When It’s Not ALS! Pure Motor

American Association of Syndromes Electrodiagnostic Medicine

Richard J. Barohn, MD Jonathan S. Katz, MD David S. Saperstein, MD Vinay Chaudhry, MD

2004 AAEM COURSE E AAEM 51st Annual Scientific Meeting Savannah, Georgia When It’s Not ALS! Pure Motor Syndromes

Richard J. Barohn, MD Jonathan S. Katz, MD David S. Saperstein, MD Vinay Chaudhry, MD

2004 COURSE E AAEM 51st Annual Scientific Meeting Savannah, Georgia

Copyright © November 2004 American Association of Electrodiagnostic Medicine 421 First Avenue SW, Suite 300 East Rochester, MN 55902

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Faculty

Richard J. Barohn, MD David S. Saperstein, MD Chairman and Professor Assistant Professor Department of Neurology Department of Neurology University of Missouri – Kansas City School of Medicine University of Kansas Medical Center Kansas City, Kansas Kansas City, Kansas Dr. Barohn is a graduate of the 6-year BA/MD program at the University Dr. Saperstein earned his medical degree from Boston University School of of Missouri – Kansas City School of Medicine. He completed a medicine Medicine, and performed both his internal medicine and neurology resi- internship at Wilford Hall United States Air Force Medical Center at dencies at Wilford Hall Medical Center. He is currently an assistant pro- Lackland Air Force (USAF) Base in San Antonio, Texas prior to serving as fessor in the Department of Neurology, and in the Department of General Medical Officer for the USAF. He completed a neurology resi- Pathology and Laboratory Medicine at the University of Kansas Medical dency there, then performed a neuromuscular fellowship at Ohio State Center. His academic interests include the clinical aspects of management University, and is now Chair of the Department of Neurology at the of neuromuscular disorders with a special interest in the classification and University of Kansas Medical Center. Dr. Barohn is board-certified by the identification of chronic acquired demyelinating polyneuropathies. In ad- American Board of Electrodiagnostic Medicine and the American Board of dition to membership in the AAEM, Dr. Saperstein is also a member of Psychiatry and Neurology with added qualifications in clinical neurophys- the Peripheral Nerve Society, the American Academy of Neurology, and iology. He is a member of many professional societies, including the the World Muscle Society. American Academy of Neurology, the American Neurological Association, and the AAEM. His present research focuses on myopathies, motor neuron disease, peripheral neuropathies, and myasthenia gravis. In 2000, Vinay Chaudhry, MD he was awarded the Alumni Achievement Award for Medicine from the Professor University of Missouri – Kansas City. Department of Neurology Johns Hopkins School of Medicine Jonathan S. Katz, MD Baltimore, Maryland Assistant Professor Dr. Chaudhry is currently a professor of neurology and Director of the Department of Neurology Neuromuscular Division at the Johns Hopkins University School of Stanford University School of Medicine Medicine in Baltimore. In addition, he is Co-Director of the Neurology EMG Laboratory and Program Director of the clinical neurophysiology Palo Alto, California residency there. Dr. Chaudhry received his bachelor of medicine and bach- Dr. Katz is currently an assistant professor in the department of neurology elor of surgery degrees from the All India Institute of Medical Sciences in and Co-director of the Neuromuscular Disease Clinic at Stanford New Delhi, and went on to study internal medicine in the UK. At the University and the director of the EMG laboratory at the Palo Alto VA University of Alabama at Birmingham’s School of Medicine, Dr. Medical Center. He is certified by the American Board of Psychiatry and Chaudhry studied neurology and became Neurology Chief Resident. Dr. Neurology, and also holds added qualifications in clinical neurophysiology. Chaudhry is certified by many organizations, including the American Dr. Katz is active in several organizations, including the American Board of Psychiatry and Neurology (Neurology and Neurology with added Academy of Neurology, the California State Myasthenia Gravis Association qualifications), the Royal College of Physicians, and the ABEM. He is a re- Medical Advisory Board, and the Stanford University Medical School viewer for several journals and is on the Editorial Board of Neurologist Faculty Senate. He is an ad hoc reviewer for several journals, including and Muscle & Nerve. Neurology, Muscle & Nerve, and Lancet. He is also a recipient of the Lisia Forno Award for Outstanding Teachers.

Authors had nothing to disclose.

Course Chair: Richard J. Barohn, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AAEM. AAEM Course When It’s Not ALS! Pure Motor Syndromes iii

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the spe- cific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may be used if, in the judgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041. iv AAEM Course v When It’s Not ALS! Pure Motor Syndromes

Contents

Faculty ii Objectives v Course Committee vi

Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome 1 Richard J. Barohn, MD

Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy 11 Jonathan S. Katz, MD

Pure Motor Neuron Syndromes 15 David S. Saperstein, MD

Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy 21 Vinay Chaudhry, MD CME Self-Assessment Test 33 Evaluation 35 Future Meeting Recommendations 37

O BJECTIVES—After attending this session, participants will be able to: (1) describe demyelinating acquired motor neuropathy syn- dromes that can resemble amyotrophic lateral sclerosis (ALS), specifically multifocal motor neuropathy (MMN); (2) discuss the variant multifocal acquired sensorimotor neuropathy and review treatments; (3) describe the phenotype of patients who present with bilateral prox- imal arm weakness (brachial amyotrophic diplegia) and its relation to ALS; (4) describe motor neuropathies that present with hand weak- ness, but have only axonal neurophysiologic findings – multifocal acquired motor axonopathy and describe this entities relationship to MMN and ALS, and treatment implications; (5) describe pure lower motor neuron syndromes such as progressive muscular dystrophy (and its relationship to ALS), juvenile monomelic amyotrophy in teenagers and young adults, and adult “distal” spinal muscular atrophy (or hereditary motor neuropathy); and (6) describe the pure or predominant upper motor neuron disease primary lateral sclerosis and its rela- tion to ALS. P REREQUISITE—This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX consultants at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX prin- ciples. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A CCREDITATION S TATEMENT—The AAEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME CREDIT—The AAEM designates attendance at this course for a maximum of 3.5 hours in category 1 credit towards the AMA Physician’s Recognition Award. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he/she actually spent in the activity. The American Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMA PMR category 1 credit. vi

2003-2004 AAEM COURSE COMMITTEE

Kathleen D. Kennelly, MD, PhD Jacksonville, Florida

Thomas Hyatt Brannagan, III, MD Dale J. Lange, MD T. Darrell Thomas, MD New York, New York New York, New York Knoxville, Tennessee

Kimberly S. Kenton, MD Andrew Mazur, MD Bryan Tsao, MD Maywood, Illinois Portsmouth, Rhode Island Shaker Heights, Ohio

Christopher J. Standaert, MD Seattle, Washington

2003-2004 AAEM PRESIDENT

Lois Margaret Nora, MD, JD Rootstown, Ohio Primary Lateral Sclerosis and the Differential of the “Pure” Upper Motor Syndrome

Richard J. Barohn, MD Professor and Chairman Department of Neurology University of Kansas Medical Center Kansas City, Kansas

INTRODUCTION Primary lateral sclerosis is considered a progressive disorder of either corticospinal or corticobulbar UMN dysfunction for Motor neuron disorders can be considered a clinical spectrum which no etiology is found. There continues to be an ongoing from pure lower motor neuron (LMN) disorders (progressive debate regarding the existence of PLS as a separate disease muscular atrophy [PMA] and spinal muscular atrophy) to pure process distinct from ALS or whether it is simply a predomi- upper motor neuron (UMN) disorders (primary lateral sclerosis nantly UMN manifestation of ALS. Several factors cause diffi- [PLS]). Amyotrophic lateral sclerosis (ALS) falls in the middle culties in definitively answering this question. The underlying and has features of both upper and lower motor neuron dys- etiology of ALS and PLS is unknown, and there is no specific di- function (Figure 1). agnostic marker for either. In addition, there are only a handful

LOWER MOTOR NEURON UPPER MOTOR NEURON Sporadic Progressive Muscular Amyotrophic Primary Lateral Atrophy Lateral Sclerosis Sclerosis

Hereditary Spinal Muscular Atrophy Hereditary Spastic Paraplegia

Figure 1 Spectrum of motor neuron disorders 2 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course of PLS patients who have been autopsied in order to determine before we express an opinion on this matter, await the if the pathology is indeed restricted to the UMN system. modifying influence of new observations.’ Up to the Therefore in practical terms, while the patient is alive, the dis- present time, gentlemen, as I shall show shortly patho- tinction between these motor neuron disorders is based on phe- logical investigation has not yet furnished any proof, notype recognition, natural history, and the indirect tests and hence the solution of the problem remains in sus- currently employed to implicate involvement of upper and lower pense. Meanwhile the clinical description deserves to motor neurons. As some patients with ALS ultimately are found exist alone. to have another diagnosis, perhaps PLS should be considered a syndrome composed of heterogenous diseases, some of which Throughout the first half of the 20th century, a number of may become apparent over time. On the other hand, the use of others attempted to address the PLS issue.9,47,48,49,51,57 Wilson, in PLS as a diagnostic disease category is useful in approaching a his authoritative textbook of neurology, was unconvinced that patient with a progressive UMN disorder, particularly in regards PLS was a distinct entity.58 He stated: to determining prognosis. Divergent views are still held in regard to so-called primary lateral sclerosis, the ‘spastic spinal paralysis’ of HISTORY Erb. Some consider it belongs to a separate class from Charcot’s disease, taking presence or absence of muscu- The earliest reported cases of possible PLS have been attributed lar atrophy for the criterion; but since ‘pure’ atonic by Erb in 1875.17 In 1902, he reviewed 10 autopsied cases and atrophy often co-exists with slight pyramidal lesions used the terms “spinal” or “spasmodic” paralysis.16 However, 4 of only disclosed after death, spasticity without wasting the 10 cases were familial and therefore the cases probably fell might well represent the opposite extreme of the same into the hereditary spastic paraplegia category. Charcot, who de- condition. Types of Charcot’s disease pass by easy gra- scribed the first cases of ALS,12 wrote a long discussion regarding dations from almost monosymptomatic muscular Erb’s early cases and described several of his own and preferred atrophy to spastic weakness with little sign of the other, the term “spasmodic tabes dorsalis.” He was not prepared to notably at an earlier period; to go a step farther in either consider PLS a distinct disease entity at that time, pending direction would seem not only allowable but requisite. analysis of further cases. A long excerpt from one of Charcot’s If this is permitted, ‘primary lateral sclerosis’ becomes a translated lectures13 is still instructive: variant of the disease without involvement of lower neurons, and ‘nuclear amyotrophy’ another, with intact Nevertheless, gentlemen, it is not uncommon clinically corticospinal paths … for these several reasons the con- to meet with a certain number of cases in which symp- ception of ‘pure’ spastic paralysis caused by progressive toms of spasmodic paralysis ... occur unaccompanied ... decay in corticospinal neurons, of endogenous source by any other symptoms. ... The affection is especially alone, and rigidly confined to that system has little to characterized also by its slow evolution, and by a substantiate it. At least some examples are eventually marked tendency to progressive invasions of the upper proved to belong to the group of Charcot’s disease, and extremities. To some physicians, of whom I am one, this may well be true of all. this spasmodic paraplegia seems to be a special variety, so that we are led to think that these are not common Rowland44 and Swash52 consider the modern era of PLS litera- cases of transverse myelitis accidentally deprived of their ture to begin with the paper by Fisher in 1977.19 Fisher described usual features. … But it is believed that the affection in an autopsied case of presumed PLS and found degeneration of question is peculiar, autonomous, and probably depen- the corticospinal tracts. Since that paper, there has been a height- dent on a specially localized lesion. Erb was the first to ened interest in the controversial topic of PLS. However, to a put forward this opinion in 1875. I soon followed him, large extent, medicine is no closer to solving the dilemma as my lectures in 1876 testify. This alleged special affec- Charcot and Wilson described in the late 19th and early 20th tion was designated by Erb spasmodic spinal paralysis. centuries. … I proposed the name of spasmodic tabes dorsalis, since the term ‘spasmodic paralysis’ represents only a symptom common to several spinal diseases. The de- EPIDEMIOLOGY AND DEMOGRAPHICS scription given by Erb differs, however, in no essential feature from that which I subsequently traced ... I ob- How Often is Primary Lateral Sclerosis Diagnosed? served that all cases of symmetrical sclerosis without participation of the anterior grey cornua were of old Primary lateral sclerosis is an uncommon diagnosis. The best date. ‘It would be necessary,’ I remarked, ‘to revive way to get an idea of how often PLS is diagnosed is to look at partly effaced remembrances. We must therefore, the larger retrospective series. In the Canadian series by Pringle AAEM Course When It’s Not ALS! Pure Motor Syndromes 3 and colleagues,42 of 500 motor neuron disease patients, 8 pa- some patients, simultaneous bilateral leg onset or simultaneous tients were diagnosed with PLS over a 10-year time span (ap- limb and bulbar onset is reported. Spasticity accounts for the proximately 1.6%). Le Forestier and colleagues34 reported 20 most of the limb dysfunction in the early stages, as opposed to PLS patients out of 450 motor neuron disease patients over 5 weakness; in ALS weakness is usually more prominent than spas- years (4.4%), and in this author’s Texas series, 13 PLS and 572 ticity.31,34,35 Therefore, patients may not complain of weakness, ALS patients were diagnosed over 5 years (2%).31 Therefore, but notice stiffness, clumsiness, or poor coordination and dex- from this small number of series, it appears that between 2% and terity as the initial limb symptoms. When limb weakness occurs 4% of patients seen in adult motor neuron disease clinics will be it is usually in a UMN dysfunction pattern, as described later. diagnosed with PLS. Some authors have described cases with slow progression from bulbar involvement to leg or from leg to bulbar without men- Age of Onset tioning significant arm involvement.42 However, even in these cases, brisk reflexes and other UMN signs are noted in the arms The typical age of onset of PLS is in the late 40s to early 50s, implicating arm involvement. similar to ALS. In this author’s series, mean age of onset was 46.3 years (range 36-73 years).31 In the Pringle series, mean age of Bulbar symptoms consist of dysarthria initially, then dysphagia, onset was 50.4 years (range 35-66 years).42 In the Salpetriere and are often associated with emotional lability, and eventually Parisian series, mean age of onset was 53.4 years (range 26-64 inappropriate laughing or crying, which is labeled “pseudo- years). In a large National Institute of Health (NIH) series of 25 bulbar” affect. Because the dysarthria is predominantly UMN patients, mean age of onset was 45.4 years.63 and not associated with tongue atrophy or fasciculations, some refer to all of the bulbar symptoms as pseudo-bulbar. The Gender dysarthria can progress to anarthria. Dysphagia can progress in a way that the patient requires a feeding tube even before there is Some series show a male predominance8,31,33,34,62 while in others, significant limb involvement. In the Salpetriere series, the both genders are equally affected.22,42,45,63 In the French series, 15 authors found the dysphagia often remained moderate.34 It is in- out of 20 cases were male.34 The Dutch series described 9 males teresting that some patients who become anarthric can still and 1 female.33 This author’s Texas series of 13 patients had 9 swallow. However, this is unusual and in this author’s experience men and 4 women.31 The Canadian and NIH series both had most bulbar patients eventually require mechanical feeding. 50% male to female ratio, while the Marseilles series by Gastaut had 2 males and 3 females.22,42,63 The recent NIH series provides the most detailed information about the timing of progression.63 In this series, 14 out of 25 pa- tients presented with spasticity of the legs and they were labeled CLINICAL FEATURES the “ascending group.”63 Symptoms spread to the second leg on average within 1.7 years after the first leg (range 1-4 years) and The two most common presentations in patients diagnosed with to the hands in 3.6 years later (range 1-6 years) and to the bulbar PLS are spastic bulbar palsy, and leg weakness with spasticity. region 1.5 years (range 0.5-5 years) after arm symptoms. The syndrome of slowly progressive leg weakness and spasticity is more common and accounted for in 56% of the presentations While most cases of limb onset eventually progress to bulbar and in the NIH series.63 In the Salpetriere series, 50% (10 out of 20) most cases of bulbar onset eventually progress to limb, there are had bulbar onset. However in the Canadian series of Pringle,42 probably cases that remain restricted to these regions for as long only 1 out of 8 had bulbar onset, and in the Dutch series 9 out as the patient is followed.22,31 How often this occurs is unknown. of 10 had limb onset.33 This author’s Texas series was similar in that 12 had leg onset, 1 had bulbar onset, and of the limb onset While cramps, fasciculations, and atrophy are usually believed to patients, only 1 progressed to bulbar symptoms.31 The syndrome be signs of LMN dysfunction and therefore incompatible with can progress from bulbar to limb involvement or from limb to pure PLS, some authors report these symptoms and signs in bulbar. In the limbs, leg onset is by far more common than their patients. Le Forestier and colleagues34,35 reported 9 out of arm/hand onset, which, while rare, does occur.33,42,63 Patients can 20 patients had fasciculations and cramps, supporting their ar- have long periods of plateau in one region with nonprogression gument that PLS is similar to ALS. to other regions. Rarely patients can present with a progressive hemiparesis (arm and leg) before progressing to the opposite side As a result of corticospinal and corticobulbar involvement, pa- or to the bulbar region.23,63 tients will demonstrate UMN signs consisting of spasticity, slow movement of limbs and tongue, hyperreflexia with reflex spread In the leg onset syndrome, symptoms usually begin in one leg (to finger flexors; crossed adductors), brisk jaw reflex, corneal- and then spread to the opposite leg so that patients have a para- mandibular reflex, Hoffman’s signs in the fingers, extensor plegia for a period of time before further progression.31,34,63 In plantar responses, and weakness in a UMN pattern. 4 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

