main side effects: Nausea, vomiting, abdominal adverse effects include cardiac arrhythmia (torsades de pain, headache, fluid retention, dizziness, rhinitis, dys- pointes), cardiac arrest, neutropenia, and seizures. pnea, rash, daytime sleepiness, sleep attacks, insomnia, Special points: Typical dopamine receptor block- and orthostatic hypotension. ing agents have long been the mainstay of suppression Special points: Pramipexole has been shown to be of severe tics. An electrocardiogram should be done at effective in Restless legs syndrome (RLS) symptoms baseline and periodically thereafter during the period of and Periodic limb movements in sleep (PLMS). dosage adjustment. Any indication of prolongation of a corrected QT interval beyond 0.45 second (children) Prednisone and or 0.52 second (adults) should be considered a basis for stopping additional dosage increases and for consider- Methylprednisolone ing a lower dosage. Monitor regularly for extrapyrami- Actions: Anti-inflammatory agents. dal side effects. Avoid the consumption of grapefruit Standard dose: Prednisone: 2 mg/kg per day in juice with pimozide. Sudden unexplained deaths have children. Methylprednisolone: intravenous, 25 mg/kg occurred in patients taking high doses (>10 mg). To per day (children) for 5 days. decrease the risk of tardive dyskinesia, use the smallest Contraindications: Hypersensitivity; systemic dose and shortest duration possible; periodically, evalu- fungal infection. ate continued need for medication. Main drug interactions: Barbituates and pehny- toin may decrease the therapeutic effect of prednisone. Piracetam The concomitant use of corticosteroids and anticoagulants has been associated with both enhanced and Actions: Nootropic agent, mechanism of action in diminished anticoagulant effects. Fluroroquinolones the treatment of myoclonus is not known. may increase the risk of tendon rupture. Standard dose: Substantial variation in dosage require- Main side effects: Hypertension, impaired skin ments. Start with a dosage of 7.2 g/day (divided into two healing, fluid retention, hypernatremia, increased risk or three daily doses), and increase by 4.8 g/day every 3–4 for infection, osteoporosis, weight gain, and depres- days to the usual effective dose of 4.8–24 g/day. sion. Serious side effects include hyperglycemia, adre- Contraindications: Severe renal insufficiency or nocorticoid insufficiency, cataract, and glaucoma. hepatic impairment. It is not recommended for use Special points: Trials in Sydenham’s chorea have in children less than 16 years of age or in pregnant suggested steroid accelerated recovery, but no change women. Avoid abrupt discontinuation, which may in rate of remission or recurrence. Prednisone is gen- trigger withdrawal seizures. erally reserved for patients with persistent, disabling Main drug interactions: Increases the serum levels chorea refractory to antichoreic agents. of warfarin, thyroid hormone, and CNS stimulants. Main side effects: Hyperkinesias, insomnia, weight gain, nervousness, diarrhea, and rash. May cause revers- Primidone ible thrombocytopenia and leukopenia. Do not discon- Actions: Anticonvulsant effects may be due to an tinue abruptly, because this may precipitate seizures. alteration of transmembrane calcium and sodium ion Special points: Not currently approved by the U.S. fluxes. Primidone has little effect on gamma-aminobu- Food and Drug Administration (FDA). Used for corti- tyric acid (GABA) or glutamate receptors. cal myoclonus. Standard dose: Start with 25–50 mg by mouth at night and gradually increase to 125–250 mg at night, Pramipexole if necessary.

Actions: Non-ergot selective D2 and D3 dopamine Contraindications: Hypersensitivity to barbitu- agonist. rates, porphyria. Caution in patients with impaired Standard dose: Titration is required to avoid side hepatic, renal, and pulmonary function. effects; start at 0.125 mg, titrate up by 0.125 mg every Main drug interactions: Anticoagulants, corti- 3 days to efficacy. Most studies show improvement in costeroids, doxycycline, phenytoin, carbamazepine, symptoms in a dose range of 0.125–1.5 mg per day. valproic acid, acetazolamide, CNS depressants, mono- Contraindication: Hypersensitivity amine oxidase inhibitors, estrogen and progesterone,

[email protected] 66485438-66485457 256 Appendix A drug Appendix isoniazid, haloperidol, cyclosporine, theophylline, Main side effects: Sedation, worsening of Parkinson’s tricyclic antidepressants. disease, induction of diabetes, stroke, and heart attacks. Main side effects: Drowsiness, lethargy, som- Special points: Better safety profile than other nolence, ataxia, dizziness, nausea, vomiting, cogni- atypical neuroleptics. A high dose (up to 600 mg/day), tive dulling, hyperirritability, emotional disturbances, but not a low dose (25 mg/day), improves levodopa- impotence, diplopia, nystagmus, granulocytopenia, red induced dyskinesia. cell hypoplasia, and Stevens-Johnson syndrome. Special points: Helpful for action-induced and stim- Reserpine ulus-induced cortical myoclonus and tremor. Primidone Actions: Catecholamine-depleting drug. metabolizes into two major compounds, phenylethyl- Standard dose: Start at a low dosage 0.25 mg/day malonamide and phenobarbital, both of which do not and increase by 0.25 mg/day every few days according significantly change tremor amplitude from baseline. to clinical response and tolerability. Reserpine can be given in dosages of 1–9 mg/day in divided doses. Propranolol Contraindications: Depression, Parkinson’s dis- Actions: β-blocker. ease, orthostatic hypotension, and pregnancy. Should Standard dose: Children 1–2 mg/kg/day; adults not be used concurrently with monoamine oxidase 80–320 mg by mouth per day, taken in three divided inhibitors. doses. Propranolol LA 60–320 mg by mouth per day. Main drug interactions: Caution with concomi- Contraindications: Hypersensitivity to β-blockers, tant use of drugs that lower blood pressure or have an sinus bradycardia, second- or third-degree heart block, additive effect on somnolence and depression. congestive heart failure, cardiac failure, bronchial Main side effects: Sedation, orthostatic hypoten- asthma, severe chronic obstructive pulmonary disease, sion, depression, drug-induced parkinsonism, insomnia, and insulin-dependent diabetes mellitus. anxiety, akathisia, cardiac arrhythmia, and impotence. Main drug interactions: Acetaminophen, antico- Special points: Usually reserved for patients with agulants, barbiturates, benzodiazepines, calcium-chan- severe tardive dystonia and hemiballismus that is unre- nel blockers, clonidine, ergot alkaloids, haloperidol, H2 sponsive to other treatments. antagonists, lidocaine, loop diuretics, monoamine oxidase inhibitors, phenothiazines, quinidine, quinolones, Risperidone rifampin, salicylates, sulfonylureas, theophylline, thy- Actions: Atypical antipsychotic. roid hormones. Standard dose: Begin with 0.25 or 0.5 mg in the Main side effects: Nonspecific weakness and fatigue. evening and gradually titrate up to 2–4 mg per day Other potential adverse reactions include weight gain, divided twice daily. nausea, diarrhea, bradycardia, dizziness, headache, Contraindication: Hypersensitivity. Known his- rash, impotence, depression, and hypotension. tory of QT prolongation or concomitant use of other Special points: β-2 blockade appears necessary drugs known to prolong QT interval. Caution is rec- for maximal tremor suppression. Propranolol is most ommended when there is concern regarding hypergly- effective against hand tremor. An extended-release for- cemia and diabetes. mulation may provide satisfactory relief with once- Main drug interactions: Beware an additive daily dosing. effect with other CNS depressants or drugs that prolong the QT interval. Fluoxetine and paroxetine may Quetiapine increase the serum concentration of risperidone and

Actions: atypical antipsychotic, dopamine D2, D3 decrease concentrations of 9-hydroxyrisperidone. receptor antagonist, has mild antimuscarinic, antisero- Dopamine agonists may decrease therapeutic effects. toninergic, antiadrenergic, and antihistaminergic prop- Main side effects: Hypotension, somnolence, erties and no effect on the D1 receptor. weight gain, hyperglycemia, akathisia, parkinsonism, Standard dose: 75–500 mg/day, average 360 mg/ or tardive syndromes, hyperprolactinemia, dysregula- day in adults. tion of body temperature, neuroleptic malignant syn- Contraindication: Use with caution in patients drome, and seizures. with congestive heart failure. Special points: Use smallest dose and shortest dura- Main drug interactions: Worsen drowsiness associ- tion possible and monitor regularly for extrapyramidal ated with dopamine agonists, diphenhydramine hydro- side effects. Risperidone is effective in reducing tics in chloride, and sleep medications. children and adults.

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Ropinirole promptly at the first signs of depression. Do not initiate treatment within 14 days of use of monoamine

Actions: Non-ergot selective D2 and D3 agonist. oxidase (MAO) inhibitors (risk of hypertensive crisis). Standard dose: Titration is required to avoid side Main drug interactions: Potentiates the systemic effects; start at 0.25 mg taken 2 hours before bed, titrate and neurologic effects of other amine depletors (reser- up by 0.25 mg every 3 days to efficacy. Effective dose pine and alpha-methylparatyrosine) and dopamine range is 0.5–4 mg per day. An additional dose 1–2 hours antagonists. Central excitation and hypertension have before symptom onset can be taken (i.e., at 4 to 6 pm). been reported when tetrabenazine was added to exist- Contraindication: Hypersensitivity. ing therapy with desipramine or MAO inhibitors. Main drug interactions: Drugs that affect cyto- Main side effects: Common side effects include chrome P1A2 may interfere with the metabolism of rop- parkinsonism, drowsiness, fatigue, sedation, anxiety, inirole. Estrogen reduces the clearance of ropinirole. depression, akathisia, tremor, nausea, vomiting, insom- Main side effects: Nausea, vomiting, abdominal nia, and orthostatic hypotension. Less common but pain, headache, fluid retention, dizziness, rhinitis, dys- potentially serious side effects include suicidality and pnea, rash, daytime sleepiness, insomnia, and ortho neuroleptic malignant syndrome. static hypotension. Special points: U.S. FDA approved for the treat- Special points: Used for the control of Restless legs ment of chorea in patients with Huntington’s disease. syndrome (RLS) symptoms and periodic limb move- Reports suggest it may also be helpful in the treatment ments of sleep (PLMS). of tics, tardive dystonia, hemiballismus, and subcortical myoclonus. Sodium Oxybate Actions: Sodium salt of gamma-hydroxybutyrate. Tetrathiomolybdate (TM) Standard dose: 3–7 g every evening; first dose at Actions: Forms a tripartite complex with copper bedtime and second dose 4 hours later. The serum half- and protein; given with food, it prevents the absorption life of sodium oxybate is very short and twice-per-night of copper, and given between meals, is absorbed into dosing usually is required. the blood and complexes blood copper with albumin, Contraindications: Succinic semialdehyde dehydro- rendering the copper nontoxic. genase deficiency, and use of sedative/hypnotic agents, Standard dose: 20 mg six times daily, three times CNS depressants, and alcohol. Caution in patients with with meals and three times separated from meals. a history of psychiatric disorders or drug abuse. Contraindications: None. Main drug interactions: Additive effects on CNS Main drug interactions: None. depressants, e.g., all benzodiazepines, barbiturates, and Main side effects: Reversible anemia. sedative/hypnotics. Special points: TM is experimental and not com- Main side effects: Headache, nausea/vomiting, diz- mercially available. TM is often combined with zinc ziness, somnolence, tremor, dissociative feelings, con- for patients with Wilson’s disease who have neurologic stipation, and suicidal gesture. symptoms. Combination of TM and zinc is used for Special points: Treatment for narcolepsy, improves approximately 8 weeks and then the patient is contin- daytime sleepiness, sleep fragmentation, and cataplexy. ued on zinc for maintenance therapy. Has potential for misuse/abuse and is only available through a centralized pharmacy. Tizanidine Actions: A centrally acting alpha-2 adrenergic stim- Tetrabenazine ulant that reduces polysynaptic spinal stretch reflexes. Actions: Presynaptic monoamine-depleting drug Standard dose: No established dosage in children, that also acts as a postsynaptic dopamine receptor but 0.1–0.3 mg/kg/day is sometimes used. blocker and dopamine reuptake inhibitor. Contraindications: Hypersensitivity or concurrent Standard dose: Start with 12.5 mg daily, and use of ciprofloxacin or fluvoxamine. increase by 12.5 mg/day every 3–5 days according to Main drug interactions: Avoid other anticholin- clinical response and as tolerated, divided into three ergic or sedating medications. daily doses. The usual effective dose is 50–150 mg/day Main side effects: Common side effects include and the maximum recommended dose is 200 mg/day. somnolence, dry mouth, dizziness, increased liver Contraindications: Patients with a history of transaminases, vomiting, and flu-like symptoms. More depression, suicidality, and parkinsonism. Discontinue serious side effects include hepatotoxicity, bradycardia,