Sensory symptoms and signs should prompt a search for another disease had fasciculation, atrophy, and a worsening needle elec- diagnosis. Patients do not complain of visual symptoms, al- tromyography (EMG), at which point ALS was diagnosed.8 though some authors have reported abnormal visual sac- cades.34,42 Some patients complain of urinary urgency or incontinence, and several report this more frequently—50% (4 LABORATORY FINDINGS out of 8) in the Canadian series, 65% (13 out of 20) in the Salpetriere, and 3 out of 5 in the initial report of the Texas pa- Creatine Kinase tients.34,42,59 These usually occur a number of years after onset of symptoms. In the Canadian series, bladder symptoms first ap- Serum creatine kinase (CK) results are often elevated in ALS peared in four out of eight patients at 5, 8, 9, and 24 years after (usually less then two times normal), and when this occurs it is onset.42 In most of the early reports, cognition was reported as probably a reflection of denervation from LMN involvement. normal.42 However, Le Forestier and colleagues reported 16 out Creatine kinase levels are usually not mentioned in published of 20 patients had errors on frontal lobe function testing. Others PLS cases. In the Texas series, serum CK was slightly elevated in have reported frank frontal lobe dementia syndrome in PLS pa- two out of nine patients.31 Similarly, in the Dutch series, 4 out tients.10,14,53 This is consistent with the recent increasing aware- of 10 had slightly elevated serum CK levels.33 ness of frontal lobe dementia in 10-20% of ALS patients39,40 Electromyography

DURATION AND PROGNOSIS Most of the smaller reports in the modern era argued that normal nerve conduction studies and needle EMG proved the Primary lateral sclerosis patients have a slowly progressive disease patients studied had PLS.2,22,23,45 However, in most of the larger which distinguishes them from typical ALS patients. In most of series, subtle but definite abnormalities on needle EMG are re- the published cases and series the patients are reported as being ported. In this author’s series, 7 out of 13 patients had features alive, and there have been only a small number of autopsied of mild active denervation in one or more muscles consisting of cases. There is no good data to tell physicians what the average increased insertional activity (5 out of 7), grade 1+ fibrillations life expectancy is for patients with PLS. There is data from nu- or positive sharp waves in (4 out of 7), or fasciculations (4 out merous papers in the modern era on the duration of symptoms of 7). Decreased recruitment of motor units (fast firing) was seen at the time patients were either diagnosed or reported. In the in three out of seven although motor unit morphology was Canadian series, median disease duration at the time of the normal. No patients had sufficient abnormalities on EMG to report was 19 years and the mean was 14.5 years (range 4-34 make a diagnosis of ALS. In the Salpetriere study, 6 out of 20 years).42 In the Salpetriere series, mean disease duration at first patients had either denervation activity at rest or denervation examination was 8.5 years (range 4-14 years).34 Disease progres- potentials with decreased recruitment, but did not meet criteria sion as reported as slow with half of the patients experiencing for definite, probable, or possible ALS.34 During subsequent ex- periods of stabilization lasting months. Follow-up on 19 patients aminations, of the 14 who initially had a normal needle EMG, showed 5 could walk unaided, 5 used a walker, and 10 needed 5 developed denervation or decreased motor unit recruitment. a wheelchair after 4-6 years duration. In the NIH series, the pa- Most patients had multiple needle EMGs and at the time of the tients had symptoms present for 7-8 years at the time of diag- last evaluation, three fulfilled electrophysiologic criteria of prob- nosis.63 Similarly, the 10 patients in the Dutch series had able ALS, but without clinical evidence of disease progression. In symptoms from 6-35 years. In the Texas series, the average du- the Dutch study, 4 out of 10 patients had enlarged motor unit ration of illness was 4.75 years (range 4-15) in 13 patients. All action potentials, but none had spontaneous denervation.33 All four of Russo’s patients had symptoms more than 5 years with of these authors argued that because of the mild needle EMG follow up from 25-42 months.45 The Columbia University abnormalities, there is some evidence of LMN dysfunction and group’s three patients who had died had symptoms 1, 6, and 8 therefore that many cases of PLS are on a spectrum with ALS. years, and their six living patients had symptoms for 2-12 In the Columbia Medical Center series, seven cases were ex- years.62 The five cases of Gastaut and colleagues had symptoms cluded because there was evidence of denervation on needle for 5, 10, 12, and 28 years.22 EMG—these cases were referred to as “PLS with EMG dener- vation.”62 One of these cases also developed clinical evidence of A few cases that were initially diagnosed as PLS eventually had LMN disease on follow-up and was diagnosed with ALS. In ad- the diagnosis changed to ALS due to progression of the dition, one of their autopsied cases previously had a needle disease.8,34,62 Bryun and colleagues described three patients who EMG showing fasciculations in multiple muscles in at least two had a pure PLS picture until 7.5 years, and 27 years into the limbs. Interestingly, in the Canadian series where the authors AAEM Course When It’s Not ALS! Pure Motor Syndromes 5 argued that PLS is a discrete disorder separate from ALS, two out Muscle Biopsy of eight patients had occasional fibrillations and positive sharp waves which were considered “indicators of a relatively minor This author biopsied one patient and found rare angulated fibers degree of denervation ... restricted to a few muscles” that ap- suggesting denervation.31 In the Salpetriere series, all 20 patients peared late in the course.42 In the proposed diagnostic criteria by underwent a deltoid muscle biopsy and signs of denervation or this group, they allow for “occasional fibrillation and increased reinnervation was seen in 13 patients; 7 were normal.34 insertional activity in a few muscles (late and minor).”42 Therefore, muscle biopsy can often be useful in finding evidence of LMN pathology in patients who clinically appear to have a Therefore, if one looks at the existing published literature, the pure UMN syndrome. conclusion is that mild needle EMG abnormalities can be found in cases that clinically appear to have a pure slowly progressive Neuroimaging PLS syndrome. In rare cases, follow-up needle EMGs can show progression and ultimately change the diagnosis to ALS.8,34,62 Routine computerized tomography and magnetic resonance imaging (MRI) brain imaging is typically normal or shows non- Transcranial Magnetic Stimulation specific changes.31,34,52,63 However, atrophy of the precentral gyrus has been reported in some series.33,34,42 A single report of Transcranial magnetic stimulation (TMS) studies in several large serial MRI scans over a 9-year course showed progressive atrophy series are typically abnormal.6,33,34,63 Brown and colleagues of premotor, parietal, and primary sensorimotor cortex, with studied TMS in seven PLS cases and all had central conduction sparing of the temporal lobe, occipital lobe, and cerebellum.46 abnormalities. The “ascending” group of Zhai and colleagues showed that motor evoked potentials could not be evoked from Magnetic resonance spectroscopy in some series has shown re- hand muscles despite maximal stimulation, and this was inter- duction of N-acetylaspartate/creatinine in the motor cortex,63 a preted as decreased cortical excitability.63 The Dutch group also finding that also has been shown in some ALS patients. had difficulty obtaining responses with TMS, but when they were obtained, the central motor conduction time (CMCT) was Positron emission tomography (PET) has shown a regional de- significantly prolonged (2-3 times normal). This is in contrast to crease in fluorodeoxygluse uptake.42 In cerebral blood flow ALS patients in which CMCT is normal or only slightly (rCBF) a decrease using flumazenil as a marker (an index of delayed.33 The Salpetriere group could not obtain responses in synaptic brain function) and regional density of benzodiazepine 12 out of 20 patients in either upper and lower limbs, and only receptors (BZRs) decrease (a putative index of cortical neuronal in the lower limbs in two patients. In six patients CMCTs were density)35 in the precentral gyrus regions. Again, these PET prolonged.34 Of the two patients reported by Swash and col- imaging findings may not distinguish PLS from ALS.35,42 leagues, one had prolonged CMCTs to the lower extremities, and one had borderline findings.52 More recently, diffusion tensor imaging has demonstrated de- creased image intensities reflecting decreased diffusion Somatosensory Evoked Potentials anisotropy in the posterior limbs of the internal capsules com- pared to normal control.55 However, that paper also indicates Somatosensory evoked potentials (SEPs) (visual, brainstem, these changes can be seen in ALS patients, and therefore they median, and tibial somatosensory) were performed in six pa- believe this tool may be useful in distinguishing PLS from other tients in this author’s series and were all normal.31 However, in disease states. It remains to be determined if this tool can be a the Salpetriere series, abnormalities in visual (prolonged P100), marker for UMN pathology in both PLS and ALS, or if it truly median (prolonged N20 and N13-20 interval, and tibial (pro- is more specific for these diseases.11 longed P40 and P22-40) SEPs were found in over half of their 20 patients.34 The abnormalities were presumably compared to Pathology normal control values at their institution. No comparison was made with ALS patients. Their findings are unexpected, partic- There have been surprisingly few autopsy reports of PLS in the ularly since this group argues that PLS frequently has subtle modern era since the description by Fisher.2,19,29,42,62 The consis- LMN findings and should be considered on spectrum with ALS. tent finding in the six autopsied patients described in these In the Dutch series, prolonged latencies were also documented studies is the loss of myelinated fibers in the entire corticospinal on median and peroneal SEPs in several patients.33 system with sparing of the cranial nerve neurons and the 6 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course anterior horn cells. Most of these cases also had atrophy of the Differential Diagnosis and Work-up pre-central gyrus and loss of Betz cells in the motor cortex.2,19,29,42 In the case by Beal and Richardson, intracytoplasmic The differential diagnosis for the progressive corticospinal and eosinophilic inclusion bodies were observed rarely in motor corticobulbar syndrome is outlined in Table 1. This is an inclu- neurons (one in the hypoglossal nuclei and two in spinal cord sive table and most of the disorders probably do not need to be anterior horn cells), and were suspicious for the Bunina bodies seriously considered when evaluating a patient for possible PLS. described in ALS.2 While some consider PLS a diagnosis of exclusion, this can be In rare cases, patients who are diagnosed with a PLS syndrome said for most sporadic degenerative conditions for which no di- during life can have changes more typical of ALS at autopsy. In agnostic test is available. In reality, if a patient presents with a the series of 45 autopsied cases of motor neuron disease by pure progressive spastic bulbar and limb syndrome, the differen- Brownell and colleagues, 3 patients who were diagnosed with tial diagnosis is limited. Most of the conditions listed in Table 1 PLS in life were found to have anterior horn cells affected at have either sensory symptoms or evidence ofinvolvement of autopsy.7 another neurologic system, such as cerebellar. Also, a number of the disorders in the degenerative group have a hereditary basis In the recent case by Tan and colleagues, an elderly patient with and therefore should have a history of other affected family a 7-year history of progressive bulbar symptoms followed by members. spasticity and dementia showed typical corticospinal tract in- volvement seen in PLS as well as marked frontotemporal The hereditary spastic paraparsis (HSP) disorders deserve partic- atrophy with ubiquitin-positive staining neurons these cortical ular consideration.18 These hereditary conditions have previously regions.53 The cortical pathology was therefore typical of fron- been referred to as Strumpell’s disease. In the last several years totemporal lobar degeneration, in addition to the pyramidal there has been an explosion in the molecular genetic identifica- changes of PLS. They also reported Bunina body inclusions in a tion of a number of genes responsible for HSP. Hereditary few LMNs. The patient never developed significant limb weak- spastic paraparsis can be autosomal dominant, autosomal reces- ness or clinical evidence of LMN dysfunction. In this paper, they sive, or X-linked. To date, 20 genetic loci (spastic gait loci [SPG]) report that seven previous autopsy cases of a PLS-like syndrome have been identified. The most common HSP appears to be due with dementia and ubiquitin immunohistochemistry had been to a mutation in the SPG4 gene which produces a protein called reported, although it appears that most of these were reported spastin. The SPG4 gene mutations account for 40% of autoso- only in the Japanese literature.30,32,41,50,54,56,60 mal dominant HSP. Other mutations are in genes coding for at- lastin (SPG3), kinesin heavy chain (SPG10), and A patient with a 10-year history and clinical features suggestive NIPA1(SPG6), heat shock protein 60 (SPG13) (all autosomal of PLS was found at autopsy to have diffuse Lewy body disease, dominant); paraplegin (SPG7) and spartin (SPG20) (both auto- but without ante-mortem clinical features of dementia or somal recessive); and L1 cell adhesion molecule (SPG1) and pto- Parkinsonism.28 teolipid protein (SPG2) (both X-linked). Genetic testing is currently available for spastin, atlastin, and NIPA1 mutations. Reports of Concurrent Diseases Hereditary spastic paraparsis usually presents in the teenage years with symmetrical leg spasticity. While the disorder progresses, There have been several reports of patients with PLS having a arm involvement is uncommon and bulbar involvement is ex- concurrent medical diagnosis, but the relationship is usually un- tremely rare. There is some range in the age of onset, and some certain. Five women were reported with breast cancer and PLS, patients are diagnosed in middle age. Bladder symptoms are and in three of these cases, ultimately diagnosed with ALS.20,43 common and some patients exhibit mild sensory loss in the feet One of the autopsied cases of Younger and colleagues had a small (vibration and proprioception deficits) suggesting posterior cell lung carcinoma.62 In addition, two of the patients in the column involvement. Therefore, while it is probable that some Younger and colleagues series were human immunodeficiency patients reported as PLS may have had one of the HSP disorders, virus (HIV) positive, and one went on to develop acquired im- the absence of a family history, middle or late life onset, and munodeficiency syndrome (AIDS).62 There has been an autop- bulbar involvement make PLS much more likely. sied case of multiple myeloma and a PLS syndrome in the absence of cord infiltration by tumor.7 A patient with PLS of 7 With regard to familial ALS (FALS), these patients have signifi- years duration has been reported to have an IgM paraprotein cant UMN and LMN involvement, and therefore usually do not and elevated cerebrospinal fluid (CSF) protein.15,52 need to be considered in the differential of a possible PLS AAEM Course When It’s Not ALS! Pure Motor Syndromes 7

patient. In one family reported by Appelbaum, two first cousins Table 1 Differential diagnosis of the progressive corticospinal had either a PLS or PMA phenotype.1 However, in families with and corticobulbar dysfunction syndrome the two identified autosomal dominant FALS mutations (SOD1 mutation on chromosome 21 or the 9q34 mutation), PLS phe- Sporadic motor neuron disease notypes have not been reported. There are at least two juvenile Primary lateral sclerosis (PLS) autosomal recessive forms of ALS. In some of these kindreds, a Amyotrophic lateral sclerosis (ALS) pure UMN presentation (limb and bulbar) has been described using the term “juvenile PLS.”3,21,25,26,27,36,61 Recently, a number Structural lesions of these rare cases have been shown to be due to mutations in a Cervical spondylytic myelopathy gene that codes for a protein called alsin.25,27,62 Many of these Other causes of spinal cord compression children present in the first 1-2 years of life. Not all families have Tumor, arteriovenous malformation, disc been shown to have the alsin mutation, and since there clearly is Syringomyelia an overlap with HSP, this phenotype has also been referred to as 37 Foramen magnum tumor infantile ascending hereditary spastic paralysis (IAHSP). Arnold-Chiari malformation In a sporadic pure UMN syndrome developing in middle age or Hydrocephalus later, the two main diseases to consider are ALS and PLS. Degenerative and hereditary diseases Amyotrophic lateral sclerosis is more common than PLS and Hereditary spastic paraplegia therefore is the ultimate diagnosis in patients presenting with Spinocerebellar ataxias this syndrome. However, if there is either minimal or no evi- Diffuse Lewy body disease dence of LMN pathology, a tentative diagnosis of PLS can be Leukodystrophies (adrenoleukodystrophy, made. In this setting, patients can be told that the prognosis is adrenomyeloneuropathy, metachromate leukodystrophies better compared to ALS and the progression is slow. However, Vitamin E deficiency they also need to be informed that they need to be followed closely to determine if their motor neuron disease will evolve Familial ALS (FALS); juvenile FALS into ALS or another diagnosis. Dysimmune disease Multiple sclerosis All patients should have standard brain and spinal cord MRI Infection imaging and EMG/nerve conduction studies. Further tests such *HTLV-1 myelopathy (tropical spastic paraplegia) as evoked potentials and muscle biopsies are determined on a **HIV-related vascular myelopathy case-by-case basis. Blood work in these patients routinely in- Neurosyphilus cludes serum CK and human T-lymphotropic virus 1 (HTLV-1) antibodies. This author also obtains serum B12, rapid treponine Metabolic, nutritional, toxic disorders test and fluorescent antibody test (for syphilis), and serum Cobalamin (Vitamin B12) deficiency protein electrophoresis/immunofixation electrophoresis, but Vitamin E deficiency without sensory symptoms or signs, the yield on these studies is Copper deficiency negligible. If there is absolutely no evidence of a LMN process, Lathyrism CSF studies should be obtained as part of a multiple sclerosis Vascular evaluation. If nerve conduction studies indicate an unsuspected sensorimotor neuropathy, this author checks for long-chain fatty Lacunar state acids. Antibodies for HIV are tested in at-risk patients. If there * HTLV1 – human T-lymphotropic virus 1 are no bulbar features, one can check for the commercially avail- ** HIV – human immunodeficiency virus able genetic mutations for HSP (SPG4, SPG3A, SPG6), but without an autosomal dominant family history, the yield is prob- ably extremely low. This author has not been routinely checking 8 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course molecular genetic mutations for the spinocerebellar ataxia genes unless there is ataxia, family history, or other evidence to suggest Table 2 Proposed diagnostic criteria by Pringle and involvement outside of the corticospinal/corticobulbar system. colleagues42

Clinical DIAGNOSTIC CRITERIA 1. Insidious onset of spastic paraesis, usually beginning in lower ex- tremities but occasionally bulbar or in an upper extremity The most recent proposed diagnostic criteria for PLS have been those of Pringle and colleagues in 1992 and are outlined in Table 2. Adult onset, usually fifth decade or later 2.42 Interestingly, a pure UMN syndrome in two regions of the 3. Absence of family history body can fulfill the El Escorial research criteria for clinically pos- 4. Gradually progressive course (i.e., not step-like) sible ALS as originally proposed in 1994.4 If one finds even 5. Duration > 3 years minimal needle EMG abnormalities in two limbs to the degree 6. Clinical findings limited to those usually associated with corti- that has been reported in some PLS publications, this would cospinal dysfunction meet the revised El Escorial criteria for clinically probable labo- 7. Symmetrical distribution, ultimately developing severe spastic ratory supported ALS.5 spinobulbar paresis

Laboratory (help in exclusion of other diseases) TREATMENT 1. Normal serum chemistry including normal vitamin B12 levels 2. Negative serologic tests for syphilis (in endemic areas, negative Treatment is symptomatic and directed toward the spasticity, Lyme, and HTLV-1 serology usually with baclofen or tizanidine.63 Rarely dantrolene can be 3. Normal CSF parameters, including absence of oligoclonal bands used. However, with the advent of the baclofen pump, this is 4. Absent denervation potentials on EMG or at most, occasional fib- probably a better alternative than dantrolene in difficult to rillation and increased insertional activity in a few muscles (late control patients. Excessive drooling can be treated with a variety and minor) of oral anti-cholingergic medications (amitriptyiline, 5. Absence of high signal lesions on MRI similar to those seen in MS hyoscyamine, benztropine mesylate, glycopyrrolate, or scoal- Additionally suggestive of PLS palamine patches). The tricyclic antidepressants can also be 1. Preserved bladder function useful for emotional lability associated with the pseudobulbar condition. There is some preliminary data indicating that botu- 2. Absent or very prolonged latency on cortical motor evoked re- sponses in the presence of normal peripheral stimulus-evoked linum toxin injections into the submandibular glands may de- maximum compound muscle action potentials crease saliva production24,38 3. Focal atrophy of precentral gyrus on MRI At this point, there is no data to indicate that riluzole is of benefit 4. Decreased glucose consumption in pericentral region on PET scan in PLS patients as all of the data pertains to typical ALS. This HTLV-1 = human T-lymphotropic virus 1; MRI = magnetic resonance imaging; author has treated some PLS patients with riluzole, but the MS = multiple sclerosis; PET = positron emission tomography; PLS = primary patient needs to be aware that the benefit is unknown in this lateral sclerosis. setting. As with all of this author’s ALS patients, patients are 42 placed on high-dose antioxidant vitamin C, E, and beta- (Used with permission, Oxford University Press.) carotene, although no good clinical data is available regarding the benefit of this approach. It is preferable for the patient to be AAEM Course When It’s Not ALS! Pure Motor Syndromes 9 managed in a multi-disciplinary ALS clinic so that their multi- 12. Charcot J, Joffroy A. Deux cas d’atrophic musculaire progressive avec ple needs can be addressed—equipment, speech, pulmonary, lésions de la substance grise et des faisceaux antéro-latéraux de la physical, and dietary, as well as having access to social workers, moelle épiniére. Arch Physiol Neurol Path 1869;2:744. 13. Charcot JM. Transverse myelitis and spasmodic tabes dorsalis. In: counselors, and occupational therapy professionals. Hadden WB, trans-ed. Lectures on the localization of cerebral and spinal diseases. London: New Sydenham Soc; 1883. p 299-300. 14. de Koning I, van doorn PA, van Dongen HR. Slowly progressive iso- SUMMARY lated dysarthria: longitudinal course, speech features, and neuropsy- chological deficits. J Neurol 1997; 244:664-667. 15. Desai J, Swash M. Primary lateral sclerosis associated with IgM para- Primary lateral sclerosis remains a difficult diagnosis to make. To proteinemia. Neuromusc Disord 1998;9:38-40. some extent, some of the same issues that Charcot, Erb, and 16. Erb WH. Spastic and syphilitic spinal paralysis. Lancet 1902;2:969- Wilson faced, are still being struggled with today; particularly re- 974. garding whether or not PLS is a distinct entity. Interestingly, 17. Erb WH. Ueber einen weinig bekannen spinalen symptomeno- there has been a renewed focus on PLS in the neuromuscular coplex. Berliner Kliische Wochenschrift 1875;12:357-359. disease literature in the last 2 decades, probably because these pa- 18. Fink JK. The hereditary spastic paraplegias. Nine genes and counting. Arch Neurol 2003; 60:1045-1049. tients continue to challenge clinicians. While there remain many 19. Fisher CM. Pure spastic paraplegia of corticospinal origin. Can J unanswered questions regarding diagnosis and nosology, it is be- Neurol Sci 1977;4:251-258. lieved that PLS is a useful concept which carries implications for 20. Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. prognosis that differ from other categories of motor neuron Motor neuron syndromes in cancer patients. Ann Neurol disease. 1997;41:722-730. 21. Gascon GG, Chavis P, Yaghmour A, Stigsby B, Shums A, Ozand P, Siddique T. Familial childhood lateral sclerosis with associated gaze paresis. Neuropediatrics 1995;26:313-319. REFERENCES 22. Gastaut J, Michel B, Figarella-Branger D, Somma-Mauvais H. Chronic progressive spinobulbar spasticity. A rare form of primary 1. Appelbaum JS, Roos RP, Salazar-Grueso EF, Buchman A, Iannaccone lateral sclerosis. Arch Neurol 1988;45:509-513. S, Glantz R, Siddique T, Maselli R. Intrafamilial heterogeneity in 23. Gastaut JL, Bartolomei F. Mills’ syndrome: ascending (or descending) hereditary motor neuron disease. Neurology 1992;42:1488-1492. progressive hemiplegia: a hemiplegic form of primary lateral sclerosis? 2. Beal MF, Richardson EP. Primary lateral sclerosis: a case report. Arch J Neurol Neurosurg Psychiatry 1994;57:1280-1281. Neurol 1981;38:630-633 24. Giess R, Naumann M, Werner E, Riemann R, Beck M, Puls I, 3. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system Reiners C, Toyka KV. Injections of botulinum toxin A into salivary diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions glands improve sialorrhoea in amyotrophic lateral sclerosis. J Neurol combining a bilateral pyramidal syndrome with limb and bulbar Neurosurg Psychiatry 2000;69:121-123. amyotrophy. Brain 1990;113:347-363 25. Gros-Louis F, Meijer IA, Hand CK, Dube MP, MacGregor DL, Seni 4. Brooks BR. El Escorial World Federaton of Neurology criteria for the MH, Devon RS, Hayden MR, Andermann F, Andermann E, diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994;124:S96- Rouleau GA. An ALS2 gene mutation causes hereditary spastic para- S107. plegia in a Pakistani kindred. Ann Neurol 2003;53:144-145. 5. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisted. 26. Grunnet ML. Leicher C, Zimmerman A, Zalneraitis E, Barwick M. Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Primary lateral sclerosis in a child. Neurology 1989;39:1530-1532. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293- 27. Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, 299. Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz 6. Brown WF, Ebers GC, Hudson AJ, Pringle CE, Veitch J. Motor- DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH evoked responses in primary lateral sclerosis. Muscle Nerve Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encod- 1992;15:626-629. ing a putative GTPase regulator is mutated in familial amyotrophic 7. Brownell B, Oppenheimer DR, Hughes JT. The central nervous lateral sclerosis 2. Nat Genet 2001;29:166-173. system in motor neuron disease. J Neurol Neurosurg Psychiatry 28. Hainfellner JA, Pilz P, Lassmann H, Ladurner G, Budka H. Diffuse 1970;33:338-357. Lewy body disease as a substrate of primary lateral sclerosis. J Neurol 8. Bruyn RP, Koelman JH, Troost D, de Jong JM. Motor neuron disease 1995;242:59-63. (amyotrophic lateral sclerosis) arising from longstanding primary 29. Hudson AJ, Kiernan JA, Munoz DG, Pringle CE, Brown WF, Ebers lateral sclerosis. J Neurol Neurosurg Psychiatry 1995;58:742-744. GC. Clinicopathological features of primary lateral sclerosis are dif- 9. Buzzard EF, Barnes S. A case of chronic progressive double hemiple- ferent from amyotrophic lateral sclerosis. Brain Res Bull gia. Rev Neurol Psychiatry 1906;4:182-191. 1993;30:359-364. 10. Caselli RJ, Smith BE, Osborne D. Primary lateral sclerosis: a neu- 30. Imai H, Furukawa Y, Sumino S, Mori H, Ueda G, Shirai T, Kondo ropsychological study. Neurology 1995;45:2005-2009. T, Mizuno Y. [A 65-year old woman with dysarthria, dysphagia, 11. Chan S, Kaufmann P Shungu DC, Mitsumoto H. Amyotrophic weakness, and gait disturbance.] No To Shinkei 1995;47:399-410. lateral sclerosis and primary lateral sclerosis: evidence-based diagnos- 31. Kojan S, Goodwin WE, Bryan WW, Nations SP, Burns DK, Barohn tic evaluation of the upper motor neuron. Neuroimaging Clin N Am RJ, Wolfe GI. Clinical and laboratory features of primary lateral scle- 2003:13;307-326. rosis. J Child Neurol 2000;15:200. 10 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

32. Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y. 49. Stark FM, Moersch FP. Primary lateral sclerosis: a distinct clinical Upper motor neuron predominant degeneration with frontal and entity. J Nerv Ment Dis 1945;102:332-337. temporal lobe atrophy. Acta Neuropathol 1998;96:532-536. 50. Sugihara H, Horiuchi M, Kamo T, Fujisawa K, Abe M, Sakiyama T, 33. Kuipers-Upmeijer J, de Jager AE, Hew JM, Snoek JW, van Weerden Tadokoro M. A case of primary lateral sclerosis taking a prolonged TW. Primary lateral sclerosis: clinical, neurophysiological, and mag- clinical course with dementia and having unusual dendritic balloon- netic resonance findings. J Neurol Neurosurg Psychaitry ing. Neuropathology 1999;19:77-84. 2001;71:615-620. 51. Swank RL, Putnam TJ. Amyotrophic lateral sclerosis and related con- 34. Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier-Buchman ditions. Arch Neurol Psychiatry 1943;49:141-177. L, Salachas F, Pradat PF, Lacomblez L, Meininger V. Does primary 52. Swash M, Desai J, Misra VP. What is primary lateral sclerosis? J lateral sclerosis exist? Brain 2001:124:1989-1999. Neurol Sci 1999;170:5-10. 35. Le Forestier N, Maisonobe T, Spelle L, Lesort A, Salachas F, 53. Tan CF, Kakita A, Piao YS, Kikugawa K, Endo K, Tanaka M, Lacomblez L, Samson Y, Bouche P, Meininger V. Primary lateral scle- Okamoto K, Takahashi H. Primary lateral sclerosis: a rare upper- rosis: further clarification. J Neurol Sci 2001:185:95-100. motor-predominant form of amyotrophic sclerosis often accompa- 36. Lerman-Sagie T, Filiano J, Smith DW, Korson M. Infantile onset nied by frontotemporal lobar degeneration with ubiquitinated hereditary ascending spastic paralysis with bulbar involvement. J neuronal inclusions? Acta Neuropathol 2003;105:615-620. Child Neurol 1996;11:54-57. 54. Tsuchiya K, Arai M, Matsuya S, Nishimura H, Ishiko T, Kondo H, 37. Lesca G, Eymard-Pierre E, Santorelli FM, Cusmai R, Di Capua M, Ikeda K, Matsushita M. Sporadic amyotrophic lateral sclerosis resem- Valente EM, Attia-Sobol J, Plauchu H, Leuzzi V, Ponzone A, bling primary lateral sclerosis: report of an autopsy case and review of Boespflug-Tanguy O, Bertini E. Infantile ascending hereditary spastic the literature. Neuropathology 1999;19:71-76. paralysis (IAHSP):clinical features in 11 families. Neurology 55. Ulug AM, Grunewald T, Lin MT, Kamal AK, Filippi CG, 2003;60:674-682. Zimmerman RD, Beal MF. Diffusion tensor imaging in the dagnosis 38. Lipp A, Trottenberg T, Schink T, Kupsch A, Arnold G. A randomized of primary lateral sclerosis. J Magn Reson Imaging 2004;19:34-39. trial of botulinum toxin A for treatment of drooling. Neurology 56. Watanabe R, Iino M, Honda M, Sano J, Hara M. Primary lateral 2003;61:1279-1281. sclerosis. Neuropathology 1997;17:220-224. 39. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic 57. Wechsler IS, Brody S. The problem of primary lateral sclerosis. JAMA lateral sclerosis and frontotemporal dementia. Neurology 1946;130:1195-1198. 2002;59:1077-1079. 58. Wilson SAK. Amyotrophic lateral sclerosis. In: Ninian BA, editor. 40. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Neurology, volume 2. Baltimore: William and Wilkins; 1940. p Miller B. Are amyotrophic lateral sclerosis patients cognitively 1015-1016. normal? Neurology 2003;60:1094-1097. 59. Wolfe GI, Katz JS, Bryan WW, Barohn RJ. Clinical features of 41. Mochizuki A, Komatsuzaki Y, Shoji S. A case of frontotemporal primary lateral sclerosis. J Child Neurol 1995;10:167. atrophy with ubiquitin cinclusions presenting with upper motor 60. Yamasaki M, Yamazaki MM, Mori O, Aral Y, Ohaki Y, Asano G, neuron signs at onset followed by extrapyramidal signs and dementia. Kanazawa I, Katayama K, Nakano I. [An autopsy case of amy- Neuropathology 2002;22:1C-4C. otrophic lateral sclerosis with upper motor neuron (UMN) predom- 42. Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers inant degeneration presenting slowly progressive aphasia: a subtype of GC. Primary lateral sclerosis: clinical features, neuropathology, and ALS with dementia (ALS-D)?] Neuropathology 2000;20:4. diagnostic criteria. Brain 1992;115:495-520. 61. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, 43. Rowland LP. Paraneoplastic primary lateral sclerosis and amyotrophic Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, lateral sclerosis. Ann Neurol 1997;41:703-705. Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique 44. Rowland LP. Primary lateral sclerosis: disease, syndrome, both or T. The gene encoding alsin, a protein with three guanine-nucleotide neither? J Neurol Sci 1999;170:1-4. exchange factor domains, is mutated in a form of recessive amy- 45. Russo L Jr. Clinical and electrophysiological studies in lateral sclero- otrophic lateral sclerosis. Nat Genet 2001;29:160-165. sis. Arch Neurol 1982;39:662-664. 62. Younger DS, Chou S, Hays AP, Lange DJ, Emerson R, Brin M, 46. Smith CD. Serial MRI finding in a case of primary lateral sclerosis. Thompson H Jr, Rowland LP. Primary lateral sclerosis. A clinical di- Neurology 2002;58:647-649. agnosis re-emerges. Arch Neurol 1988;45:1304-1307. 47. Spiller WC. Primary degeneration of the pyramidal tracts: a study of 63. Zhai P, Pagan F, Statland J, Butman JA, Floeter MK. Primary lateral 8 cases with necropsy. Univ Pa Med Bull 1905;17:390-395. sclerosis: a heterogeneous disorder composed of different subtypes? 48. Spiller WC. Primary degeneration of the pyramidal tracts: a study of Neurology 2003;60:1258-1265. 8 cases with necropsy. Univ Pa Med Bull 1905;17:407-414. 11

Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy

Jonathan S. Katz, MD Stanford University Medical Center Department of Neurology Stanford, California

INTRODUCTION than discrete variables, making it even far more complex). This means a minimum of over 500 potential presentations. The goal of this manuscript, other than to describe brachial amytrophic diplegia (BAD) and multifocal acquired motor ax- onopathy (MAMA), is to discuss why these definitions need to exist. These terms are used to demonstrate practical problems Table 1 Nine observations for motor presentations that clinicians face in the area of diagnosis in pure motor pre- sentations, and it is hoped that some light can be shed on the un- 1. Proximal or distal muscles affected derlying reasoning process in this domain. 2. Symmetric or asymmetric 3. Multifocal, generalized, or regional There are three aspects of neuromuscular diseases that, at times, 4. Upper limbs, lower limbs, neck, trunk involved can make practicing in this area particularly daunting. These are: 5. Upper motor neuron signs present or not 1. Complexity (making numerous observations about each 6. Acute, subacute, or chronic patient). 7. Hereditary or sporadic 8. Axonal or demyelinating 2. Lack of exhaustiveness (the nomenclature is too small to 9. Antibody against nerve is present account for every presentation).

3. No gold standard tests (physicians are left to rely on their observations for diagnosis). Since no individual observation can prove or disprove the pres- ence of a disease by itself, physicians must rely on summations COMPLEXITY of findings, or “the patterns.” For example, amyotrophic lateral sclerosis (ALS) is a pure motor, chronic, asymmetrical disorder There are at least nine basic features used to describe any given with upper motor neuron (UMN) signs. It often presents pure motor presentation (Table 1). Although this may not sound without antibodies, sometimes with a family history, and with like a lot, consider that this means there are at least 29 possible axonal pathophysiology. It is virtually always progressive. patterns derived from these observations (actually some features Knowledge about these “clusters” of observations is at the root of have three or more choices and some have continuous rather pattern recognition. The complexity becomes evident because 12 Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy AAEM Course some ALS patients never develop observable UMN signs. Here, Since ALS presents with diffuse weakness and is axonal, and a slightly different pattern has been created, but one which still multifocal motor neuropathy (MMN) is multifocal but de- handles the logic that UMN signs may not be evident. myelinating, it is quickly apparent that one box is unfilled. It is clear that not every case will fit into the rubric of motor neuron Now consider two cases; one where the weakness remains largely disease or motor neuropathy, as they are defined. While cases in confined to one region (like the arms for long periods of time) the upper right corner are rare, they do exist and they might best and lacks UMN signs, the other with rapidly progressing weak- be reasoned about as a discrete clinical entity. The situation of ex- ness, involvement of all four distal limbs at the time of initial haustiveness becomes obvious when situations with more than presentation, and clear UMN signs. When do these patterns two observations are considered. The only solution is to keep an become so different that a physician cannot be confident these open mind on how to manage these cases, to think about their are the same condition? Going a step further, when is it useful to pathophysiology, and to move forward with the reasoning think about these presentations as though they are two different process. disorders? The discussion of BAD will be a practical approach to these questions. GOLD STANDARDS

LACK OF EXHAUSTIVENESS Finally, there are few “gold standards” or simple diagnostic tests to aid physicians in diagnosis. In most cases the existence of a Many physicians practice in a way that assumes every disease has given diagnosis can never absolutely be proven. With no tests, a actually been named. It should be understood that this assump- complex reasoning domain, and the absence of exhaustive tion might be incorrect. Without a deeper understanding of naming, physicians are left with pattern recognition as the main pathophysiology, it might be assumed that there is more than diagnostic tool. It is inevitable that they will meet circumstances one way that a motor nerve might die, and differences in pre- of real uncertainty. It might be wise to coin the term “nonevi- sentations may signal different underlying mechanisms. dence-based medicine” as the science behind creating rules for managing this area. From a practical standpoint, physicians clearly see presentations that do not fit neatly into a diagnostic “pigeon hole.” These cases can be dealt with by applying the designation variant (ALS MULTIFOCAL ACQUIRED MOTOR AXONOPATHY variant, etc.). Practicing as though an exhaustive universe exists simplifies the reasoning process. Focusing on a single technology In the early 1990s after MMN was described and physicians had has the same effect. Splitting cases simply by the presence or no experience with its diagnosis, there were several cases carrying absence of conduction block (CB), no matter what the pheno- the diagnosis of ALS or atypical motor neuron disease making type, can cut the number of diseases down to only two. the rounds through this author’s clinic. Before physicians were able to diagnose these cases correctly, they had to overcome a At the same time, the possibility that atypical patterns could rep- cognitive dilemma. Specifically, they needed to reconsider the resent an as-yet unnamed disease is often neglected. Table 2 role of CB in the diagnosis of MMN since, at that time, the dis- points out one situation where physicians are forced to consider order carried the label of “multifocal motor neuropathy with the nonexhaustive universe. CB.” Through a series of discussions (in Texas at the time) this author’s group began to think of the condition by its phenotype rather than by electrodiagnostic (EDX) testing. Multifocal motor neuropathy became a phenotype marked by the presence Table 2 of distal, asymmetric, primarily upper limb and stepwise weak- ness, with absence of retained reflexes.3