[email protected] 66485438-66485457 258 Appendix A drug Appendix hypotension, hypertension, and confusion. There is is often combined with zinc for patients with hepatic an increased risk of prolonged QT interval, especially disease and continued for approximately 4 months, when used in combination with other medications that followed by maintenance therapy with zinc alone. are known to affect the QT interval. Trientine is moderately toxic but may be safer than Special points: Not extensively studied in penicillamine. Has known teratogenicity. children. Trihexyphenidyl Topiramate Actions: Centrally acting anticholinergic. Actions: Anticonvulsant. Multiple mechanisms Standard dose: Start at a low dosage of 0.5–1 mg/ of action, including inhibiting voltage-gated sodium day and increase gradually by 1 mg every 3–5 days, channels, augmenting the inhibitory chloride ion influx until benefit or adverse effects. The usual effective dos- mediated by GABA, increasing endogenous GABA age is highly variable, ranging from 6–60 mg/day, but production, modestly inhibiting carbonic anhydrase some patients require higher dosages. Usually given in activity, and antagonizing the AMPA/kainate subtype three divided doses. of the glutamate receptor. Contraindications: Narrow-angle glaucoma, Standard dose: Start with a dose of 25 mg/day, grad- severe constipation, gastroparesis, pyloric or duodenal ually increasing until benefit or side effects. The usual obstruction, achalasia, urinary retention, myasthenia effective dose is 50–300 mg/day, given in divided doses. gravis, confusion, and dementia. The maximum recommended dose is 400 mg/day. Main drug interactions: Use with caution in Contraindications: Use lower doses in renal impair- patients taking other drugs with anticholinergic activ- ment. Monitor serum bicarbonate levels. ity, such as antihistamines, tricyclic antidepressants, or Main drug interactions: May decrease the efficacy amantadine, since these may cause increased confusion of estrogen-based oral contraceptives. Concomitant or side effects. Reduces plasma levels of antipsychotic use with phenytoin may increase the levels of phe- medications. nytoin and decrease the levels of topiramate. Main side effects: Dry mouth, sedation, pupil dila- Combined use with other carbonic anhydrase inhibition, blurred vision, constipation, urinary hesitancy or tors (such as acetazolamide) may increase the risk of retention, fatigue, confusion, hallucinations, weakness, nephrolithiasis. tachycardia, increased intraocular pressure, precipita- Main side effects: Confusion, cognitive impair- tion of narrow-angle glaucoma, impaired concentration ment, paresthesias, altered taste, ataxia, diplopia, som- and memory, delirium, and anhidrosis with suscepti- nolence, dizziness, fatigue, depression, nervousness, bility to hyperthermia. Other side effects may include ciliary edema, and weight loss. Uncommon but poten- dizziness, nausea, vomiting, and anxiety. Patients may tially serious side effects include nephrolithiasis, meta- develop tolerance to these effects with continued low- bolic acidosis, oligohidrosis, hyperthermia, and acute dose treatment. angle closure glaucoma. Special points: Trihexyphenidyl may be more Special points: Second-line agent for the treatment effective and better tolerated in children than adults. of cortical myoclonus and essential tremor. No evidence that trihexyphenidyl is superior to benztropine. Increase dosage very slowly to avoid Trientine side effects; relatively low doses may be helpful. Anticholinergics may exacerbate tardive dyskinesias Actions: Chelator that increases the excretion of and chorea, but have been helpful for tardive dysto- copper. nia. Rapid taper can cause malignant hyperthermia, Standard dose: 250 mg four times a day at least 30 worsening dystonia, or cholinergic symptoms. Not minutes before or 2 hours after meals. highly recommended in Segawa’s disease and should Contraindication: None. not be used in place of levodopa therapy which actu- Main drug interactions: Interacts with zinc, ren- ally replaces the primary deficiency. Anticholinergic dering both drugs less effective. drugs should be discontinued gradually. Main side effects: Proteinuria and autoimmune disorders such as systemic lupus erythematosus and Valproic Acid Goodpasture's syndrome. Special points: Used in Wilson’s disease to establish Actions: Anticonvulsant; mechanism includes a more rapid negative copper balance and to reduce modulation of sodium channels and potentiating the body’s copper burden relatively quickly. Trientine GABAergic transmission.

[email protected] 66485438-66485457 Appendix A drug Appendix 259

Standard dose: Start with 125 mg twice daily and one anticopper drug is not recommended. Zinc does gradually titrating as tolerated. Antimyoclonic doses in not have the propensity to cause the neurologic wors- children are typically in the range of 15–25 mg/kg/day, ening that can occur with penicillamine. Anticopper given in three divided doses. agents control only copper and its toxicity and have no Contraindications: Hepatic dysfunction, urea cycle immediate direct effect on symptoms. disorders, and children younger than 2 years. Main drug interactions: Valproic acid alters Ziprasidone blood levels of several medications: increases carba Actions: Atypical neuroleptic. mazepine, phenobarbital, primidone, amitriptyline, Standard dose: Start with 5 mg orally every eve- lamotrigine, and warfarin levels and decreases levels ning, and then titrate as necessary. The effective dosage of rifampin. Cimetidine may increase the serum levels usually is 20 or 40 mg daily in divided doses. of valproic acid. Contraindications: Hypersensitivity. Known his- Main side effects: Common side effects include tory of QT prolongation or concomitant use of other nausea, vomiting, diarrhea, weight gain, drowsi- drugs known to cause torsades de pointes or prolong ness, fatigue, peripheral edema, tremor (postural and QT interval. Caution is recommended when there is action), ataxia, hyperammonemia, nystagmus, depres- concern regarding hyperglycemia, orthostatic hypotension, alopecia, and livedo reticularis. Uncommon, sion, and diabetes. but serious, side effects include hepatic injury, pan- Main drug interactions: Beware an additive effect creatitis, rashes (Stevens-Johnson syndrome), ana- on prolongation of the QT interval with concomi- phylaxis, bone marrow suppression, and polycystic tant use of other antipsychotic agents. Ziprasidone ovary disease. Reversible parkinsonism has also been may enhance the effects of certain antihypertensive reported. agents. CYP-450-3A4 inhibitors, such as erythro- Special points: Liver function tests should be mon- mycin and ketoconazole, may increase serum levels; itored closely. Valproate has been used in Sydenham’s CYP-450-3A4 inducers, such as carbamazepine and chorea and may be helpful for action-induced and rifampin, may decrease serum levels. Drugs that pro- stimulus-induced cortical myoclonus. Avoid use long QT/QTc intervals increase the risk of life-threat- of sodium valproate in women of childbearing age to ening arrhythmias. prevent teratogenesis. Main side effects: Hypotension, somnolence, weight gain, hyperglycemia, akathisia, parkinsonism, Zinc tardive syndromes, hyperprolactinemia, insomnia, dysregulation of body temperature, neuroleptic malignant Actions: Induces metallothionein, which in the syndrome, and seizures. Ziprasidone causes more pro- intestinal cell blocks absorption of copper. Hepatic longation of the QT interval than risperidone, olan- metallothionein will also sequester some potentially zapine, or haloperidol. toxic copper in the liver and possibly protect it from Special points: A baseline electrocardiogram is rec- further damage. ommended. Monitor patient regularly for extrapyrami- Standard dose: For children younger than 6 years of dal side effects. A placebo-controlled study has shown age dose is 25 mg twice daily and for children between that ziprasidone may be beneficial in reducing tics. ages 6 and 16, or with a body weight of 125 pounds or less, 25 mg three times daily. Zonisamide Contraindication: None. Main drug interactions: Interacts with either tri- Actions: Anticonvulsant, mechanism of action entine or penicillamine during maintenance therapy; involves blockade of sodium and/or calcium channels. penicillamine is partially occupied by zinc, as is Standard dose: Start with a dose of 25 mg by trientine. mouth twice a day, and gradually increase as tolerated Main side effects: Gastric irritation, mitigated by to a usual effective dosage of 300–400 mg/day, given taking the first dose of the day in midmorning or tak- in divided doses. ing with a small amount of protein. Contraindications: Zonisamide is a sulfonamide Special points: Zinc is often combined with tri- and is contraindicated in the presence of an allergy to entine for patients with Wilson’s disease and hepatic sulfa. Titrate slowly in renal disease. disease and with tetrathiomolybdate for treatment of Main drug interactions: The serum levels of zonis- the patient with neurologic disease. However, beyond amide are decreased by hepatic enzyme-inducing the initial treatment period, combination of more than drugs (phenobarbital, carbamazepine, oxcarbazepine,

[email protected] 66485438-66485457 260 Appendix A drug Appendix phenytoin, and rifampin) and increased by enzyme- loss. Uncommon but potentially serious side effects inhibiting drugs (erythromycin, fluvoxamine, protease include Stevens-Johnson syndrome, hepatic necrosis, inhibitors). agranulocytosis, aplastic anemia, psychosis, suicidality, Main side effects: Drowsiness, dizziness, ataxia, nephrolithiasis, oligohidrosis, and hyperthermia. confusion, cognitive symptoms, depression, headache, Special points: Second-line drug for myoclonus of anorexia, nausea, vomiting, abdominal pain, and weight subcortical or unknown origin.