Axonal NCS/EMG Demyelinating NCS This relatively simple change in the way the disease was viewed Multifocal phenotype ? MMN led to a new set of conclusions about the nature of the condition. Diffuse weakness ALS/PMA Pure Motor CIDP? It followed that only about 40% of MMN patients diagnosed this way actually fulfilled standard EDX criteria for CB. While a ALS = amyotrophic lateral sclerosis; CIDP = chronic inflammatory demyelinating small number of cases had multiple pure CBs, these were the ex- polyneuropathy; EMG = electromyography; MMN = multifocal motor neuropathy; NCS = nerve conduction study; PMA = progressive muscular atrophy. ception and made up approximately 10% of the phenotypic caseload. Instead, the most salient feature was the presence of other evidence of demyelination (temporal dispersion of wave- AAEM Course When It’s Not ALS! Pure Motor Syndromes 13 forms without changes in area, conduction slowing, and pro- dynamic CB, which cannot be discovered with routine testing. longed distal latencies) in virtually all patients. Moreover, in Here antibodies are able to cause weakness via CB that occurs weak nerve distributions, individual nerves often showed axonal only during volleys of nerve action potentials, but not at baseline manifestations only (low compound muscle action potential with a single stimulus, as is the case with standard testing. [CMAP] amplitude denervation potentials) with no evidence of denervation. Overall, the complete picture of EDX testing in It is still unclear whether MAMA and MMN are, if fact, the MMN that emerged was a mixture of features, with axonal find- same disease, or even if MAMA represents a single underlying ings predominate in some affected nerves, obvious CB at other disorder. Like MMN, these cases have weakness in the distribu- sites, and a combination of other demyelinating findings. It fol- tion of individual peripheral nerves. However, they tend to have lowed that the same underlying pathophysiologic process caused proximal involvement more commonly than MMN and onset different electrophysiological manifestations. at a relatively young age in a few cases (around 20). Three of six cases that this author treated responded favorably to therapy, em- From here, it was only a short step to the concept of MAMA. Of phasizing the pitfalls in characterizing MAMA as a “motor this author’s initial 19 cases, 1 patient had no EDX evidence of neuron disease variant” based solely on needle electromyography demyelination at all. After several more years, eight similar cases (EMG) findings. One case of MAMA was prednisone respon- were identified with multifocal involvement clinically, a lack of sive, a finding that differs from MMN, which responds to intra- progression, and axonal-appearing EDX testing. It made little venous immunoglobin (IVIg) but not prednisone. Finally, some sense to diagnose these patients with motor neuron disease based of these cases have confluent or overlapping mononeuropathies on the EDX testing since this implied progression with time and resulting in a pattern of proximal and distal weakness reminis- since motor neuron disease is not supposed to have such clear cent of chronic inflammatory demyelinating polyneuropathy. multifocal involvement. It was further reasoned that if some Thus, it is currently believed that the axonal cases are somehow nerve territories had no evidence of demyelination in MMN, it different. was plausible that in some patients every affected nerve would lack evidence of demyelination, if not by chance alone. It fol- Multifocal acquired motor axonopathy cases also generally lack lowed that the same neuropathy would, at times, show up elec- GM-1 antibodies, and given that antibodies are present in at trodiagnostically as an axonal disorder. least 35% of definite MMN cases, it is hard to understand how no antibodies were found in these first nine cases if this is simply In the initial report of MAMA,1 and in subsequent letters to the an MMN variant. By pure chance this would amount to a 1% editor, it was postulated that several mechanisms for a purely chance if MAMA and MMN were the same disease. (A subse- axonal motor neuropathy.4 First, this may simply be a variant of quent case did have anti-GM1 antibodies suggesting at least MMN where the nerve lesions may be too proximal. In this sce- some of these could be an MMN variant.) nario, a physician would only be able to find secondary axonal loss since the demyelinating lesions are in a segment where the conduction abnormalities cannot be easily identified (without BRACHIAL AMYOTROPHIC DIPLEGIA root stimulation). F waves may also miss a very proximal lesion if there is slowing over only a short segment of nerve or if there Another group of patients examined at this author’s clinic had is only a partial block of conduction. Second, the lesions might been diagnosed with ALS but were not dying quickly nor were be too distal. Conduction block in the terminal segment of a they showing constant progression that is typical of that disease. nerve fiber may be incorrectly interpreted as axonal loss. Third, Most of these cases had a specific phenotype for which the term the injury may actually be directed against the axon. Even using brachial amyotrophic diplegia (BAD) was used.2 This was the most common hypotheses—that MMN is an antibody me- marked by the onset of weakness of one arm that spread rela- diated disorder, marked by an immunological attack directed tively quickly over periods ranging from 1-2 years to become bi- against myelin, myelin/axonal interactions, or ion channels in lateral, eventually reaching the point where the arms hung the axonal membrane—it follows that the same antibodies limply at the patients’ sides. There was a complete absence of might actually damage the axon through an inflammatory weakness outside of the upper limbs, sparing the neck flexors process without causing much in the way of conduction abnor- and extensors, breathing, bulbar muscles, and the legs. Thirteen malities. A related method would be a chronic immune attack of the first 15 patients had absent reflexes, while 2 others had against a nerve, where the demyelinating features become brisk reflexes in the upper limbs. “hidden” because there is severe damage of the underlying axon over time. Fourth, if there are few nerves injured or if the injured Brachial amyotrophic diplegia, by definition, remains localized nerves are difficult to study, or simply not studied on routine to the arms for at least 2 years after the first onset of weakness. testing (anterior interosseous, musculocutaneous, or sciatic) the The rationale was that every case where weakness spread beyond chances of discovering a demyelinating lesion are reduced simply the arms earlier than 2 years, turned out to be clear ALS. While because the opportunity is lost. Last, others have suggested a this raises the possibility of a circular argument that those who 14 Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy AAEM Course do not progress are the ones who do not progress, it turns out growth phase in teenagers is postulated to be the root cause of that these patients often continue to have focal weakness for up JMA. One can only speculate as to whether a similar mechani- to 5 years. More importantly, it is among this population that cal factor is at play in BAD. there exists a group of patients with no progression at all. In contrast, it should be clear that some BAD patients die ap- Needle EMG shows denervation in the upper limbs. Some pa- proximately 5-8 years from onset, with a gradually progressive tients had a few positive sharp waves and fibrillation potentials cause leading to respiratory failure that is typical of ALS. The in the legs or paraspinal muscles, a finding suspicious for ALS, overall point is that BAD is actually a clinical syndrome com- but still did not show progression with time. Creatine kinase can prised of two types of progression. Obviously, the longer the be mildly elevated or normal. Magnetic resonance imaging scan- condition remains localized to the arms, the more hope there is ning was nonrevealing except for nonspecific spondylosis. that the patient does not have a life-threatening illness.

This clinical presentation is important to distinguish from ALS Under any circumstance, BAD does not appear to be treatable. because of the differences in prognosis. It should be clear that Several patients were treated when they failed to progress over within the first 2 years after onset, it is impossible to predict with time, and the initial diagnosis of ALS was questioned. The ra- accuracy exactly how a patient with hanging arms will eventually tionale was that if the patient did not have ALS, they could have progress. However, it is clear that some of these cases ultimately a potentially treatable neuropathy. This is not totally unjustified turn out to have benign courses (except for the devastating in- since reports of ill-defined lower motor neuron disorders that volvement of the arms). This may benefit patients by offering respond to IVIg exist. Given that there is no way to know about some hope. In fact, 6 of this author’s 15 patients have failed to the response without a trial of therapy, it made sense to give develop any involvement outside of the arms to date, even after treatment at least a resort. 8 years from onset. The longest duration of static weakness in BAD is now over 30 years. From these observations, it can be concluded that there are “benign” motor presentations. Bibliography

The underlying pathophysiology of BAD is not known. Among 1. Katz JS, Barohn RJ, Kojan S, Wolfe GI, Nations SP, Saperstein DS, this author’s patients, a specific subset had the onset of weakness Amato AA. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology 2002;58:615- mainly in the C5 and C6 muscles, which became bilateral, re- 620. mained asymmetric, and continued to spare the triceps, wrists, 2. Katz JS, Wolfe GI, Andersson PB, Saperstein DS, Elliott JL, Nations and hands. Some cases with severe involvement of the proximal SP, Bryan WW, Barohn RJ. Brachial amyotrophic diplegia: a slowly arms at onset developed only mild to moderate hand involve- progressive motor neuron disorder. Neurology 1999;53:1071-1076. ment and had a benign prognosis. It might be useful to think of 3. Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn RJ. some BAD cases as a variant of juvenile monomelic amyotrophy Electrophysiologic findings in multifocal motor neuropathy. Neurology. 1997;48:700-707. (JMA), but with involvement of the proximal rather than the 4. Menkes DL, Ghosh A, Donaghy M, Katz JS, Barohn RJ, Saperstein distal limbs. In contrast to JMA, which tends to affect male D, Amato AA. Axonal multifocal neuropathy without conduction teenagers, BAD typically affects men in their late 30s or early block or other features of demyelination. Neurology 2002;59:1666 - 40s. Chronic mechanical impingement of the lower cervical 1667. spine, associated with flexing the neck, which develops during a 15

Pure Lower Motor Neuron Syndromes

David S. Saperstein, MD Assistant Professor of Neurology University of Kansas Medical Center Kansas City, Kansas

INTRODUCTION In some cases, UMN signs may have been present before the patient was evaluated, but subsequently became undetectable Diagnosing amyotrophic lateral sclerosis (ALS) is often difficult due to progressive LMN loss. During a PMA patient’s lifetime, largely because this disease is uncommon (with a prevalence of UMN pathology may be detected with magnetic resonance approximately 1 per 100,000). However, when both upper and imaging (MRI) or transcranial magnetic stimulation (TMS).26 lower motor neuron features are present, diagnosis is usually rel- Conventional MRI sequences may demonstrate evidence of atively straightforward. Furthermore, ALS is the most common UMN involvement, but more specialized modalities such as motor neuron disease (MND). Diagnostic difficulty is more sig- magnetic resonance spectroscopy (MRS) are usually needed.14 nificant when a patient has purely lower motor neuron (LMN) involvement. This manuscript will focus on this situation. The Opinions differ on how to refer to patients with an acquired LMN syndromes are heterogeneous and consist of idiopathic LMN syndrome. For patients presenting with a clinical picture conditions similar to ALS, inherited disorders, and—of most resembling ALS (asymmetrical, progressive weakness), but interest—immune-mediated disorders. The potentially treatable lacking UMN findings, many clinicians will give a diagnosis of disorders, multifocal motor neuropathy and its variants, will be ALS. This is based on the high incidence of UMN features that discussed elsewhere in this course. Overall, the remaining LMN can be found in these patients on imaging, TMS, or autopsy. disorders progress more slowly and tend to have a better prog- Other clinicians tell patients presenting with these symptoms nosis than ALS. that they do not meet criteria for ALS at the time and are, instead, diagnosed with PMA. Another semantic issue involves The nomenclature used for these disorders can be confusing. the terms PMA and spinal muscular atrophy (SMA). Some Patients with an idiopathic purely LMN disorder are typically re- physicians use the term SMA synonymously with PMA or ferred to as having progressive muscular atrophy (PMA) or pro- PSMA. Many reserve the term SMA for patients with a genetic gressive spinal muscular atrophy (PSMA). The term PMA will LMN disorder. It is usually impossible to know with certainly be used here. It is clear that a significant proportion of PMA pa- the cause of a particular patient’s LMN syndrome. Although a tients actually have ALS and lack clinical evidence of upper patient may have a genetic cause for his weakness, if there is no motor neuron (UMN) involvement. This is supported by family history and no gene defect identified, the patient may be autopsy series showing UMN pathology in approximately 50% classified as PMA. However, certain clinical features, such as of PMA patients.1,12,13,19,20 Up to one-third of MND patients symmetrical and proximal weakness with legs weaker than arms lack UMN signs at presentation.21 A significant proportion of would favor SMA over PMA, as will be discussed later. The exact PMA patients, if followed over time, will develop UMN exami- classification is not as important; the key is arriving at the best nation findings and, therefore, can then be diagnosed with ALS. determination of clinical course, prognosis, and management. 16 Pure Lower Motor Neuron Syndromes AAEM Course

Several different LMN syndromes have been described. Brain MRI using conventional sequences may reveal abnormal- Although there is overlap, there are distinguishing aspects with ities of the corticospinal tract in ALS patients. However, this regard to age of onset, etiology, site of involvement (regional lacks sensitivity and specificity.14 Magnetic resonance spec- predilections and restrictions), progression, and mortality (Table 1). troscopy, which permits assessment of regional brain biochem- istry, has shown mixed results in the past for detecting UMN pathology in ALS patients.14,26 Recently, Kaufmann and col- PROGRESSIVE MUSCULAR ATROPHY leagues16 found MRS to be 86% sensitive for identifying UMN pathology in MND patients with and without clinical UMN Progressive muscular atrophy (also referred to as Aran- findings. Autopsies performed in some patients confirmed Duchenne syndrome)22 comprises approximately 10% of pa- UMN involvement. Research from German investigators sug- tients with MND.31 It is slightly more common in men, with an gests that a new MRI imaging technique called diffusion tensor earlier mean age of onset than ALS. Patients receiving the diag- MRI may be an effective way to detect UMN pathology in nosis of PMA represent a mixed group—some are patients who MND patients.26 This modality permits the estimation of the have ALS but lack clinical features of UMN involvement, while orientation of white matter on the basis of the diffusion charac- others are patients with a purely LMN disorder. Therefore, it is teristics of water. It showed abnormalities in 15 ALS patients, 6 impossible to know for certain the clinical course and prognosis of whom had no UMN findings at the time of testing (but later of PMA. As a group, patients with PMA have a much better developed UMN findings and met full diagnostic criteria for prognosis than patients with ALS. In one series, PMA patients ALS).26 Transcranial magnetic stimulation is another test that showed a 5-year survival of 56%.3 In contrast, the average 5-year may permit the identification of UMN pathology. Studies of the survival for ALS patients is approximately 25%.30 usefulness TMS in ALS have provided mixed results.14,26

Table 1 Features of adult motor neuron disorders

Amyotrophic Progressive Spinal Kennedy’s Monomelic Brachial Lateral Muscular Muscular Disease Amyotrophy Amyotrophic Sclerosis Atrophy Atrophy Diplegia

Age of Onset (yrs) 30-60 30-60 20-50 30-60 15-35 30-60

Duration Months-years Years Decades Decades Progression Years over 2-3 years with subsequent stabilization

Distribution Asymmetrical, Asymmetrical, Symmetrical, Symmetrical, Asymmetrical, Symmetrical, of Weakness Distal Distal Proximal Proximal Restricted to 1-2 Proximal extremities upper extremities

UMN signs Present Absent Absent Absent Absent Absent

LMN signs Present Present Present Present Present Present

Inheritance Sporadic (90%) Sporadic AR, AD XR Sporadic Sporadic AD, AR, XR (Gene unknown) (CAG repeats)

Distinct Features Gynecomastia, Male Preservation of Diabetes, predominance respiratory and Impotence, bulbar function Infertility

AD = autosomal dominant; AR = autosomal recessive; CAG = cytosine-adenine-quanine nucleotidase; LMN = lower motor neuron; UMN = upper motor neuron; XR = X-linked re- cessive. AAEM Course When It’s Not ALS! Pure Motor Syndromes 17

Currently, MRI and TMS are not routinely used in clinical prac- in 10-20% of patients. Genetic testing can be performed to tice. The appropriate roles of these technologies in the diagnosis confirm the presence of an abnormal trinucleotide-repeat expan- and management of patients with MND remains to be deter- sion (CAG) in the androgen receptor gene on the X chromo- mined. some.18 In healthy individuals, the repeats range from 17-26 in this coding area whereas, in Kennedy’s disease, the number of There is no data regarding treatment of PMA, therefore, at the repeats range from 40-65. The number of the enlarged CAG present time, these patients are managed the same as those with repeat is significantly correlated with the age of onset, but has no ALS. correlation with severity of weakness, degree of sensory neu- ropathy, presence of gynecomastia, or impotence.

SPINAL MUSCULAR ATROPHY REGIONAL VARIANTS Spinal muscular atrophy is a diverse group of hereditary motor neuron diseases selectively involving LMNs, particularly the an- Regional variants of MND are disorders that are atypical pre- terior horn cells of the spinal cord.23 Adult-onset SMA, referred sentations of generalized MND due to the selected distribution to as type IV, has several forms and usually begins over the age of affected muscles. Several named disorders will be discussed. It of 20. The prevalence is estimated to be 0.32 per 100,000 pop- is not known whether they constitute distinct pathophysiologi- ulation and accounts for less than 10% of all SMA cases.23 cal entities or if they are a subset of generalized MND (e.g., Weakness is usually greater in the legs than the arms.31 The most PMA or ALS). Some entities do appear very distinct. common inheritance pattern (seen in approximately two-thirds Monomelic amyotrophy, for example, occurs at a young age and of patients) is autosomal recessive, with a mean age of onset in remains restricted to specific myotomes. the fourth decade.25 The autosomal dominant form accounts for one-third of cases and shares a similar clinical phenotype.23 The Monomelic Amyotrophy (Focal Motor Neuron Disease, adult-onset disease is slowly progressive with only a small pro- Hirayama Disease) portion of patients becoming wheelchair-dependent after 20 years. Patients typically present with symmetrical, proximal, or Monomelic amyotrophy usually refers to an MND originally generalized weakness, and fasciculations. Spinal muscular described as juvenile muscular atrophy of the distal upper ex- atrophy rarely affects bulbar muscles and respiratory muscles tremity by Hirayama in 1959 in which muscle weakness remains generally remain unaffected. Upper motor neuron signs are limited to several myotomes (usually C5 - T1) within a single ex- absent. Other forms of SMA can involve predominantly distal tremity.10 The mean age of onset is typically 20-35 years of age muscles (so-called “distal SMA”).8 Distal SMA can also be either with a male predominance (2:1). Patients demonstrate preferen- autosomal recessive (two-thirds of patients) or autosomal domi- tial weakness in the hand and forearm muscles which progresses nant (one-third of patients). Although SMA types I, II, and III rapidly over a period of 2-3 years and subsequently remains are usually caused by deletions in the survival motor neuron gene stable. Approximately 75% of cases involve the upper extremi- on chromosome 5, no genes responsible for SMA type IV have ties and the remainder involve the lower extremities. Reflexes in been identified.27 the involved muscles are invariably hypoactive or absent. There are no UMN signs and sensory symptoms are limited to hypes- thesia to pin and touch in approximately 20% of patients. In SPINOBULBAR MUSCULAR ATROPHY (KENNEDY’S DISEASE) 50% of cases, the weakness remains localized to one limb, and the other 50% of cases show clinical evidence of involvement in Kennedy’s disease is a form of SMA that is associated with bulbar the contralateral limb. Electrodiagnostic studies often show evi- involvement and X-linked recessive inheritance.17 The disease dence of bilateral involvement although weakness may be clini- affects only males, usually beginning in the third or fourth cally apparent in only one extremity.6 decade of life. The initial symptoms include muscle cramps, a limb-girdle distribution of muscle weakness, and bulbar symp- Magnetic resonance imaging may reveal a normal cervical spinal toms. Distinguishing clinical features include facial and perioral cord, but bilateral or unilateral cord atrophy is often seen.2 fasciculations that are present in more than 90% of patients, Hirayama and colleagues9 have suggested that this syndrome hand tremor, and tongue atrophy associated with a longitudinal may be related to either local compression of the cervical cord or midline furrow. There is no evidence of UMN involvement. circulatory insufficiency caused by an anterior shift of the poste- Although sensory examination is typically normal, sensory nerve rior dura during neck flexion. Sometimes, abnormalities may be conduction studies are frequently abnormal. Other systemic seen on MRI only when images are acquired with the neck in a manifestations, include gynecomastia in 60-90% of patients due flexed position (forward displacement of cervical dural sac).9 to elevated gonadotropin levels associated with testicular atrophy, Neck flexion may also produce decreased abnormalities on feminization, impotence, and infertility. Diabetes mellitus is seen somatosensory evoked potentials.24 A recent report from Taiwan 18 Pure Lower Motor Neuron Syndromes AAEM Course describes a useful finding that can be seen in cervical spine MRI SUMMARY scans taken in a neutral, nonflexed position.2 These investigators found that an increased separation between the posterior dural Patients with LMN disorders represent a heterogeneous group. sac and adjacent lamina was a highly sensitive and specific Some have ALS whereas others will have conditions with a much finding in Hirayama patients. They endorse a pathogenic theory more favorable prognosis). Some are hereditary, but the under- involving imbalance between the spinal cord and spinal column lying pathophysiology for most of these entities is unknown. that results in a “tight dural sac.”2 Careful use of history, physical examination, electrodiagnosis, MRI, and genetic testing will usually allow for appropriate diag- The appropriate management of patients with Hirayama disease nosis. is unknown. Uncontrolled data from Japan suggests that wearing a hard cervical collar (to prevent neck flexion) may halt disease progression.28 REFERENCES

There are MND patients who develop nonprogressive weakness 1. Brownell B, Oppenheimer D, Hughes JT. The central nervous system restricted to the lower limb. This entity has been described in motor neurone disease. J Neurol Nerosurg Psychiatry mostly in India, but has been reported in Westerners as well.31 1970;33:338-357. 2. Chen CJ, Hsu HL, Tseng YC, Lyu RK, Chen CM, Huang YC, Wang This is often described under the term “monomelic amyotro- LJ, Wong YC, See LC. Hirayama flexion myelopathy: neutral-posi- phy,” but most likely represents an entity distinct from the focal tion MR imaging findings–importance of loss of attachment. upper limb weakness described above.4,5,7 Radiology 2004;231:39-44. 3. Chio A, Brignolio F, Leone M, Mortara P, Rosso MG, Tribolo A, Flail Arm Syndrome Schiffer D. A survival analysis of 155 cases of progressive muscular atrophy. Acta Neurol Scand 1985;72:407-413. 4. de Visser M, Ongerboer de Visser BW, Verbeeten B Jr. Flail arm syndrome is an MND regional variant consisting of Electromyographic and computed tomographic findings in five pa- weakness exclusively confined to the upper extremities. Cases tients with monomelic spinal muscular atrophy. Eur Neurol have also been described under the name of “hanging arm syn- 1988;28:135-138. drome,” and “neurogenic man-in-the-barrel.” These patients 5. Di Muzio A, Delli Pizzi C, Lugaresi A, Ragno M, Uncini A. Benign have bilateral upper extremity weakness and atrophy that affects monomelic amyotrophy of lower limb: a rare entity with a character- istic muscular CT. J Neurol Sci 1994;126:153-161. predominantly the proximal arms and shoulder girdle. The 6. Donofrio PD. AAEM Case Report #28: Monomelic amyotrophy. average age of onset does not differ from that of ALS, but com- Muscle Nerve 1994;17:1129-1134. pared with ALS, this syndrome is significantly more common in 7. Gourie-Devi M, Suresh TG, Shankar SK. Monomelic amyotrophy. men.11 Average survival is approximately 5 years, compared with Arch Neurol 1984;41:388-394. 3 years for ALS patients.11 Although, the overall survival is longer 8. Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci than for ALS, some patients presenting with a flail arm pheno- 1980;45:337-348. type can go on to develop a typical ALS course. A flail arm 9. Hirayama K, Tokumaru Y. Cervical dural sac and spinal cord in ju- pattern is seen in approximately 10% of MND patients, al- venile muscular atrophy of distal upper extremity. Neurology though it is much more common in those of African descent.11,29 2000;54:1922-1926. Curiously, these patients do not show the same prolonged sur- 10. Hirayama K, Tomonaga M, Kitano K, Yamada T, Kojima S, Arai K. vival as Caucasian patients with the flail-arm phenotype.29 Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry 1987;50:285-290. Within the flail arm clinical phenotype, another significant divi- 11. Hu MT, Ellis CM, Al-Chalabi A, Leigh PN, Shaw CE. Flail arm syn- sion can be made. Among patients with this presentation, if drome: a distinctive variant of amyotrophic lateral sclerosis. J Neurol weakness remains confined to the arms for at least 18 months, Neurosurg Psychiatry 1998;65:950-951. clinically significant progression outside of the upper extremities 12. Ince PG, Evans J, Knopp M, Forster G, Hamdalla HH, Wharton SB, 15 Shaw PJ. Corticospinal tract degeneration in the progressive muscu- does not occur and survival is quite prolonged. In the series of lar atrophy variant of ALS. Neurology 2003;60:1252-1258. 15 Katz and colleagues, after a mean follow-up of 5.5 years, weak- 13. Iwanaga K, Hayashi S, Oyake M, Horikawa Y, Hayashi T, ness remained restricted to the upper extremities in 7 out of 10 Wakabayashi M, Kondo H, Tsuji S, Takahashi H. Neuropathology of patients. When present, leg involvement was mild. No patient sporadic amyotrophic lateral sclerosis of long duration. J Neurol Sci lost the ability to ambulate independently and none developed 1997;146:139-143. bulbar or respiratory involvement. One patient had restricted 14. Kalra S, Arnold D. Neuroimaging in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4:243- weakness for greater than 10 years. This clinical presentation has 248. 15 been named bibrachial amyotrophic diplegia (BAD). Patients 15. Katz JS, Wolfe GI, Andersson PB, Saperstein DS, Elliott JL, Nations with BAD (showing no progression beyond arms by 18 months) SP, Bryan WW, Barohn RJ. Brachial amyotrophic diplegia: a slowly represent approximately 2% of all MND patients.15 progressive motor neuron disorder. Neurology 1999;53:1071-1076. AAEM Course When It’s Not ALS! Pure Motor Syndromes 19

16. Kaufmann P, Pullman SL, Shungu DC, Chan S, Hays AP, Del Bene 25. Rudnik-Schoneborn S, Rohrig D, Morgan G, Wirth B, Zerres K. ML, Dover MA, Vukic M, Rowland LP, Mitsumoto H. Objective Autosomal recessive proximal spinal muscular atrophy in 101 sibs out tests for upper motor neuron involvement in amyotrophic lateral scle- of 48 families: clinical picture, influence of gender, and genetic im- rosis (ALS). Neurology 2004;62:1753-1757. plications. Am J Med Genet 1994;51:70-76. 17. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and 26. Sach M, Winkler G, Glauche V, Liepert J, Heimbach B, Koch MA, bulbar muscular atrophy of late onset. A sex-linked recessive trait. Buchel C, Weiller C. Diffusion tensor MRI of early upper motor Neurology 1968;18:671-680. neuron involvement in amyotrophic lateral sclerosis. Brain 18. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. 2004;127:340-350. Androgen receptor gene mutations in X-linked spinal and bulbar 27. Somerville MJ, Hunter AG, Aubry HL, Korneluk RG, MacKenzie muscular atrophy. Nature 1991;352:77-79. AE, Surh LC. Clinical application of the molecular diagnosis of spinal 19. Lawyer T Jr, Netsky MG. Amyotrophic lateral sclerosis: a clini- muscular atrophy: deletions of neuronal apoptosis inhibitor protein coanatomic study of fifty-three cases. AMA Arch Neurol Psychiatry and survival motor neuron genes. Am J Med Genet 1997;69:159- 1953;69:171-192. 165. 20. Leung DK, Hays AP, Geysu K, DelBene ML, Rowland LP. Diagnosis 28. Tokumaru Y, Hirayama K. Cervical collar therapy for juvenile mus- of ALS: clinicopathologic analysis of 76 autopsies. Neurology cular atrophy of distal upper extremity (Hirayama disease): results 1999;52:A164. from 38 cases. Rinsho Shinkeigaku 2001;41:173-178. 21. Mortara P, Chio A, Rosso MG, Leone M, Schiffer D. Motor neuron 29. Tomik B, Nicotra A, Ellis CM, Murphy C, Rabe-Hesketh S, Parton disease in the province of Turin, Italy, 1966–1980: survival analysis in M, Shaw CE, Leigh PN. Phenotypic differences between African and an unselected population. J Neurol Sci 1984;66:165-173. white patients with motor neuron disease: a case-control study. J 22. Norris F, Shepherd R, Denys E, U K, Mukai E, Elias L, Holden D, Neurol Neurosurg Psychiatry 2000;69:251-253. Norris H. Onset, natural history, and outcome in idiopathic adult 30. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. motor neuron disease. J Neurol Sci 1993;118:48-55. Clinical features of amyotrophic lateral sclerosis according to the El 23. Pearn J. Autosomal dominant spinal muscular atrophy: a clinical and Escorial and Airlie House diagnostic criteria: a population-based genetic study. J Neurol Sci 1978;38:263-275. study. Arch Neurol 2000;57:1171-1176. 24. Restuccia D, Rubino M, Valeriani M, Mirabella M, Sabatelli M, 31. Van Den Berg-Vos RM, Van Den Berg LH, Visser J, de Visser M, Tonali P. Cervical cord dysfunction during neck flexion in Hirayama’s Franssen H, Wokke JH. The spectrum of lower motor neuron syn- disease. Neurology 2003;60:1980-1983. dromes. J Neurol 2003;250:1279-1292. 20 AAEM Course 21

Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

Vinay Chaudhry, MD Professor and Vice Chairman Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

INTRODUCTION MULTIFOCAL MOTOR NEUROPATHY

Multifocal motor neuropathy (MMN) is a disorder character- Multifocal motor neuropathy is an acquired immune-mediated ized by slowly progressive asymmetrical weakness predominantly demyelinating neuropathy with distinctive clinical and electro- affecting the upper extremities. The lack of sensory involvement physiological manifestations, and response to treatment. Earlier and the progressive weakness mimic the presentation of a lower descriptions of MMN described a progressive multifocal pure motor neuron (LMN) form of amyotrophic lateral sclerosis motor demyelinating disorder that clinically resembled an LMN (ALS). However, unlike ALS, electrophysiological testing reveals variant of ALS with progressive asymmetric weakness with demyelinating findings with partial motor conduction block atrophy, fasciculations, and cramps in the absence of sensory (PMCB) in multiple motor nerves; approximately half the symptoms and signs.5,6,11,13,14,16,19,24,29,35,38,43,44,46,59,64-66,69,74,84 The MMN patients have anti-GM1 antibodies in the serum; and relatively benign course of the disease led one case report to be over 80% respond dramatically to treatment with intravenous entitled “. . . a reversible motor neuron syndrome.”13 The term immunoglobulin (IVIg).56,58,90 Multifocal acquired demyelinat- “multifocal motor neuropathy” was first used in 1988 by ing sensory and motor (MADSAM or Lewis-Sumner syndrome) Pestronk and coworkers66 and is now commonly used in all de- neuropathy on the other hand does not mimic ALS. The pre- scriptions of such cases. The multifocality, the selective motor in- sentation can be similar to MMN with asymmetrical involve- volvement, and the demyelinative electrophysiology (with ment of multiple nerves and with PMCB. However, unlike PMCB) have become the distinctive hallmarks of this disorder. MMN, sensory involvement is as prominent as motor both clin- ically and electrophysiologically; the disorder is not associated Clinical Features with anti-GM1 antibodies; and the disorder responds to corti- costeroid treatment.72 Both disorders, MMN, and MADSAM The prevalence of MMN is unknown, but based on the litera- neuropathy share the demyelinating features and response to ture and experience at large centers, MMN is a rare disorder. immune treatment, making them different from ALS (Table 1). Since its original description approximately 20 years ago, more There are some who would consider both disorders to be vari- than 300 patients have been reported with MMN. At this ants of chronic inflammatory demyelinating polyneuropathies author’s institution, it is estimated that 1 MMN patient is seen (CIDP).39 Until immunopathogenesis are understood and until for every 20 patients with ALS. One quoted estimate of preva- biological markers become available, it is best to consider them lence is 1-2 per 1,000,000.58 Cases in the literature indicate the separately. This manuscript will describe the clinical features, male to female ratio is 3:1, with the age range varying from the electrodiagnosis, immunopathogenesis, treatment, and progno- second to the eighth decade (mean age 40 years). The duration sis of these two conditions. of the disease ranges from several months to up to 30 years 22 Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy AAEM Course