[email protected] 66485438-66485457 Search Strategy for Genetic O B Movement Disorders O

Making a precise genetic, molecular diagnosis, even if The OMIM search strategy should be optimized it us untreatable, is highly valued by individual patients for efficient use of the clinician’s time and the health and families. It narrows the possibilities in terms of prog- care dollar. Cognitive efforts toward difficult diagno- nosis, and helps with identifying and networking with ses are poorly reimbursed, and genetic laboratory test- other affected individuals and families. In some cases, ing is very expensive and not always covered by health rational, disease-specific therapies are available. Because insurance.

the number of genetic movement disorders and their Table B-2 shows the major types of movement dis- O diverse phenotypes is ever expanding, an efficient online orders and the results of searches in OMIM. As can search strategy is extremely helpful. The following be seen in the first column, simply entering the move- strategy, using Online Mendelian Inheritance in Man ment disorder as a search term leads to a large number (OMIM) (www.ncbi.nlm.nih.gov/omim) and Genetests of “hits”—usually more than one need search through. (www.genetests.org) websites, may be helpful. Therefore using a term such as ataxia without limits is OMIM is a database focusing on phenotype inefficient. and genotype, available through the United States Using the movement disorder term, for example, National Library of Medicine and National Center ataxia, but using the LIMIT function to select only for Biotechnology Information. OMIM is easy to use entries where ataxia appears in the CLINICAL during or after clinic encounters to search diseases and SYNOPSIS means that the movement is listed as a key related genes. This database was initiated by Dr. Victor symptom of the disease. This is useful, because a par- A. McKusick at Johns Hopkins University and is edited ticular movement disorder may be present but may not and updated through the McKusick-Nathans Institute be in the title. of Genetic Medicine at Johns Hopkins University, As seen in Table B-2, using TITLE results in a under the direction of Dr. Ada Hamosh. In OMIM, smaller number of hits, but this is not always advisable. diseases are assigned numbers and symbols, as shown For example, a child with ataxia telangiectasia may be in Table B-1. seen before 3 years of age with choreiform movements OMIM can be searched using any term, with lim- or dystonia but not ataxia. A TITLE search for chorea its, similar to searching for medical publications using misses this disease. However, a CLINICAL SYNOPSIS MEDLINE PUBMED. OMIM is fully integrated and search for choreoathetosis does yield this disease. Thus linked to PUBMED and to multiple other gene and it is also important to be flexible in selecting a search protein databases. Each disease entry has subsections, term, for example, myoclonus OR myoclonic, or chorea including general text, clinical features, molecular OR choreoathetosis. genetics, and clinical synopsis. An extremely useful and efficient strategy is to search • CLINICAL FEATURES presents and summarizes by the movement disorder AND by an accompany- the series of articles published describing the disease, ing neurologic or nonneurologic symptom. As seen in with links to the references. Table B-2, where selected examples are demonstrated, • MOLECULAR GENETICS, if known, presents additional features greatly narrow the diagnostic pos- the key papers where linkage and the disease-causing sibilities. This shows the value in time and money of a gene were published. thorough physical examination. • CLINICAL SYNOPSIS is a tab off to one side. This After executing the search, OMIM defaults to links to an outline of organ systems involved in the DISPLAYING ENTRIES BY TITLES, including brief disease, age of onset, and any other associations or identifying information. However, it can be more effi- problems that persons with the disease have. cient to reset the DISPLAY from TITLES to CLINICAL 261 [email protected] 66485438-66485457 262 Appendix B Search Strategy for Genetic Movement Disorders

Table B-1 oMIM—Code The list of diagnoses in OMIM conveniently contains a series of links. The two most clinically useful First Digit Mode of Inheritance are PUBMED and Genetests. PUBMED generates 1 Autosomal dominant the search results for publications about that disease. Reading case series is critical because it provides a bet- 2 Autosomal recessive ter sense of the phenotype than does the CLINICAL 3 X linked SYNOPSIS. The Genetests link is present when there 4 Y linked is clinical testing, as shown in Table B-2, or research genetic testing is available. 5 Mitochondrial The Genetests website, at www.genetests.org, is also 6 Entered in OMIM since 1994 publicly funded and extremely useful. This site contains hundreds of concise reviews of genetic diseases Symbol Status and provides all contact information for laboratories * Gene with known sequence—this worldwide that perform genetic tests for over 1000 dis- type of entry does not discuss the eases. The laboratory directory also explains the type of disease, just the gene and protein testing, for example, sequencing the entire gene or just + Gene with known sequence and checking for common mutations, as well as whether associated phenotype prenatal testing is available. This site also provides tuto- rials on genetic diseases and resources such as disease- # Phenotype described, molecular basis related advocacy groups. known—most well-characterized diseases with gene tests available So, to summarize, the following is a useful approach have this symbol to identifying genetic diseases: % Mendelian phenotype or locus, 1. Go to the OMIM website (www.ncbi.nlm.nih.gov/ but molecular basis unknown, omim). that is, cases have been described supporting heritability; linkage may 2. Execute SEARCH: or may not be known a. Use a main movement disorder phenomenology term, for example, ataxia, AND another key None Others, mainly phenotypes with symptom. suspected mendelian inheritance b. Or use a main movement disorder term and use a LIMIT. CLINICAL SYNOPSIS is recommended. 3. Reset Display from TITLES to CLINICAL SYNOPSIS. Then each disease appears with the key SYNOPSIS. features in outline form. This facilitates rapid scan- 4. Visually scan through the CLINICAL SYNOPSIS ning down the list of diagnoses to identify those whose for pattern of inheritance, age range, and clinical features fit well, fit somewhat, or fit poorly. features. The LIMIT Genemap Locus can be helpful, as it 5. When necessary, link through PUBMED to case narrows the search to those diseases where the gene or series for more detailed phenotypic descriptions. locus is known. However, this strategy may be insen- 6. Use this information to generate a list of most likely sitive. It is probably more useful to move to the genes diseases. after using clinical features to narrow the differential 7. If possible, link to the Genetests website through diagnosis as much as possible. Another search limit OMIM at the disease(s) of interest or at www. that is occasionally useful is to select by chromosome. genetests.org. This is mainly useful for the X chromosome, but in 8. In Genetests, click on “Laboratory Directory” and cases where karyotyping or gene microarrays identify type in disease names for lists of genetic tests avail- anomalies, this strategy may be used as well. able and laboratory contact information.

[email protected] 66485438-66485457 Appendix B Search Strategy for Genetic Movement Disorders 263

GENETE S T S E A RCH CLINIC A L TE S TING 34 1 15 10 14 22 13 2 1 2

M DO A ND Symptom 17 3 3 13 5 16 13 21

acidosis

E xample of non-M DO Signs or Symptoms Diabetes Malformed ears Hypothyroidism Short stature Renal tubular Hepatomegaly Scoliosis Pes cavus

LI M IT to positive GENE MA P LOC US 79 42 51 77 10 71 45 2 80

O M I S E A RCHE

LI M IT to DO in TITLE 139 6 15 35 5 34 29 9

99 LI M IT to DO in CLINIC A L S YNOP I 297 57 69 96 10 96 51

230 M DO O nly, N o Qualifiers 725 72 132 211 52 256 261 11 18

erm

isorder Searches Using O M I and G enetests Movement D isorder Searches

lesions, basal ganglia calcification, or striatal necrosis choreoathetosis parkinsonism movements le B-2 Tab Movement D isorder T (M DO ) Search Ataxia Bilateral basal ganglia Chorea or athetosis Dystonia Leigh syndrome Myoclonus or myoclonic disease or Parkinson’s Stereotyped hand Tics Tremor

[email protected] 66485438-66485457 C Video Atlas O Chapter 6 Tic Disorders Trunk-Abdominal Tics Eye and Facial Tics 6-9. This young woman with Tourette syndrome demonstrates repetitive and sustained truncal 6-1. This boy demonstrates frequent blinking, which movements resulting in bending of the trunk is associated with alternating facial contractions, causing trunk flexion, also called camptocormia. tongue protrusions, and mouth openings, typical This movement is preceded by a strong premon- of Tourette syndrome. itory sensation in her lower back and an intense 6-2. This girl demonstrates facial tics manifested need to stretch the lower back muscles. by repetitive, sustained contractions of facial mus- 6-10. This girl with severe Tourette syndrome and cles resulting in grotesque grimacing, as well as obsessive-compulsive disorder demonstrates neck muscle contractions, typical of dystonic dystonic contractions of the rectus abdomi- tics. nus, resulting in a side-to-side movement of her O6-3. This boy with Tourette syndrome demonstrates abdomen, the so-called belly dancer dyskinesia. persistent blinking and more sustained contrac- 6-11. This boy with Tourette syndrome demonstrates tions of the eyelids in a form of blepharospasm, repetitive, complex movements produced by an example of a dystonic facial tic. In addition, contractions of his shoulder and trunk muscles, he demonstrates facial grimacing and oculogyric preceded by an intense premonitory sensation of deviations. a chill. 6-4. This boy demonstrates oculogyric deviations, Limb Tics typical of ocular tics associated with Tourette syndrome. 6-12. This girl with Tourette syndrome demonstrates repetitive, clonic, adducting movements of her Cervical Tics legs. 6-13. This boy with Tourette syndrome demonstrates 6-5. This girl with Tourette syndrome and severe repetitive flexion of his arms as part of his dys- obsessive-compulsive disorder manifests repeti- tonic limb tics. tive movement of her neck in a consistent pattern Complex Motor Tics of six, which is her “favorite” number. 6-6. This girl demonstrates dystonic tics of the neck 6-14. This young boy with Tourette syndrome exhibits resulting in repetitive neck flexion, which could complex motor tics manifested by trunk bend- be possibly wrongly diagnosed as anterocollis due ing and hopping. to cervical dystonia. Simple Phonic Tics

Shoulder Tics 6-15. This boy with Tourette syndrome demonstrates a dystonic extension of his neck associated with 6-7. This young man demonstrates repetitive move- repetitive expiratory grunting sounds. In addi- ments of either the left or right scapula, an tion, he demonstrates a holding or blocking tic example of a dystonic tic often preceded by a pre- during which time he stops breathing and is monitory sensation in the region of the shoulder. completely motionless. This shoulder movement is highly characteristic 6-16. This boy with Tourette syndrome demonstrates of and relatively specific for Tourette syndrome. continuous grunting sounds associated with 6-8. This young man demonstrates dystonic tics of the repetitive extensions of his neck, the so-called shoulder and trunk. whiplash tics. 264 [email protected] 66485438-66485457 Appendix c Video Atlas 265

6-17. This 17-year-old girl with severe Tourette syn- 7-9. This girl demonstrates a pattern of clenching drome exhibits complex motor tics and loud stiffening-posturing (38%)—repeated tensing of screaming phonic tics. hands, arms, or head that mimics dystonia and includes prolonged facial grimacing or shoulder Complex Phonic Tics raising. 6-18. This young woman with severe Tourette syndrome 7-10. This boy has a ritualized sequence of purposeful exhibits loud vocalizations, including coprolalia. behaviors usually involving a pattern of voli- 6-19. This boy with severe Tourette syndrome exhibits tional movements (eg, repetitive bending over or complex motor tics and loud phonic tics, includ- pacing). O ing vocalizations. Videos 7-7 through 7-10 from Mahone, E.M, et al. 6-20. This boy has very severe coprolalia as a manifestation Repetitive arm and hand movements (complex of Tourette syndrome. In 1996, he was the first case motor stereotypies) in children. Journal of Pediatrics of coprolalia reported to improve after botulinum 2004;145:395-5; http://www.us.elsevierhealth.com/ toxin injections into the vocal cords, which resulted jpeds. in nearly complete abolishment of the vocal premonitory urge. (Scott BL, Jankovic J, Donovan DT: Botulinum toxin into vocal cord in the treatment Chapter 8 Paroxysmal Dyskinesia of malignant coprolalia associated with Tourette’s 8-1. Young man with paroxysmal kinesigenic dystonia syndrome, Mov Disord 11:431–433, 1996.) manifested by transient truncal dystonia triggered by sudden voluntary movement. Chapter 7 Stereotypies 8-2. A girl with paroxysmal kinesigenic dystonia manifested by transient facial dystonia imitating 7-1. Home video of a young girl showing repetitive, a smile and right arm flexion precipitated by stereotypic flexion of the right leg associated with voluntary movement such as jumping jacks. some pelvic movements. This stereotype represents The patient also has a family history of infantile a self-stimulatory or masturbatory behavior, almost convulsions, a seizure disorder, and migraines. exclusively observed in girls before age 5 years. 8-3. This adolescent has many brief episodes per day 7-2. Young boy with otherwise normal development of involuntary, asymmetric dystonic posturing. and normal neurologic examination demon- Here, after sitting for several minutes conversing, strates side-to-side head movement, believed to be an episode is triggered when he stands and begins normal, “physiologic” stereotypy. to walk. Consciousness is preserved throughout. 7-3. This young girl with Rett syndrome, an autistic dis- Treatment with carbamazepine was successful. order found predominantly in girls due to a mutation in the MECP2 gene on the X chromosome, Chapter 9 Chorea, Athetosis, and demonstrates typical hand washing, hand clapping Ballism stereotypic movement along with toe walking. 7-4. This young girl with Rett syndrome demonstrates 9-1. This 6-year-old girl with adoptive parents was classic hand stereotypies and dystonic flexion of her developing well until age 3.5 years when she gradu- toes, typically associated with this autistic disorder. ally stopped talking, became ataxic, and developed 7-5. This young girl with Rett syndrome manifests hand facial and generalized chorea. She was found to and finger repetitive, stereotypic movements. have juvenile Huntington’s disease with over 100 7-6. This boy with Norrie’s syndrome manifests CAG repeats in the Huntington gene. Over the head stereotypy, which may represent a form of next year she developed myoclonic jerks, seizures, self-stimulatory behavior. He also exhibits self- and progressive ataxia; became bedridden in a fetal injurious behavior. position; and died about 1 year after this video. 7-7. This boy demonstrates an arm flapping stereotypy, 9-2. This teenage girl with documented lupus ery- during excitement. The child flaps or waves hands thematosus has severe chorea of the face and the and arms, includes larger-amplitude, rhythmic entire body, including some involuntary expira- movements tory sounds and dysarthria. The chorea markedly 7-8. This child demonstrates a rapid, smaller-amplitude, improved with tetrabenazine. back-and-forth movements of hands and arms 9-3. Young girl with mitochondrial encephalomyop- or trunk characterized by overall smaller range of athy manifested chiefly by generalized chorea, motion, includes tremulousness; while pacing. dystonia, and ataxia.

[email protected] 66485438-66485457 266 Appendix c Video Atlas

9-4. This 10-year-old boy with chorea and some tics sign, and genetic studies confirmed a mutation in was found to have a de novo chromosome 15 para- the PANK2 gene. Her brother had onset of symp- centric inversion. toms at age 17 with difficulty with handwriting, 9-5. This girl has predominantly distal chorea follow- tightness of fingers, and foot dystonia. He later ing streptococcal infection with serologic evidence developed gait difficulties, falls, dysarthria with of Sydenham’s chorea. unintelligible speech, difficulties with chewing, 9-6. This boy has Sydenham’s chorea manifested by left and oro-lingual dystonia. The proband’s cousin hemichorea involving chiefly his left hand. has had progressive parkinsonism and dystonia. 9-7. This 8-year-old girl, a product of an alcoholic This family was reported in 2004. (Thomas M, mother who was a heavy cocaine abuser, was born Hayflick SJ, Jankovic J: Clinical heterogeneity prematurely and now manifests generalized cho- of neurodegeneration with iron accumulation–1 rea and cognitive impairment. (Hallervorden-Spatz syndrome) and pantothenate kinase–associated neurodegeneration (PKAN), 19:36–42, 2004.) Chapter 10 Dystonia Mov Disord 10-5. This 9-year-old boy with oromandibular, jaw 10-1. This boy with strong family history of DYT1 dys- opening, dystonia, which improved with injec- tonia developed rapidly progressive generalized tions of botulinum toxin into bilateral masseter dystonia that evolved into a dystonic storm (or sta- muscles, has a rapidly progressive generalized tus dystonicus), associated with muscle breakdown dystonia and MRI of the brain consistent with and myoglobinuria. Despite three thalamatomies PANK2 mutation. he eventually succumbed to the disease. He is a 10-6. This 12-year-old boy with genetically doc- proband of a family first reported in 2002. (Opal umented Friedreich’s ataxia has congenital P, Tintner R, Jankovic J, et al: Intrafamilial phe- torticollis associated with fibrotic contracture notypic variability of the DYT1 dystonia: from of the clavicular portion of the right sterno- asymptomatic TOR1A gene carrier status to dys- cleidomastoid muscle restricting his range of tonic storm, Mov Disord 17:339–345, 2002.) movement. This case was reported as part of 10-2. This girl with DYT1 dystonia manifested by oro- series of patients with congenital muscular mandibular, truncal, and leg dystonia, as well as torticollis. (Collins A, Jankovic J: Botulinum camptocormia, is the first reported case of marked toxin injection for congenital muscular tor- improvement of generalized dystonia following ticollis presenting in children and adults, bilateral pallidotomy. (Ondo WG, Desaloms M, Neurology 67:1083–1085, 2006.) Jankovic J, Grossman R: Surgical pallidotomy for the treatment of generalized dystonia, Mov Disord Chapter 11 Myoclonus 13:693–698, 1998.) She later required bilateral pal- 11-1. This young woman has Baltic myoclonus, also lidal deep brain stimulation to sustain the improve- known as Unverricht-Lundborg disease, due to ment. (Diamond A, Shahed J, Azher S, Dat-Vuong a gene mutation, called EPM1 on chromosome K, Jankovic J: Globus pallidus deep brain stimula- 21, manifested by jerk-like, myoclonic move- tion in dystonia, Mov Disord 21:692–695, 2006.) ments involving the face and upper body. 10-3. This girl has autosomal dominant DYT1 dys- 11-2. This girl has dystonia-myoclonus syndrome tonia, manifested by dystonic rapid movements due to epsilon-sarcoglycan mutation on chro- and dystonic gait disorder, requiring the assis- mosome 7, manifested by jerk-like, myoclonic tance of her mother, who is also affected by movements predominantly affecting her left DYT1 dystonia. She markedly benefited from arm, associated with dystonic writer’s cramp. bilateral pallidal deep brain stimulation. Both her father and her brother are similarly 10-4. This 17-year-old Latin American girl with child- affected by this jerk-like dystonic movement. hood history of hyperactivity and aggressiveness, 11-3. Young girl with documented Huntington’s and progressive cognitive and language deficit, disease, manifested by parkinsonism, myoclonus, developed dystonia of her left foot at age 10, chorea, and ataxia. which later evolved into generalized dystonia. In addition, she manifests stereotypic touching of Chapter 12 Tremor the ear and nose, and restless movements. Her T2-weighted MRI showed hypointensity of the 12-1. Home video of an infant girl with hereditary globus pallidus consistent with “eye-of-a-tiger” chin tremor.

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12-2. Young boy with multiple sclerosis and severe cer- Chapter 17 Cerebral Palsy ebellar outflow tremor benefited markedly from contralateral thalamic deep brain stimulation. 17-1. This boy has generalized chorea and ataxia with 12-3. This 18-year-old man had a long-standing pro- preserved cognitive function, characteristic of gressive gait difficulty and a 3-year history of head, “extrapyramidal” cerebral palsy. hand, and leg tremor. In addition to the lateral head oscillation and hand tremor, he manifests Chapter 18 Drug-Induced stork-like gait and distal leg and foot deformity Movement Disorders consistent with Charcot-Marie-Tooth disease. 12-4 This young man manifests symptoms of essen- 18-1. This 9-month-old girl developed orofacial stereo- tial tremor, a bilateral, regular tremor of the typy at age 2 months after 17-day treatment with hands present maintaining posture and on fin- metoclopramide for gastroesophageal reflux. This ger to nose testing approaching the target. is the youngest reported case of tardive dyskinesia. 12-5. This boy has developmental delay, with fine (Mejia N, Jankovic J: Metoclopramide-induced motor skill clumsiness, low tone, and tremulous- tardive dyskinesia in an infant, Mov Disord 20: ness. His hand tremor is brought out by posture, 86–89, 2005.) fatigue, finger to nose testing, and manipulating 18-2. This girl has severe generalized dyskinetic move- small objects. ments due to rapid withdrawal from haloperidol 12-6. This adolescent has a learning disabilities, tall – a drug withdrawal dyskinesia. stature, and resting and postural tremor associ- 18-3. This boy developed generalized dyskinesia after ated with 48, XXYY chromosomal aneuploidy. approximately 5 years of treatment with risperidone and fluphenazine. Symptoms resolved Chapter 13 Ataxias completely over 12-18 months. 18-4. This boy with Asperger’s Disorder developed 13-1. This home video shows a 22 month old boy with progressive, asymmetric dystonia with dystonic Ataxia Telangiectasia. He was referred for evalu- tremor after prolonged treatment with risperi- ation of delayed gait and involuntary move- done. Two years after discontinuing risperidone, ments. Although he has a broad based, lurching symptoms resolved nearly completely. gait, his predominant symptoms are intrusive choreic and dystonic movements. 13-2. This boy has an early onset, progressive, and severe Chapter 19 Psychogenic Movement phenotype of a spinocerebellar ataxia (SCA), Disorders affecting gait, fine motor control, finger to nose 19-1. This girl with psychogenic movement disorder testing, postural maintenance of limbs, and eye is able to move her legs normally and effort- movements. He has autosomal dominant SCA 5 lessly while seated. On standing, she develops a bizarre gait, characterized by tapping the ball of Chapter 14 Parkinsonism her right foot twice with each step. When her 14-1. This 15-year-old boy, previously diagnosed right leg is held stationary, a tremor develops in with “mental retardation” because of cognitive the right upper extremity. She also demonstrates impairment since age 6 years, began to develop convergence spasm. involuntary jerk-like movements at age 9, fol- 19-2. This girl has a resting, postural, and kinetic lowed by problems with his balance and general- tremor of the right arm. The psychogenic ori- ized slowness, dysarthria, myoclonus, ataxia, and gin of the tremor is suggested by its distracti- generalized seizures. The video demonstrates bility and variable frequency and amplitude. parkinsonian bradykinesia, blepharospasm, and Following a placebo challenge, there is immedi- stimulus-sensitive myoclonus. His father com- ate and complete resolution of the tremor. mitted suicide at age 41. DNA test confirmed 19-3. This patient with psychogenic dystonia mani- the diagnosis of juvenile Huntington’s disease fests violent limb and trunk posturing “when she with 89 CAG repeats in the Huntington gene. lets go” and no longer tries to suppress the move- 14-2. This 15-year-old girl has juvenile Huntington’s ments. Her affect is inappropriately cheerful, the disease with 67 CAG repeats in the Huntington so-called la belle indifference. gene. She manifests marked hypomimia and 19-4. This 16-year-old girl suddenly developed gener- bradykinesia consistent with parkinsonism. alized shaking of the body that occurred shortly

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after other girls in her school developed similar to match) by voluntary tasks with the same or shaking, suggestive of “mass hysteria.” contralateral hand. 19-5. This girl has an asymmetric, predominantly 19-6. This girl had a unilateral tremor which stopped unilateral tremor with variable amplitude and and started suddenly and was not present during frequency, affected by posture in ways not char- this neurology consultation. Home video shows acteristic of a neurologic postural tremor. The a unilateral hand and arm tremor with variable tremor is resolves briefly during distraction. The direction and rate characteristic of psychogenic tremor frequency can be entrained (modulated tremor.