Table 1 Differential diagnosis for multifocal motor neuropathy and Lewis-Sumner syndrome

Amyotrophic Lateral Sclerosis Multifocal motor neuropathy Lewis-Sumner Syndrome CIDP

Anatomical Motor Neuronopathy Motor Myelinopathy Sensory Motor Myelinopathy Sensory Motor Myelinopathy

Age (Sex) 5th-6th decade 15-60 yrs 5th decade All ages (M>F, 2:1) (M>F, 3:1) (M>F, 2:1) (M>F, 1.5:1)

Distribution Asymmetrical onset; distal> Asymmetrical Asymmetrical Symmetrical proximal at onset; progresses distal > proximal distal > proximal proximal & distal to to all 4 limbs, bulbar, upper > lower limbs upper > lower lower > upper diaphragm muscles; myotome distribution asymmetrical distribution asymmetrical distribution symmetrical may have a of peripheral nerves- of peripheral nerves- length-dependent pure motor sensory and motor distribution

Progression Rapidly progressive; Stepwise/insidious; Stepwise/insidious; progressive >2 months fatal in 3-5 yrs some functional limitation some functional limitation

Fasciculations/ Very common Common with myokymia May be present Uncommon Cramps

Reflexes Hyperactive Asymmetrically reduced Reduced Areflexia

SNAP Normal Normal Abnormal Abnormal-symmetric

CMAP Reduced Reduced or normal Reduced or normal Reduced

PMCB Absent Present and localizable Present and localized to Present to small segments small segments

CV/DL & F wave Normal or mildly reduced/nl Reduced segmentally/ may Reduced segmentally/ Reduced/prolonged or mildly prolonged be prolonged May be prolonged or absent

Fibs/PSW Widespread ++++ Localized — to +++ Localized — to +++ Length-dependent +

CSF protein Usually normal Usually normal Usually elevated Usually elevated

Anti-GM1 antibodies Rare Frequent (50%) Rare Rare

Sural nerve biopsy Normal Minor evidence of demyelination Prominent demyelination, Demyelination, and remyelination remyelination remyelination, inflammation

Treatment response None; riluzole may slow IVIg, cytoxan Steroids, IVIg Steroids, PE, IVIg down the progression

Prognosis Invariably progressive Remains focal— Remains focal—slow Progressive; relapsing and and fatal slow progression over progression over many years and remitting; monophasic many years

Pathophysiology Excitotoxic, free radical, Immune-mediated Immune-mediated Immune-mediated oxidative stress, retrovirus; mitochondrial

CIDP = chronic inflammatory demyelinating polyneuropathy; CMAP = compound muscle action potential; CSF = cerebrospinal fluid; CV = conduction velocity; DL = distal latency; fibs = fibrillation potentials; F = female; IVIg = intravenous immunoglobulin; M = male; PE = plasma exchange; PMCB = partial motor conduction block; PSW = positive sharp wave; SNAP = sensory nerve action potential. AAEM Course When It’s Not ALS! Pure Motor Syndromes 23

(average, 7.5 years) with the progressive course superimposed on not as prominent as one would see in CIDP and often do not a step-wise deterioration. meet the proposed demyelinating criteria. The presence of these additional demyelinating findings suggest concomitant, though The clinical presentation is fairly distinctive with the initial less intense, diffuse involvement of motor nerves. Remarkably, symptom being asymmetrical progressive weakness in the upper sensory nerve conductions are normal, even in those mixed limbs, distal greater than proximal. Unilateral wrist drop, finger nerves where motor fibers are affected (Figure 1). drop, grip, problems with dexterity, or biceps weakness are often noted at onset. Asymmetrical lower limb weakness, especially While some authors have used a reduction in amplitude or area foot drop, is less often a presenting symptom.54 Cranial nerve in- of the proximally evoked response by ∃A 40%,49,59 others have volvement and respiratory failure are rare, but have been re- used a decrease by greater than 30% with a duration change less ported.38,51 Cramps, twitching of the muscles, fatigue, and cold than 15%.29 More commonly, a greater than 50% reduction in sensitivity are additional features. By definition, sensory symp- the proximally evoked amplitude or negative peak area is toms such as numbness or tingling are absent or minimal. used.11,16,44,46,52 The American Association of Electrodiagnostic Medicine criteria are shown in Table 2.61 These criteria require a Physical examination confirms asymmetrical weakness in the reduction of proximal versus distal CMAP amplitude in the distribution of named peripheral nerves without sensory distur- nerves of upper limbs by greater than 50% and of lower limbs bance in the same distribution. Although weakness can occur in by more than 60% for definite PMCB. the distribution of any nerve, the posterior interosseous branch of the radial nerve, and the median, ulnar, peroneal, and mus- In most patients, when the distal CMAP amplitude is normal in culocutaneous nerves are most commonly affected. Weakness is an affected weak muscle, there is seldom any difficulty in de- often more pronounced than the degree of atrophy would tecting PMCB, especially if all proximal stimulation sites are also suggest; marked weakness (MRC < 4) is frequently detected in chosen. The difficulty arises in those cases where the atrophy is muscles where the bulk is completely preserved. Myokymia and significant and the CMAP amplitudes are reduced. In this situ- fasciculations are frequently noted. Muscle-stretch reflexes are ation, because of “interphase cancellation” that occurs due to asymmetrically reduced in the affected limbs and sometimes overlap of positive and negative components of different motor even in clinically asymptomatic limbs. Occasionally, reflexes are units, a conduction block may be misdiagnosed. Thus, extra described as “brisk,” but pathological pyramidal signs—clonus, caution should be used when defining PMCB in situations spasticity, extensor plantar responses—do not occur. In spite of where CMAP amplitude is less than 50% of the lower limit of the multifocal weakness, most MMN patients retain useful normal (LLN). Whenever possible, inching should be per- function and continue working for long periods. formed between those segments with documented conduction block. If the segment where conduction block is detected is Electrophysiological Features between 50 and 100 mm in length, the confidence level for true conduction block is much higher since temporal dispersion and The classic finding in MMN is a well-localized, persistent, seg- phase cancellation have relatively little effect over this short dis- mental, PMCB detected outside the usual sites of entrapment. tance. Technical errors must be minimized by ensuring that Conduction block, thought to be the electrophysiological hall- supramaximal stimulation is achieved, that anatomical variants mark of focal demyelination, is defined as a reduction in ampli- such as Martin-Gruber anastomosis are excluded, and ensuring tude or area (or both) of the compound muscle action potential that the spread of stimulus to adjacent nerves does not occur, (CMAP) obtained by proximal stimulation versus distal stimu- such as with stimulation distally.20 It should also be kept in mind lation of the motor nerve. Conduction block may go undetected that there are other causes of PMCB other than a focal demyeli- unless several nerves are each tested at multiple sites of stimula- nating process, e.g., the acute phase of partial nerve injury sec- tion. Forearm segments of the median and ulnar nerves are most ondary to trauma or vasculitis, and functional conduction frequently affected, followed by the Erb’s point-to-axilla block.20,36 segment. In assessing PMCB, the usual sites of entrapment must be excluded, i.e., the across-elbow segment of the ulnar nerve Indirect evidence of a very proximal PMCB can be inferred (1) and the across-fibular head segment of the common peroneal by finding F-wave responses that are absent, prolonged, or dis- nerve. Partial motor conduction block may also be seen in motor persed in a weak muscle with normal distal amplitudes, or (2) by nerves not clinically affected. In addition, other electrophysio- showing that voluntarily evoked muscle action potentials pro- logical features of peripheral nerve demyelination are invariably duced by maximal effort (recorded by surface electrodes) are found: reduced conduction velocity, especially segmentally markedly reduced compared to the response evoked by distal across sites of partial motor conduction block; absent or pro- electric stimulation (described later). A very distal block may also longed F-wave responses; and prolonged distal motor laten- be inferred if the CMAP amplitudes are reduced in a weak cies.11,17,19,40 These other features of demyelination are, however, muscle, but then improve rapidly to normal after treatment.62 24 Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy AAEM Course

MOTOR NERVE CONDUCTION SENSORY NERVE CONDUCTION

Figure 1 Example of partial motor conduction block localized to a 50-mm forearm segment of the median nerve. The conduction velocity in this segment is reduced to 29 m/s. Sensory conduction velocity (right panel) in the identical segment is normal.

Another indirect sign of distal conduction block is a low ampli- conduction block, the V/E ratio was between 12-15%. Patients tude response on distal stimulation, at a time when needle ex- with upper motor neuron lesions secondary to stroke showed amination provides no evidence of axonal degeneration. similar findings, with V/E ratios between 11-15% (Figure 2).15

This author and colleagues have used a surface recording tech- Needle EMG is always abnormal in MMN patients, but the ab- nique combined with standard electric stimulation to confirm or normality is restricted to the symptomatic muscles. Unlike ALS, detect PMCB in MMN. Distally stimulated electrical (E) re- widespread LMN dysfunction is not detected, even in cases sponse is compared to volitional (V) response obtained by the where the disease has existed for a long time. Prominent fibrilla- same recording electrode without electrical stimulation but with tion potentials and positive sharp waves are rare but fasciculation maximal voluntary activity. The V/E ratio is markedly reduced potentials are common, in 71% of patients.10 Myokymia, al- in patients with documented conduction block and is signifi- though not frequent, is important to note if present since it is cantly different from V/E ratios in healthy subjects or patients not seen in ALS patients. Typically, patients have reduced motor with motor neuron disease. The V/E ratio in control subjects unit recruitment with fast firing units. Giant potentials have varies from 56-58%, similar to that in ALS patients (58-67%). been observed only in weak muscles and nerves in normal By contrast, in patients with demyelinating neuropathy with muscles. AAEM Course When It’s Not ALS! Pure Motor Syndromes 25

Table 2 AAEM criteria for conduction block

Minimal Temporal Dispersion Abnormal Temporal Dispersion* Definite (probable) Conduction Block Probable Conduction Block Nerve Amplitude reduction Area reduction Amplitude reduction Area reduction Median** > 50% (40-49) >40% (30-39) >50% >40% Ulnar** >50% (40-49) >40% (30-39) >50% >40% Radial** (>50%) (> 40%) >50 % >40% Peroneal*** >60% (50-59) >50% (40-49) >60% >50% Tibial*** >60% (50-59) >50% 40-49) >60% >50%

*Abnormal Temporal Dispersion > 30% duration **Erb’s point-axilla segments are not accepted *** thigh and sciatic notch are not accepted

Other Laboratory Features of large-caliber axons with thinly myelinated fibers, sometimes associated with minor onion bulbs, are reported in sural nerve High titers of IgM antibody directed against GM1 and other biopsies. Unlike CIDP, MMN is not marked by epineural and gangliosides are reported in 22-84% of patients.44,65 Some endonuclear mononuclear cell infiltrates or endoneurial and MMN sera that show anti-GM1 activity also react with other subperineurial edema. Two reports of motor or mixed nerve similar glycolipids, including GA1 or GM2 ganglioside. biopsy have showed noninflammatory demyelination with Although high titers of anti-GM1 antibody are supportive of the onion bulbs.6,37 More recently, Taylor and colleagues performed diagnosis, they are not required to be present for a diagnosis and fascicular nerve biopsies of the motor nerve at the site of con- furthermore are not helpful in predicting response to therapy. duction block.75 These authors report reduced density of large The presence of high titers of these antibodies in a patient with myelinated fibers (in a multifocal pattern), regenerating clusters, multifocal LMN weakness, however, should mandate a careful alterations in size distribution, and low grade axonal degenera- electrophysiological evaluation. An elevated serum creatine tion in 7 of 8 nerves studied. The authors did not find evidence kinase (CK) level is frequently found, probably secondary to the to suggest demyelination in paranodal or internodal regions or myokymia and cramps in the muscles. Cerebrospinal fluid remyelination in the form of onion bulbs. Based on this patho- (CSF) is usually normal or may reveal a slight elevation in total logical study, the authors favor the hypothesis of an antibody- protein content. Serum immunofixation electrophoresis may oc- mediated attack directed against components of axolemma at casionally reveal the presence of monoclonal gammopathy, the nodes of Ranvier (resulting in functional conduction block mostly of the IgM isotype. followed by demyelination, and axonal degeneration if the attack is severe) rather than an attack on components of paranodal Imaging Studies myelin (with segmental demyelination and axonal degenera- tion).75 Magnetic resonance imaging (MRI) scans of the affected regions may show hypertrophic nerve segments with increased signal in- Pathogenesis tensity in T2-weighted images or in T1-weighted images after gadolinium enhancement.38,63,91 Magnetic resonance neurogra- Multifocal motor neuropathy is now widely accepted to have an phy is a potential noninvasive technique for identification of immune-mediated pathogenesis. Clinical improvement observed focal abnormalities at the level of brachial plexus or along the with immunomodulation is the strongest supporting evidence course of a peripheral nerve. Increased signal intensities on T2- for its immunopathogenesis.6,16,29,35,38,43,59,66,84 Why motor fibers weighted MRI of the brachial plexus were detected in one-third of a mixed nerve are selectively affected is unknown. Possible hy- of patients with MMN in one study.82,83,91 potheses include: (1) the distribution of the demyelination may be determined by fascicular arrangement within the nerve trunk, Pathology and demyelinative lesions may be restricted to the “motor fasci- cles” and, therefore, result in pure motor symptoms; (2) the po- Frequent, albeit mild, morphological abnormalities are seen in tential target antigen for this immune disorder may be different for sensory fibers in patients with MMN.21,43,59 Increased numbers myelin in motor axons than in sensory axons; (3) the underlying 26 Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy AAEM Course

Figure 2 An example of V/E recording in a patient with left foot drop due to partial motor conduction block across fibular head. On the left (A) is the recording from the left tibialis anterior muscle with supramaximal stimulation of the common peroneal nerve at the fibular head (segment 1) and popliteal fossa (segment 2). Segment 3 represents volitional activity of the patient captured randomly. Partial motor con- duction block is present between segments 1 and 2. Like segment 3, the right panel (B) represents surface recording of maximal volitional activity but captured on a free-running mode. Note that the negative peak amplitudes of the responses in segment 2, segment 3, and in the free-running mode (B) are similar.