[email protected] 66485438-66485457 O Note: Page numbersfollowed by Arousal disorders, 209–210 Aromatic 168–169 L-aminoaciddecarboxylase (ALAAD), Aripiprazole, 47 APS. SeeAntiphospholipidantibodysyndrome AOA. SeeAtaxia withoculomotorapraxia Anxiety, 43 Antiseizure medication,238 Antiphospholipid antibodysyndrome (APS),82,85–87 Angelman syndrome, 123 AMPT. SeeAlpha-methyl-para-tyrosine Amitriptyline, 259 Amino aciddisorders, 177–179 Amantadine, 249 ALT. SeeAlanineaminotransferase 236 Alpha-methyl-para-tyrosine (AMPT), Alanine aminotransferase(ALT), 182,183f SeeAromatic L-aminoaciddecarboxylaseALAAD. Aicardi-Goutières syndrome, 191 ADSL. SeeAdenylosuccinate lyasedeficiency Adrenocorticotrophins (ACTH), 121 Adolescent-onset mixed-type 103 dystonia(DYT6), ADHD. SeeAttention-deficit/hyperactivity disorder Adenylosuccinate lyase(ADSL)deficiency, 187 ADEM. SeeAcute disseminatedencephalomyelitis Acute disseminatedencephalomyelitis (ADEM), Acute ataxia,142–144,143t ACTH. SeeAdrenocorticotrophins AChE. SeeAcetylcholinesterase Acetylcholinesterase (AChE), 4 Acetylcholine, 14 Acetazolamide, 71,249,255 Aceruloplasminemia, 171,173 A treatment for, 87 pathophysiology of, 85–87 diagnostic approach to,87 clinical features of, 85 treatment of, 123 pathophysiology of, 123 clinical features of, 123 PKU, 178–179 Maple urinedisease,178 syrup homocystinuria, 177–178 disease,178 Hartnup clinical features of, 143–144 78f, 144 [email protected] 66485438-66485457 f andtindicatefigures andtables,respectively. Ataxia withisolatedvitaminEdeficiency Ataxia telangiectasia (AT), 148 Ataxia, 16–17, 139,140f,141 AT. SeeAtaxia telangiectasia ASDs. SeeAutism disorders spectrum Atomoxetine, 237 ATL. SeeAlanineaminotransferase Athetosis, 17,76–96,265–266 Ataxia withoculomotorapraxia(AOA), 148 pathophysiology of, 148 diagnosis of, 148 clinical features of, 148 of, 151 summary patient/family resources for, 151 localization/pathophysiology of, 139,140t introduction/overview of, 139 nonprogressive ataxiaII,142 nonprogressive ataxiaI,139–142 metabolic-chronic progressive, 150 metabolic-acute intermittent,144 chronic progressive/degenerative, 145,146t autosomal recessive, 147–150 autosomal dominantspinocerebellar/episodic, 145–147 acute, 142–144,143t diseases/disorders of, 139–150 diagnostic approach to,150–151 definition of, 139 clinical characteristicsof, 139 sleepwalking, 210 sleep terrors, 210 confusional arousals, 210 therapeutics of, 92 neurophysiology of, 79 neuroanatomy of, 77–79 localization/pathophysiology of, 77–79 introduction/overview of, 76 etiologic categoriesof, 79–80,81t diseases/disorders of, 79–92 diagnostic/therapeutic approach to,92 definition of, 76 clinical characteristicsof, 76–77 clinical features of, 148 treatment/outcomes of, 149 pathophysiology of, 148 diagnosis of, 148–149 clinical features of, 148 (AVED), 148–149 OIndex

269 O 270 Index

Attention-deficit/hyperactivity disorder (ADHD), 42 C DIMDs associated with, 236–237 CACH. See Childhood ataxia with central hypomyelination Autism, 60 Canavan, van Bogaert, Bertrand disease, 191 Autism spectrum disorders (ASDs), 236 Carbamazepine, 69, 106, 238, 249–250, 251, 255, 259 Autoimmune disorder, 43–44, 82 Carbidopa, 105, 166–167, 168, 253–254 Autosomal dominant spinocerebellar/episodic ataxia, Catechol-O-methyltransferase (COMT), 166–167 145–147 CDG. See Congenital disorders of glycosylation Autosomal recessive ataxias, 147–150 Cerebellum Autosomal recessive torsion dystonia anatomy/biochemistry/physiology of, 9–15 (DYT2), 101–102 conclusion on, 15 AVED. See Ataxia with isolated vitamin E deficiency functional anatomy of, 10t Azathioprine, 121 introduction to, 9 lobes/pathways in, 11t B macro/microscopic structure of, 9, 13t Baclofen, 47, 105–106, 172–173, 225, 250 afferent fiber types, 12 Baclofen intrathecal pump (ITB), 250 anatomic regions, 11, 11f Ballism, 17, 76–96, 265–266 cerebellar cortex layers, 12 clinical characteristics of, 76–77 functional regions, 11 definition of, 76 peduncles, 11, 12f, 12t diagnostic/therapeutic approach to, 92 “threes”, 9–11 diseases/disorders of, 79–92 neurotransmitters in, 13 etiologic categories of, 79–80, 81t acetylcholine/dopamine/norepinephrine/serotonin, 14 introduction/overview of, 76 endocannabinoid, 14 localization/pathophysiology of, 77–79 GABA, 14 neuroanatomy of, 77–79 glutamate, 13 neurophysiology of, 79 glutamate transporters, 13–14 therapeutics of, 92 structure/function/symptom overview of, 9, 12t Basal ganglia, 2–8, 3f, 6f Cerebral palsy (CP), 68–69, 219–230, 267 direct/indirect pathways of, 6f, 7, 7f diagnostic tests for, 223–224 motor output of, 4–6 assessment instruments, 224 Bassen-Kornzweig syndrome, 190–191 laboratory tests, 224 Benign familial myoclonic epilepsy, 119 neuroimaging, 223–224 clinical features of, 119 differentiating hypertonia, 220–221, 221t treatment of, 119 epidemiology of, 219 Benign hereditary chorea (BHC), 80–82 etiology of, 219–220, 220t clinical features of, 80 essential criteria for, 220b diagnostic approach to, 80 introduction to, 219 pathophysiology of, 80 management of, 224–226 treatment of, 80–82 IBP, 225, 226 Benign idiopathic dystonia of infancy, 35 neurolytic agents, 225 Benign infantile spams. See Benign myoclonus oral medications, 224–225, 226 of early infancy orthopedic surgery, 225–226 Benign myoclonus of early infancy (BMEI), pharmacotherapy/surgical approach, 224–226 32–33, 118 physical therapy, 224 clinical features of, 118 surgery, 226 Benign neonatal sleep myoclonus, 32, 206–207 syndromes of, 221–223 Benign paroxysmal torticollis, 35 ataxic type, 223 Benztropine, 236, 250 dyskinetic type, 222–223 BH4. See Tetrahydrobiopterin metabolism mixed type, 223 BHC. See Benign hereditary chorea spastic type, 221–222 BMEI. See Benign myoclonus of early infancy Cerebrotendinous xanthomatosis, 150 Botox. See Botulinum toxin B clinical features of, 150 Botulinum toxin B (Botox), 47, 106, Childhood absence epilepsies with myoclonia, 119–120 250–251 clinical features of, 119 Brain iron accumulation disorders, 173 pathophysiology of, 119–120 Branched-chain organic acidurias, 180–181, 180f phenomenology of, 119 methylacetoacetyl-CoA deficiency, 181 treatment of, 120 3-methylglutaconic aciduria, 181 Childhood ataxia with central hypomyelination (CACH), methylhydroxybutyryl-CoA dehydrogenase, 149–150, 149f 181 clinical features of, 149 MMA, 180–181 diagnosis of, 149–150 propionic acidemia, 181 pathophysiology of, 149 Brief Tumor Rating Scale, 135t treatment/outcomes of, 150

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Childhood parkinsonism, 156–157, 157t Cofactor disorders, 189 drug-induced, 159 molybdenum cofactor deficiency, 189 hereditary/degenerative diseases, 157 COMT. See Catechol-O-methyltransferase HD, 157–158 Confusional arousals, 210 Kufor-Rakeb syndrome, 158 Congenital disorders of glycosylation (CDG), NIID, 158 191–192, 192f pallido-pyramidal syndrome, 158 Corticosteroids, 255 RS, 158 Cortico-striatal-thalamocortical (CSTC), 44 infectious/postinfectious disease, 158 CP. See Cerebral palsy JPD, 156–157 Creatine metabolism disorders, 188–189 metabolic disease, 158–159 GAMT deficiency, 188, 188f Fahr syndrome, 158–159 other deficiency syndromes, 188–189 secondary causes of, 157–159 CSTC. See Cortico-striatal-thalamocortical Children with movement disorders diagnostic evaluation, CTD. See Chronic tic disorder 19–29, 20t, 26t, 27f, 263 Cyclosporine, 255 in clinic, 20–24 diagnosis strategy, 24–28 anatomic substrate identification, 25 D neurologic/psychiatric condition family history, 25 D-2-hydroxyglutaric acidemia, 182 nonneurologic/key features of history/physical Dantrolene, 225, 252 examination, 25 DAT. See Dopamine transporters OMIM/Genetests, 25–28 DBS. See Deep brain stimulation organized approach to, 24–28 Deep brain stimulation (DBS), 47–48, 106 pattern recognition, 24 Demyelinating disease, 68 phenomenology classification, 24–25 Depression, 43 proximate causes, 24 Desferrioxamine, 172–173 time course incorporation, 25 DHPR. See Dihydropteridine reductase introduction to, 19–20 Diabetes-associated subacute hemichorea, 88 preclinic, 20, 20t Diagnostic and Statistical Manual of Mental Disorders, summary of, 28–29 Fourth Edition, Text Revision (DSM-IV), 56 Chorea, 17, 76–96, 79f, 265–266 Diffusion-tensor magnetic resonance imaging (DT-MRI), clinical characteristics of, 76–77 44–45 definition of, 76 Dihydropteridine reductase (DHPR), 165 diagnostic/therapeutic approach, 92 DIMDs. See Drug-induced movement disorders diseases/disorders of, 79–92 Diphenhydramine, 236 etiologic categories of, 79–80, 81t DMD. See Dystonia musculorum deformans examination for, 76–77 Dopamine, 14, 45, 253 history of, 76–77 Dopamine transporters (DAT), 45 introduction/overview of, 76 Dopa-responsive dystonia (DRD) (DYT5), 98–99, localization/pathophysiology of, 77–79 102–103, 167 neuroanatomy of, 77–79 clinical features/natural history of, 102 neurophysiology of, 79 management/treatment of, 102–103 multisystem/genetic diseases and, 88–92 pathophysiology of, 102 HD, 88 Doxycycline, 255 IBSN, 88–92 DRD. See Dopa-responsive dystonia physiologic, 80 Dream anxiety attacks, 211 primary, 80–82 Drug-induced movement disorders (DIMDs), 61, secondary/acquired, 82–88 231–241, 267 therapeutics of, 92 ADHD treatment association with, 236–237 Choreoathetosis, 82 clinical features of, 236–237 Chronic bilirubin encephalopathy, 87–88 diagnosis of, 237 clinical features of, 87 epidemiology of, 236 pathophysiology of, 87–88 pathophysiology of, 237 Chronic progressive/degenerative treatment of, 237 ataxia, 145, 146t chemotherapeutic medications associated with, 238 clinical features/diagnostic approach of, 145 clinical characteristics of, 231–232 Chronic tic disorder (CTD), 41 conclusion of, 238 Cimetidine, 255 definition of, 231 Ciprofloxacin, 257 dopamine receptor blockade association with, 232–236 Clonazepam, 47, 104, 106, 251 clinical features of, 235 Clonidine, 47, 236–237, 251–252, 253 diagnosis of, 235–236 Clozapine, 252 epidemiology of, 232–235 Codeine, 252 NMS, 236

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Drug-induced movement disorders (DIMDs) (continued ) genetics/pathophysiology of, 99–101 pathophysiology of, 235 management/treatment of, 101 treatment of, 236 EDS. See Excessive daytime sleepiness forms of, 232t EM. See Essential myoclonus introduction/overview of, 231 Endocannabinoid, 14–15 neuroleptics/atypical antipsychotic drugs associated with, Enhanced physiologic tremor, 132 232–236, 233t clinical features of, 132 other medications associated with, 237–238 diagnostic approach/treatment of, 132 antiseizure medication, 238 pathophysiology of, 132 SSRIs, 237–238 EPC. See Epilepsia partialis continua DSM-IV. See Diagnostic and Statistical Manual of Mental Epilepsia partialis continua (EPC), 121 Disorders, Fourth Edition, Text Revision clinical features of, 121 DT-MRI. See Diffusion-tensor magnetic resonance imaging pathophysiology of, 121 DTY1. See Early-onset primary torsion dystonia treatment of, 121 Dyskinesias. See Paroxysmal dyskinesia; Paroxysmal Episodic ataxia type 1 (EA1), 144 exertion-induced dyskinesia; Paroxysmal hypnogenic clinical features of, 144 dyskinesia; Paroxysmal kinesigenic dyskinesia; Episodic ataxia type 2 (EA2), 144–145 Paroxysmal nonkinesigenic dyskinesia clinical features of, 144–145 Dyskinetic/choreoathetoid cerebral palsy, 87 Erythromycin, 251 Dyssomnia, 207–209 Essential myoclonus (EM), 114–118 narcolepsy, 207–208 clinical features of, 114 PLMS, 209 diagnostic approach to, 118 RLS, 208 pathophysiology of, 114–118 Dystonia, 17, 97–109, 98t, 100t, 245, 266 treatment of, 118 clinical characteristics of, 97–99 Essential tremor (ET), 133–135 diagnostic approach of, 105 clinical features of, 133 etiologies of, 99–106 consensus criteria for, 134t dystonic storm, 105 diagnostic approach to, 133–134 DYT1, 99 pathophysiology of, 133 DYT2, 101–102 treatment of, 134–135 DYT4, 101–102 Essential Tremor Rating Scale (TETRAS), 134 DYT5, 102–103 ET. See Essential tremor DYT6, 103 Ethosuximide, 120 DYT11, 103–104 Excessive daytime sleepiness (EDS), 207 DYT12, 104 Excessive fragmentary myoclonus, 207 DYT13, 104 Excitatory amino acid transporters (EAAT), 13–14 DYT16, 104 secondary dystonias, 101b, 101t, 104–105 F introduction/definition of, 97 FA. See Friedreich ataxia localization/pathophysiology of, 98–99 Fahr syndrome, 158–159 management/treatment of, 105–106 Fentanyl, 252 nonpharmacologic treatment of, 106 Fluoxetine, 256 patient/family resources for, 106 Fluphenazine, 47, 252 Dystonia musculorum deformans (DMD), 97 Fluvoxamine, 257 Dystonic storm, 105 Friedreich ataxia (FA), 147–148 DYT1. See Early-onset primary torsion dystonia clinical features of, 147 DYT2. See Autosomal recessive torsion dystonia diagnosis of, 147 DYT4. See Non-DYT1 dystonia pathophysiology of, 147 DYT5. See Dopa-responsive dystonia treatment of, 147–148 DYT6. See Adolescent-onset mixed-type dystonia Fumarase deficiency, 183–184 DYT11. See Myoclonus dystonia syndrome DYT12. See Rapid-onset dystonia-parkinsonism G DYT13. See Early-onset multifocal/segmental dystonia DYT16. See Early-onset dystonia-parkinsonism GABA. See Gamma-aminobutyric acid Gabapentin, 69, 135 GABA-related neurotransmitter disease, 169 E Gamma-aminobutyric acid (GABA), 2–3, 14 EA1. See Episodic ataxia type 1 GAMT. See Guanidinoacetate methyltransferase deficiency EA2. See Episodic ataxia type 2 Gaucher disease, 175 EAAT. See Excitatory amino acid transporters GCDH. See Glutaryl-CoA dehydrogenase Early-onset dystonia-parkinsonism (DYT16), 104 Genetests, 25–28, 263t Early-onset multifocal/segmental dystonia (DYT13), 104 GLAST. See Glutamate aspartate transporter Early-onset primary torsion dystonia (DYT1), 99–101 Glucose transport defect (GLUT1), 189 diagnostic features/natural history of, 99 GLUT1. See Glucose transport defect

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Glutamate, 13, 46 expressive/receptive language, 23 Glutamate aspartate transporter (GLAST), 13–14 general physical examination, 22 Glutamate transporters, 13–14 mental status/general cognitive/emotional cerebral Glutaric aciduria type 1, 179–180 function, 22–23 Glutaryl-CoA dehydrogenase (GCDH), 179 neurologic examination, 22–23 Glycolysis/pyruvate metabolism/tricarboxylic acid cycle sensory examination, 23–24 disorders, 182–184 tremor examination, 24 fumarase deficiency, 183–184 waiting room/check-in process, 21 2-Ketoglutarate dehydrogenase deficiency, 183 INAD. See Infantile neuroaxonal dystrophy PC deficiency, 182 INCL. See Infantile neuronal ceroid lipofuscinoses PDH deficiency, 182–183 Infancy chorea, 80 TPI deficiency, 182 clinical features of, 80 GMFM. See Gross Motor Function Measure Infantile bilateral striatal necrosis (IBSN), 88–92 Gross Motor Function Measure (GMFM), 224 Infantile neuroaxonal dystrophy (INAD), 173 GTP. See Guanidine triphosphate Infantile neuronal ceroid lipofuscinoses (INCL), 176 Guanfacine, 47, 252–253 Infantile-onset spinocerebellar ataxia (IOSCA), 149 Guanidine triphosphate (GTP), 102 clinical features of, 148–149 Guanidinoacetate methyltransferase (GAMT) deficiency, Inherited metabolic disorders associated with extrapyramidal 188, 188f symptoms, 164–204, 164b. See also Metabolic disorders H BH4 defects with hyperphenylalaninemia, 165–167 Hallervorden-Spatz syndrome (HSS), 171 BH4 defects without hyperphenylalaninemia, 167–168 Haloperidol, 47, 61, 232, 253, 255 BH4 metabolism, 164–165 HARP syndrome, 172f, 173 GABA-related neurotransmitter disease, 169 Hartnup disease, 178 monoamine biosynthesis primary defects, 168–169 HD. See Huntington’s disease pediatric neurotransmitter diseases, 164 Head nodding stereotypies, 34–35, 58–59 Intermittent tremor in adolescent, 132–133 Hemiballism, 88 Intermittent tremor in young child, 132 Hemichorea, 88 Intravenous immune globulin (IVIG), 253 Hereditary hyperekplexia, 112–114 IOSCA. See Infantile-onset spinocerebellar ataxia clinical features of, 112–113 Isoniazid, 255 diagnostic approach to, 113 ITB. See Baclofen intrathecal pump pathophysiology of, 113, 113t IVIG. See Intravenous immune globulin treatment of, 113–114 5-HIAA. See 5-hydroxyindoleacetic acid J Homocysteine metabolism, 177f Jansky-Bielschowsky disease. See Late-infantile neuronal Homocystinuria, 177–178 ceroid lipofuscinoses HSS. See Hallervorden-Spatz syndrome JME. See Juvenile myoclonic epilepsy Huntington’s disease (HD), 78f, 88, 157–158 JNCL. See Juvenile neuronal ceroid lipofuscinoses clinical features of, 88 JPD. See Juvenile Parkinson’s disease diagnostic approach to, 88 Juvenile myoclonic epilepsy ( JME), 119 treatment of, 88 clinical features of, 119 5-hydroxyindoleacetic acid (5-HIAA), 164 diagnostic approach to, 119 Hyperglycemia, 88 pathophysiology of, 119 clinical features of, 88 treatment for, 119 diagnostic approach to, 88 Juvenile neuronal ceroid lipofuscinoses ( JNCL), 176–177 pathophysiology of, 88 Juvenile Parkinson’s disease ( JPD), 156–157 treatment of, 88 Hypnagogic jerks, 206 Hypnic jerks, 206 K Hypothyroidism, 82 Kernicterus, 87–88 Ketoconazole, 249–250, 259 I 2-Ketoglutarate dehydrogenase deficiency, 183 Kufor-Rakeb syndrome, 158 IBSN. See Infantile bilateral striatal necrosis Idiopathic myoclonus in oromandibular region, 207 In clinic diagnosis, of childhood movement disorders L cerebellar examination, 24 L-2-hydroxyglutaric aciduria, 181–182 child interview, 21 Lactate dehydrogenase (LDH), 182 cranial nerves, 23 Lafora disease, 122–123 first physician encounter, 21 clinical features of, 122 motor examination, 23 pathophysiology of, 122–123 parent/guardian interview, 21–22 Lamotrigine, 69, 120, 238, 259 physical/neurologic examination, 22–23 Late-infantile neuronal ceroid lipofuscinoses (LINCL), 176

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LDH. See Lactate dehydrogenase mitochondrial disorders, 184–186 Leber hereditary optic neuropathy (LHON), 185 Leigh syndrome, 185 Leigh syndrome, 185 MTS, 185–186 Lesch-Nyhan disease (LND), 186–188 other types of, 185 Leukoencephalopathies, 191 organic acid disorders, 179–182 Levetiracetam, 47, 69, 104, 118, 121, 253 branched-chain organic acidurias, 180–181 Levodopa, 71, 102–103, 105, 159, 166–167, 168, 253–254 lysine catabolism disorders, 179–180 LHON. See Leber hereditary optic neuropathy other types of, 181–182 LINCL. See Late-infantile neuronal ceroid lipofuscinoses other disorders, 189–192 Lipoic acid, 182 CDG, 191–192, 192f Lithium, 249 GLUT1 deficiency, 189 LND. See Lesch-Nyhan disease leukoencephalopathies, 191 Long-term depression (LTD), 4 neuroacanthocytosis, 189–191 Long-term potentiation (LTP), 4 purine metabolism disorders, 186–188, 186f LTD. See Long-term depression ADSL, 187 LTP. See Long-term potentiation LND, 186–187 Lysine catabolism disorders, 179–180, 179f PRPS1 deficiency, 188 Lysosomal disorders, 173–177 PRPS1 superactivity, 187–188 Gaucher disease, 175 white matter disorders, 177 NCLs, 175–177 Metabolic/toxic disorders, 69. See also Inherited Niemann-Pick disease, 175 metabolic disorders associated with extrapyramidal symptoms M Metachromatic leukodystrophy (MLD), 177 Maple syrup urine disease, 178 3-Methylglutaconic aciduria, 181 Masturbation, posturing during, 35–36 3-methyoxy-4-hydroxylphenylglycol (MHPG), 164 McLeod syndrome, 190 Methylacetoacetyl-CoA deficiency, 181 MDS. See Myoclonus dystonia syndrome Methylhydroxybutyryl-CoA dehydrogenase, 181 MELAS. See Mitochondrial encephalomyopathy, lactic Methylmalonic acidemia (MMA), 180–181 acidosis, and stroke-like episodes Methylphenidate, 236–237, 251–252 Mental retardation, 60 Methylprednisolone, 255 Meperidine, 252 Metoclopramide, 232, 235 MERRF. See Myoclonus epilepsy with ragged red fibers MHPG. See 3-methyoxy-4-hydroxylphenylglycol Metabolic ataxia-acute intermittent, 144 Mineral accumulation, 169–173 Metabolic ataxia-chronic progressive, 150 aceruloplasminemia, 171 Metabolic disorders, 169 brain iron accumulation disorders, 173 amino acid disorders, 177–179 HARP syndrome, 173 Hartnup disease, 178 NBIA, 171 homocystinuria, 177–178 PKAN, 171–172 Maple syrup urine disease, 178 Wilson’s disease, 169–171 PKU, 178–179 MIRAS. See Mitochondrial recessive cofactor disorders, 189 ataxia syndrome molybdenum cofactor deficiency, 189 Mitochondrial disorders, 184–186, 184f creatine metabolism disorders, 188–189 Leigh syndrome, 185 GAMT deficiency, 188 MTS, 185–186 other deficiency syndromes, 188–189 other types of, 185 glycolysis/pyruvate metabolism/tricarboxylic acid cycle Mitochondrial encephalomyopathy, lactic acidosis, and disorders, 182–184 stroke-like episodes (MELAS), 185 fumarase deficiency, 183–184 Mitochondrial neurogastrointestinal encephalopathy 2-Ketoglutarate dehydrogenase deficiency, 183 (MNGIE), 185 PC deficiency, 182 Mitochondrial recessive ataxia syndrome (MIRAS), 149 PDH deficiency, 182–183 clinical features of, 149 TPI deficiency, 182 MLD. See Metachromatic leukodystrophy lysosomal disorders, 173–177 MMA. See Methylmalonic acidemia Gaucher disease, 175 MNGIE. See Mitochondrial neurogastrointestinal NCLs, 175–177 encephalopathy Niemann-Pick disease, 175 Mohr-Tranebjaerg syndrome (MTS), 185–186 mineral accumulation, 169–173 Molybdenum cofactor deficiency, 189 aceruloplasminemia, 171 Monoamine biosynthesis primary defects, 168–169 brain iron accumulation disorders, 173 ALAAD, 168–169 HARP syndrome, 173 TH deficiency, 168 NBIA, 171 Morphine, 252 PKAN, 171–172 Motor stereotypies, 56–65, 57t Wilson’s disease, 169–171 classification of, 58–61, 59t

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primary, 58–60 therapeutics/treatment of, 124 secondary, 60–61 Myoclonus dystonia syndrome (MDS) (DYT11), definition of, 56 103–104, 118 differentiating of, 56–57 clinical features/natural history of, 103, 118 introduction to, 56 diagnostic approach to, 118 pathophysiology of, 57–58 management/treatment of, 104 therapy for, 61 pathophysiology of, 103–104, 118 Movement disorder classifications, 16–18 treatment of, 118 ataxia, 16–17, 139 Myoclonus epilepsy with ragged red fibers athetosis, 17, 76–96 (MERRF), 122 ballismus, 17, 76–96 clinical features of, 122 chorea, 17, 76–96 pathophysiology of, 122 dystonia, 17, 97–109 treatment for, 122 myoclonus, 17, 110–128 parkinsonism, 17, 154–162 N stereotypies, 17, 56–65 NBIA. See Neurodegeneration with brain iron tics, 17, 41 accumulation tremors, 17–18, 129–138 NCLs. See Neuronal ceroid lipofuscinoses MSLT. See Multiple Sleep Latency Test Neonatal respiratory distress, 82 MTS. See Mohr-Tranebjaerg syndrome Neuroacanthocytosis, 189–191 Multiple Sleep Latency Test (MSLT), 207 Neurodegeneration with brain iron accumulation Mycophenolate, 121 (NBIA), 171 Myoclonia continua, 121 Neuroleptic malignant syndrome (NMS), 236 clinical features of, 121 Neuronal ceroid lipofuscinoses (NCLs), pathophysiology of, 121 123, 175–177, 176t treatment of, 121 clinical features of, 123 Myoclonus, 17, 110–128, 111t, 112t, 245, 266–267 diagnostic approach to, 123 See also Sleep-related myoclonic disorders INCL, 176 clinical characteristics of, 110–111, 110t pathophysiology of, 123 clinical differentiation of, 111 treatment for, 123 definition of, 110 Neuronal intranuclear inclusion diagnostic/therapeutic approach of, 123–124 disease (NIID), 158 diseases/disorders of, 112–123 Neuronal storage diseases, 174f introduction/overview of, 110 Neuropsychiatric startle syndromes, 114 localization/pathophysiology of, 111–112 clinical features of, 114 neurophysiology of, 111–112, 112t Niemann-Pick diseases, 175 physiologic, 112 NIID. See Neuronal intranuclear benign forms of, 112 inclusion disease PME, 121–123 NMS. See Neuroleptic malignant syndrome Angelman syndrome, 123 Nocturnal tooth grinding, 212 Lafora disease, 122–123 Non-DYT1 dystonia (DYT4), 101–102 MERRF, 122 Nonprogressive ataxia I, 139–150 NCLs, 123 clinical features of, 139–142 sialidoses, 123 diagnostic approach to, 141–142 Unverricht-Lundborg disease, 122 outcomes of, 142 primary, 114–118 pathophysiology of, 139–141 BMEI, 118 treatment of, 142 DYT11, 118 Nonprogressive ataxia II, 142 EM, 114–118 Non-rapid eye movement (NREM), 205 primary epileptic, 118–120 Norepinephrine, 14 benign familial, 119 NREM. See Non-rapid eye movement childhood absence epilepsies with, 119–120 JME, 119 secondary, 120–121 O EPC/Rasmussen’s encephalitis/myoclonia Obsessive compulsive behaviors (OCBs), 42 continua, 121 Obsessive-compulsive disorder (OCD), OMAS, 120 42–43, 57–58 postanoxic, 121 OCBs. See Obsessive compulsive behaviors startle syndromes and, 112–114 OCD. See Obsessive-compulsive disorder hereditary hyperekplexia, 112–114 Olanzapine, 47, 254 neuropsychiatric startle syndromes, 114 OMAS. See Opsoclonus myoclonus startle epilepsies, 114 (ataxia) syndrome symptomatic startle disorders, 114 OMIM. See Online Mendelian Inheritance in Man

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Online Mendelian Inheritance in Man (OMIM), 25–28, 263 demyelinating disease, 68 Opsoclonus myoclonus (ataxia) syndrome (OMAS), differential diagnosis/evaluation of, 69 120–121 etiology of, 67–68 clinical features of, 120 metabolic/toxic disorders, 69 diagnostic approach to, 120–121 pathophysiology of, 69 pathophysiology of, 120 treatment/outcome of, 69 treatment of, 121 Paroxysmal nonkinesigenic dyskinesia (PNKD), 68t, 69–71 Organic acid disorders, 179–182 differential diagnosis of, 70 branched-chain organic acidurias, 180–181 etiology of, 70 lysine catabolism disorders, 179–180 pathophysiology of, 70–71 other types of, 181–182 treatment/outcome of, 71 Oxcarbazepine, 69 Paroxysmal tonic upgaze of infancy, 34 Oxidative phosphorylation (OXPHOS), 184 PC. See Pyruvate carboxylase deficiency OXPHOS. See Oxidative phosphorylation PD. See Parkinsonism PDD. See Pervasive disorders of development P PDH. See Pyruvate dehydrogenase complex deficiency PED. See Paroxysmal exertion-induced dyskinesia Pallido-pyramidal syndrome, 158 PEDI. See Pediatric Evaluation of Disability Inventory PANDAS. See Pediatric autoimmune neuropsychiatric Pediatric autoimmune neuropsychiatric disorders associated disorders associated with streptococcal infection with streptococcal infection (PANDAS), 41 PANK. See Pantothenate kinase Pediatric Evaluation of Disability Inventory (PEDI), 224 Pantothenate kinase (PANK), 171f Pelizaeus-Merzbacher disease, 191 Pantothenate kinase-associated neurodegeneration (PKAN), Penicillamine, 254, 259 104–105, 171–172 Periodic limb movements in sleep (PLMS), 209 Parasomnia, 209–212 Periventricular leukomalacia (PVL), 222 arousal disorders, 209–210 Pervasive disorders of development (PDD), 22–23 confusional arousals, 210 PHD. See Paroxysmal hypnogenic dyskinesia sleep terrors, 210 Phenobarbital, 251, 256, 259 sleepwalking, 210 Phenylethylmalonamide, 256 REM sleep disorders, 211 Phenylketonuria (PKU), 165, 178–179 nightmares, 211 Phenytoin, 69, 238, 251, 255, 258 RBD, 211 Phosphoribosylpyrophosphate synthase (PRPS1) sleep-wake transition disorders, 210–211 deficiency of, 188 PHD, 211–212 superactivity of, 187–188 RMDs, 210 Physiologic chorea Parkinsonism (PD), 17, 154–162, 267 chorea minor, 80 childhood etiology of, 156–157, 157t in infancy, 80 JPD, 156–157 clinical features of, 80 secondary parkinsonism, 157–159 Physiologic myoclonus, 112 clinical features of, 154 benign forms of, 112 introduction to, 154 clinical features of, 112 pathophysiology of, 154–156 diagnostic approach, 112 akinesia, 155–156 pathophysiology of, 112 bradykinesia, 155 Pimozide, 47, 232, 254–255 postural instability, 156 Piracetam, 118, 255 rigidity, 156 PKAN. See Pantothenate kinase-associated neuro tremor, 155 degeneration treatment of, 159–160 PKD. See Paroxysmal kinesigenic dyskinesia Paroxetine, 256 PKU. See Phenylketonuria Paroxysmal dyskinesia, 66–74, 67t, 265 PLMS. See Periodic limb movements in sleep clinical characteristics of, 66–67 PMDs. See Psychogenic movement disorders introduction to, 66 PMEs. See Progressive myoclonic epilepsies specific disorders of, 67–72 PNET. See Primitive neuroectodermal tumor Paroxysmal exertion-induced dyskinesia (PED), 68t, 71 PNKD. See Paroxysmal nonkinesigenic dyskinesia etiology of, 71 Postanoxic myoclonus, 121 pathophysiology of, 71 clinical features of, 121 treatment/outcome of, 71 pathophysiology of, 121 Paroxysmal hypnogenic dyskinesia (PHD), 71–72, treatment of, 121 211–212 Postpump chorea, 87 etiology of, 72 clinical features of, 87 treatment/outcome of, 72 pathophysiology of, 87 Paroxysmal kinesigenic dyskinesia (PKD), 67–69, 68f, 68t treatment of, 87 CP, 68–69 Pramipexole, 255

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Preclinic diagnosis, of childhood movement disorders, 20 LND, 186–187 previsit data gathering, 20 PRPS1 deficiency, 188 scheduling process, 20 PRPS1 superactivity, 187–188 urgent referrals for, 20, 20t PVL. See Periventricular leukomalacia Prednisone, 255 Pyridoxine, 254 Pregabalin, 135 Pyruvate carboxylase (PC) deficiency, 182 Primary chorea, 80–82 Pyruvate dehydrogenase complex (PDH) deficiency, BHC, 80–82 182–183 choreoathetosis/hypothyroidism/neonatal Pyruvate metabolism. See Glycolysis/pyruvate respiratory distress, 82 metabolism/tricarboxylic acid cycle disorders Primary epileptic myoclonus, 118–120 benign familial, 119 Q childhood absence epilepsies with, 119–120 Quetiapine, 47, 256 JME, 119 Quinidine, 249–250 Primary motor stereotypies, 58–60 Quinine, 255 common stereotypies as, 59 complex movement stereotypies as, 59–60 R head-nodding stereotypies as, 59 Ranitidine, 255 Primary myoclonus, 114–118 Rapid eye movement (REM), 205 BMEI, 118 Rapid-onset dystonia-parkinsonism DYT11, 118 (RDP) (DYT12), 104 EM, 114–118 Rasmussen’s encephalitis, 121 Primary tremors, 132–135 clinical features of, 121 enhanced physiologic tremor, 132 pathophysiology of, 121 ET, 133–135 treatment of, 121 intermittent tremor in adolescent, 132–133 RBD. See REM sleep behavioral disorder intermittent tremor in young child, 132 RDP. See Rapid-onset dystonia-parkinsonism Primidone, 135, 249, 255–256, 259 Refsum disease, 150 Primitive neuroectodermal tumor (PNET), 145 clinical features of, 150 Prochlorperazine, 232 REM. See Rapid eye movement Progressive myoclonic epilepsies (PMEs), 121–123 REM sleep behavioral disorder (RBD), 211 Angelman syndrome, 123 REM sleep disorders, 211 Lafora disease, 122–123 nightmares, 211 MERRF, 122 RBD, 211 NCLs, 123 RER. See Rough endoplasmic reticulum sialidoses, 123 Reserpine, 256 Unverricht-Lundborg disease, 122 Restless legs syndrome (RLS), 208 Propionic acidemia, 181 Rett syndrome (RS), 60–61, 158 Propranolol, 135, 256 Rhythmic movement disorders (RMDs), 210 Propriospinal myoclonus, 207 Risperidone, 61, 232–234, 256 PRPS1. See Phosphoribosylpyrophosphate synthase Rituximab, 121 Pseudoephedrine, 249 RLS. See Restless legs syndrome Psychiatric disorders, 61 RMDs. See Rhythmic movement disorders Psychogenic movement disorders (PMDs), 242–247, 267 Ropinirole, 256–257 clinical features of, 242–243 Rough endoplasmic reticulum (RER), 191–192 conclusion on, 246 RS. See Rett syndrome diagnosis of, 243–244 in children, 243b S diagnostic aids for, 244–245 Sandifer syndrome, 35 diagnostic criteria for, 244 SC. See Sydenham’s chorea clinically established, 244 SCA. See Spinocerebellar ataxia documentation, 244 SCA1. See Spinocerebellar atrophy type 1 possible, 244 SCA2. See Spinocerebellar atrophy type 2 probable, 244 SCA3. See Spinocerebellar atrophy type 3 epidemiology of, 242 SCA7. See Spinocerebellar atrophy type 7 pathophysiology of, 243 SCA13. See Spinocerebellar atrophy specific movement disorder types of, 245 type 13 dystonia, 245 Secondary chorea, 82–88 myoclonus, 245 dyskinetic/choreoathetoid cerebral palsy, 87 tremor, 245 hyperglycemia/diabetes-associated subacute treatment/outcome of, 245–246 hemichorea/hemiballism, 88 Purine metabolism disorders, 186–188, 186f in immunologic/autoimmune disease, 82 ADSL, 187 SC, 82–85

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Secondary chorea (continued ) clinical features of, 145 kernicterus/chronic bilirubin encephalopathy, 87–88 Spinocerebellar atrophy type 2 (SCA2), 145–147 in SLE/APS, 85–87 clinical features of, 145–147 vascular/hypoxic ischemic, 87 Spinocerebellar atrophy type 3 (SCA3), 147 postpump chorea, 87 clinical features of, 147 Secondary dystonia, 101b, 101t, 104–105 Spinocerebellar atrophy type 7 (SCA7), 147 Secondary motor stereotypies, 60–61 clinical features of, 147 autism/mental retardation association with, 60 Spinocerebellar atrophy type 13 (SCA13), 147 drug-induced, 61 clinical features of, 147 inborn metabolism errors associated with, 61 SPR. See Sepiapterin reductase psychiatric disorders associated with, 61 SSADH. See Succinic semialdehyde dehydrogenase RS association with, 60–61 deficiency sensory deprivation association with, 61 SSRIs. See Selective serotonin reuptake inhibitors Secondary myoclonus, 120–121 Startle syndromes, 112–114 EPC/Rasmussen’s encephalitis/myoclonia hereditary hyperekplexia, 112–114 continua, 121 neuropsychiatric startle syndromes, 114 OMAS, 120 startle epilepsies, 114 postanoxic, 121 symptomatic startle disorders, 114 Secondary parkinsonism, 157–159 Stereotypies, 17, 265 See also Motor stereotypies; Primary hereditary/degenerative disease, 157 motor stereotypies; Secondary motor stereotypies structural lesions of, 157 common behavior, 58–59 Secondary tic disorder, 41 complex motor movement, 58–60 Selective serotonin reuptake inhibitors (SSRIs), 237–238 head nodding, 34–35, 58–59 Sepiapterin reductase (SPR) deficiency, 165, 167–168 Striatum, 2, 44–45 Serotonin, 14, 45–46. See also Selective serotonin reuptake Substantia nigra pars compacta (SNpc), 2–3 inhibitors Succinic acid synthesis, 169f Serotonin transporter (SERT), 45–46 Succinic semialdehyde dehydrogenase (SSADH) SERT. See Serotonin transporter deficiency, 169 Sialidoses, 123 Sulfamethoxazole, 121 clinical features of, 123 Sulpiride, 47 pathophysiology of, 123 Sydenham’s chorea (SC), 77, 78f, 82–85 SLE. See Systemic lupus erythematosus clinical features of, 82–83 Sleep diagnostic approach to, 84 bruxism, 212 laboratory testing, 84 disorders of, 43 neuroimaging, 84 hyperkinetic movement disorders during daytime and, specialty consultation, 84 212 pathophysiology of, 83–84 movements occurring in, 205–218 treatment of, 84–85 classifications of, 205 immune modulation, 85, 86t physiology overview of, 205–206, 206f secondary prevention, 84–85 seizures in/around time of, 212–213 symptom suppression, 85 starts, 206 Symptomatic startle disorders, 114 terrors, 210 clinical features/pathophysiology of, 114 Sleep-related movement disorders, 205–212 Symptomatic tremor, 135, 136t sleep physiology overview of, 205–206, 206f Systemic lupus erythematosus (SLE), 82, 85–87 Sleep-related myoclonic disorders, 206–207 clinical features of, 85 benign neonatal sleep myoclonus, 206–207 diagnostic approach to, 87 excessive fragmentary myoclonus in NREM sleep, 207 pathophysiology of, 85–87 hypnic jerks, 206 treatment for, 87 idiopathic myoclonus in oromandibular region during sleep, 207 T propriospinal myoclonus, 207 TCA. See Tricarboxylic acid cycle Sleep-wake transition disorders, 211–212 Tetrabenazine, 85, 92, 236, 257 PHD, 211–212 Tetrahydrobiopterin (BH4) metabolism, 164–165 RMDs, 210 with hyperphenylalaninemia defects, Sleepwalking, 210 165–167 SNpc. See Substantia nigra pars compacta clinical presentation of, 165–166 Sodium oxybate, 104, 257 treatment of, 166–167 Sodium valproate, 118, 119, 120, 122 without hyperphenylalaninemia defects, Spielmeyer-Vogt-Sjögren disease. See Juvenile neuronal 167–168 ceroid lipofuscinoses treatment for, 168 Spinocerebellar ataxia (SCA), 145 synthesis of, 166f Spinocerebellar atrophy type 1 (SCA1), 145 TETRAS. See Essential Tremor Rating Scale

[email protected] 66485438-66485457 Index 279

Tetrathiomolybdate (TM), 171, 257, 259 benign paroxysmal torticollis, 35 TH. See Tyrosine hydroxylase deficiency BMEI, 32–33 Theophylline, 255 head nodding, 34–35 Thiamine, 182 introduction to, 32 Thioridazine, 61 jitteriness, 33 Tic(s), 17, 40–55, 111, 111t masturbation posturing, 35–36 cervical, 264 paroxysmal tonic upgaze of infancy, 34 motor stereotypies v, 57t Sandifer syndrome, 35 phenomenology of, 40–41 shuddering, 33–34 suppression of, 46–47 Tremor, 17–18, 129–138, 155, 245, 266–267 nonpharmacologic treatments, 46–47 clinical characteristics of, 129–130, 130t pharmacotherapy, 47, 47f clinical differentiation of, 130 Tic disorders, 41, 261–262 definition of, 129 cervical tics, 264 diagnosis/management of, 135–136 complex motor tics, 264 disease/disorders of complex phonic tics, 265 primary, 132–135 diagnosis deferred, 41 symptomatic, 135 eye/facial tics, 264 introduction/overview of, 129 limb tics, 264 localization/pathophysiology of, 130–131 neurobiology of, 44–46 Tricarboxylic acid (TCA) cycle, 182, 183f neuroanatomic localization, 44–45 Tricarboxylic acid cycle disorder. neurotransmitter abnormalities, 45–46 See Glycolysis/pyruvate metabolism/ shoulder tics, 264 tricarboxylic acid cycle disorders simple phonic tics, 264 Trientine, 171, 258, 259 trunk-abdominal tics, 264 Trihexyphenidyl, 103, 105, 258 Titubation, 111 Trimethoprim, 121 Tizanidine, 225, 257–258 Triosephosphate isomerase (TPI) deficiency, 182 TM. See Tetrathiomolybdate TS. See Tourette syndrome Topiramate, 47, 69, 135, 249, 258 Tyrosine hydroxylase (TH) deficiency, 168 Tourette disorder, 41 Tourette syndrome (TS), 40–55 U associated behaviors/psychopathologies in, 42–43 Unverricht-Lundborg disease, 122 academic difficulties, 43 clinical features of, 122 ADHD, 42 pathophysiology of, 122 anxiety/depression, 43 episodic outbursts/self-injurious behavior, 43 V OCD, 42–43 sleep disorders, 43 Valproate, 104 epidemiology of, 41–42 Valproic acid, 251, 255, 258–259 etiology of, 43–44 Ventral pallidum (VP), 4 autoimmune disorder, 43–44 Ventral tegmental area (VTA), 5 genetic basis of, 43 Verapamil, 252, 255 introduction to, 40 Vigabatrin, 169 outcome of, 42 VP. See Ventral pallidum surgical approach to, 47–48 VTA. See Ventral tegmental area treatment of, 46–47 general principles of, 46 W tic suppression, 46–47, 47f Warfarin, 259 Tourette-like disorder, 41 White matter disorders, 177 TPI. See Triosephosphate isomerase deficiency Wilson’s disease, 169–171, 170f Transient/developmental movement disorders, 32–37 Z benign idiopathic dystonia of infancy, 35 Ziprasidone, 47, 259 benign neonatal sleep myoclonus, 32 Zonisamide, 259–260

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