E = electrical; V - volitional pathologic process in MMN may affect the sensory and motor induced block of conduction when injected into rat sciatic or fibers equally, but cause conduction failure only in the motor tibial nerve in vivo70,79 or in a mouse phrenic nerve preparation fibers because of a greater safety factor of conduction in the in vitro.4,68 These results, however, were not confirmed by sensory fibers. It has been shown that sensory fibers are less likely Harvey and colleagues33 using purified anti-GM1 antibodies. to develop activity-dependent conduction block, a feature Experimentally, anti-GM1 antisera produced in rabbits immu- shown for motor fibers of MMN patients.36 nized with GM1 ganglioside increased K+ current and blocked Na+ channel current in isolated rat myelinated nerve fibers.73 As noted above, under pathological observations, some have sug- This, however, could not by confirmed by Hirota and col- gested that in MMN the immune attack is primarily directed leagues.34 At this time, anti-GM1 antibodies can at best be con- against components of the axon rather than myelin.75 Kiernan sidered a marker of the disease. and colleagues, using excitability testing in patients with MMN, have also shown evidence of membrane hyperpolarization distal Response to Treatment to the site of conduction block. They have hypothesized that the conduction block and ectopic discharges are caused primarily by Since MMN is recognized to be an immune-mediated disorder, juxtaposed lengths of depolarized and hyperpolarized axonal several immunomodulatory therapies have been tried, including membrane, and that the block is accompanied by degeneration prednisone, azathioprine, chlorambucil, cyclophosphamide, when the depolarization is severe.41 plasma exchange, and IVIg. High-dose IVIg has been found to be invariably effective in patients reported in the litera- The pathogenic role of anti-glycolipid antibodies in the serum of ture.6,9,11,14,16,19,24,35,37,40,46,55,59,77,80,81 Four randomized trials of a MMN patients remains speculative. Some studies correlated total of 46 patients have confirmed the benefit of IVIg as clinical improvement with reduction in titers of the antibod- well.6,28,46,82 Treatment generally begins with IVIg at a dose of 2 ies,8,65,66 thus suggesting that these antibodies are pathogenic, but g/kg divided over 2-5 days. Beneficial effects begin within days, this has not been true in other studies.16,59 Immunoglobulin de- sometimes hours after the infusion, and peak at an average of 2 posits have been found at the nodes of Ranvier in biopsied nerve weeks. The effect lasts from several weeks to months. Most pa- from a patient with MMN70 and in rat sciatic nerve treated with tients require periodic maintenance doses of IVIg. The dose and anti-GM1 antibody.33 Sera from patients with MMN has frequency of IVIg administration needs to be individualized AAEM Course When It’s Not ALS! Pure Motor Syndromes 27 depending on the length of benefit received, which appears to side effects. The lot number and name of the commercial prepa- vary between patients, but is relatively constant in an individual rations of IVIg used in each case should be recorded. Caution patient. After administering the first dose of IVIg, the duration should be used in giving IVIg to the elderly and to patients with of effectiveness should be determined. Most patients who expe- IgA deficiency, borderline renal dysfunction, or cardiac dysfunc- rience a dramatic benefit have a relapse, which again responds to tion. IVIg treatment. For most, this “yo-yo effect” is unacceptable, and it is prudent to give these patients another dose before the The mechanism of IVIg’s immunomodulatory effects are not anticipated time of relapse. Patients who experience minimal fully understood. The rapidity of clinical and electrophysiologi- benefit or patients whose disease is stable may not need a second cal improvement after IVIg suggests that improvement is un- treatment for years. Occasional patients have a long lasting re- likely to be due to structural remyelination of demyelinated mission after a single course of IVIg.7,59,89 In cases where more axons. Different hypotheses include supply of an anti-idiotypic frequent administrations are needed (< 2 months), it is worth- antibody, interference with antibody binding or accessibility to while to try reducing the dose of IVIg at each administration, the antigen, Fc receptor blockade, modulation of cytokine se- and thus to arrive at the minimal dose with maximal effective- cretion, regulation of B cell and T cell expression or function, ness. Some of the alternative dosing strategies that may work in neutralization of superantigents, and induction of remyelina- individual patients are 0.4 g/kg weekly, 0.8 g/kg every 2 weeks, tion.22,23,92 or 1 g/kg every month. In one study, the interval between IVIg infusions could be prolonged with concomitant use of oral cy- Prednisone and plasma exchange, two therapies used in the stan- clophosphamide.55 dard treatment of CIDP, have rarely been effective in the treat- ment of MMN.5,14,24,29,30,40,42,43,64-66,74 It is important to note that In this author’s experience, and from limited reports of long- some patients with MMN may worsen in strength after initia- term IVIg treatment, no patient has become absolutely refrac- tion of corticosteroids treatment24,29,66,83 or after PE.12 tory to treatment.7,55,81 However, deterioration of muscle Azathioprine “stabilized” one of four reported patients who were strength may occur with long-term IVIg treatment.27,81 treated with this medication,16,43,64 but no patient’s strength im- Increasing the frequency of administration of IVIg may offset proved. any chance of deterioration. Improvement in strength correlates with a reduction in PMCB,16,55,59 but no change in anti-GM1 Among the immunosuppressive agents available, cyclophos- antibody titers.9,11,16,29,81 Predictors of a better response include a phamide is perhaps the only one shown to have consistent effi- younger age at onset, a smaller number of affected limb regions, cacy (50-80%) in the treatment of MMN.7,16,24,29,38,40,55,65,66,74 elevated GM1 antibody titers, definite conduction blocks, and However, cyclophosphamide is not routinely given because of its higher distal amplitudes. On the other hand, older age at onset, toxic side effects, including bone marrow suppression, increased more widespread weakness, and elevated serum CK values are as- risk of infections, hemorragic cystitis, infertility, teratogenecity, sociated with relatively poor response.83 alopecia, nausea, vomiting, and an increased risk of hematologi- cal malignancies. Daily oral (100-150 mg/day) or periodic in- Although the high cost of IVIg appears to be the main obstacle travenous (1-3 g/m2) regimens have been used for 6 months. A to its use, there are some serious, albeit rare, side effects that need few anecdotal patients have been successfully treated with to be monitored. Transient headache, chills, myalgia, and nausea another alkylating agent, chlorambucil. Interferon-∃1 has been are common and can be managed by non-steroidal anti-inflam- successfully used as an alternate treatment of MMN patients.53,88 matory drugs and slowing the infusion rate. Severe headaches or In one study, cyclosporin A was shown to improve MMN in two other intolerable allergic side effects can be prevented by pre-ad- patients.57 ministration methylprednisolone (60-100 mg IV) and diphen- hydramine (25-50 mg IV) 30 minutes prior to IVIg infusion. Although long term maintenance therapy with IVIg has benefi- Moderately severe reactions, including aseptic meningitis and cial effect on muscle strength and upper limb disability, it does skin rash (urticaria, lichenoid lesions, pruritis, petechiae), occur not prevent decrease in strength over time and does not induce within days of the infusion and generally require no treatment. remission.88 It has been suggested that early treatment may More serious reactions are fortunately rare and include anaphy- prevent future progression of weakness and disability.85 laxis (in patients with severe IgA deficiency, test prior to IVIg ad- ministration), renal failure (in patients with preexisting renal disease and volume depletion), thromboembolic episodes, such FUTURE DIRECTIONS as stroke, myocardial infarction, pulmonary embolism (in pa- tients with increased risk such as elderly, diabetic, thrombocy- While the immune pathogenesis clearly needs to be defined totic, hypergammaglobulinemia), and volume overload further, there is a need to find alternative treatment strategies to (necessitating caution in congestive heart failure patients).23 IVIg. In some patients, the duration of response decreases over Sometimes a different brand of IVIg may be necessary to avoid time, leading to increased frequency of IVIg administration. The 28 Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy AAEM Course natural course of the disease is of slow progression over long rather than a generalized stocking or glove pattern is noted. periods of time, even with treatment.28,76,81,86 However, despite Cranial nerves, including optic, oculomotor, trigeminal, and the progression, the disease rarely, if ever, leads to death or severe facial nerves, can be involved.50,60,71 Decreased or absent muscle disability. Most patients are able to maintain near-normal func- stretch reflexes in a multifocal, asymmetric distribution are tion. New conduction block and axonal loss has been shown to noted, although complete areflexia can also occur. In patients occur despite treatment as well. with the above symptoms, hereditary neuropathy with liability to pressure palsies should also be included in the differential di- A course of IVIg is expensive and the patient’s disability pro- agnosis. gresses despite continued treatment. Repeated infusions of IVIg leads to loss of venous access and the frequent need for central Electrophysiological Features venous access. By reducing the B-cell population, rituximab may provide an alternate therapy in MMN.26 Levin and Pestronk Like MMN, the electrophysiological features include focal de- have reported improvement in patients who have motor neu- myelinative features such as conduction block, temporal disper- ropathy and elevated GM1 antibodies, with four weekly intra- sion, prolonged distal latencies, prolonged F waves, and slow venous infusions of rituximab (375 mg/m2).47,67 conduction velocities in one or more motor nerves. However, in Immunoablative treatment with high-dose cyclophosphamide contrast to MMN, the sensory nerve action potential (SNAP) (50 mg/kg/day IV for 4 days followed by granulocyte colony amplitudes are absent or reduced in amplitude in the affected stimulating factor) does not damage hematopoietic “stem cells,” nerves.3,32,50,60,71,78,89 Electromyography can reveal fibrillation po- and permits repopulation of the immune system without bone tentials and positive sharp waves as well as polyphasic, long-du- marrow transplant. Recent evidence indicates that this treatment ration MUAPs that recruit early. can induce durable remissions in autoimmune diseases.25 Laboratory Features

MULTIFOCAL ACQUIRED DEMYELINATING SENSORY AND In contrast to MMN, CSF protein is elevated in 60-82% of MOTOR NEUROPATHY MADSAM neuropathy patients (mean level of around 70 mg/dl).72 Also in contrast to MMN, most patients do not have Lewis and colleagues described five cases of multifocal demyeli- IgM anti-GM1 antibodies.72 However, IgG antibodies ganglio- nating neuropathy with conduction block in 1982.50 These cases sides were reported in patients with multifocal acquired sensory looked like MMN with upper extremity asymmetrical weakness and motor neuropathy with or without demyelinating features.2 progressing over years and associated with multifocal demyelina- tion and conduction block, but with prominent sensory abnor- Pathology malities clinically and electrophysiologically. Recently, similar cases have been reported in the literature under different titles in- Sensory nerve biopsies demonstrate features expected to be seen cluding “focal upper limb predominant, multifocal CIDP, and in CIDP with thinly myelinated large diameter fibers, demyeli- multifocal inflammatory demyelinating neuropathy.”32,60,71,78,85 nated fibers, subperineurial and endoneurial edema, and mild The term Lewis-Sumner syndrome has been suggested as the onion bulb formations.72 Teased fiber preparations revealed de- preferred term in recognition of its description by Lewis and myelinated or remyelinated internodes in 3-88% of the fibers.71 Sumner,48,50 even though Adams and colleagues had described A smaller percentage of teased fibers show features of axonal de- two similar cases of asymmetric pseudohypertrophic inflamma- generation. Fascicle-to-fascicle variability may also be noted.31,71 tory neuropathy with onion bulb formation in 1965.1 Pathogenesis

CLINICAL FEATURES The pathogenic basis for MADSAM neuropathy is not known. The clinical, electrophysiological, and treatment response favor Approximately 50 patients with MADSAM neuropathy have an immune basis. If the asymmetry is taken away, the disorder is been reported in the literature.3,32,50,60,71,78,89 From the reported rather similar to CIDP and is therefore likely to have a similar cases, there appears to be a 2:1 male predominance with mean pathogenesis. In fact, MADSAM neuropathy meets the CIDP age of onset in the early 50s (range 14-77 years). Like MMN, criteria formulated by the ad hoc subcommittee of the American the onset is usually insidious with a slowly progressive course. Association of Neurology task force. Also like MMN, initial asymmetrical involvement of upper limbs is typical. Both sensory and motor symptoms are present. Treatment The presentation is of mononeuropathy multiplex, but with a chronic progressive course. Multifocal weakness and numbness The response rate to IVIg appears similar to MMN and CIDP. (or pain) conforming to a discrete peripheral nerve distribution Retrospective series have demonstrated that 72% of patients AAEM Course When It’s Not ALS! Pure Motor Syndromes 29 with MADSAM neuropathy improved with IVIg treatment.72 4. Arasaki K, Kusunoki S, Kudo N, Kanazawa I. Acute conduction However, in contrast to MMN (but similar to CIDP), 71% of block in vitro following exposure to antiganglioside sera. Muscle patients with MADSAM neuropathy have also demonstrated Nerve 1993;16:587-593. 72 5. Auer RN, Bell RB, Lee MA. Neuropathy with onion bulb formation improvement with corticosteroid treatment. and pure motor manifestations. Can J Neurol Sci 1989;16:194-197. 6. Azulay JP, Blin O, Pouget J, Boucraut J, Billé-Turc F, Carles G, Serratice G. Intravenous immunoglobulin treatment in patients with SUMMARY motor neuron syndromes associated with anti-GM1 antibodies: A double-blind, placebo-controlled study. Neurology 1994;44:429- 432. Multifocal motor neuropathy and MADSAM neuropathy are 7. Azulay JP, Rihet P, Pouget J, Cador F, Blin O, Boucraut J, Serratrice two multifocal demyelinating disorders of the peripheral nerves. G. Long term follow up of multifocal motor neuropathy with con- Both respond to immunomodulation. Multifocal motor neu- duction block under treatment. J Neurol Neurosurg Psychiatry ropathy may clinically resemble an LMN form of ALS while 1997;62:391-394. MADSAM neuropathy is more akin to CIDP (Table 1). Sensory 8. Bech E, Andersen H, Orntoft TF, Jakobsen J. Association of IgM symptoms and signs, both clinical and electrophysiological, and type anti-GM1 antibodies and muscle strength in chronic acquired demyelinating polyneuropathy. Ann Neurol 1998;43:72-78. the symmetrical nature of proximal and distal weakness should 9. Biessels GJ, Franssen H, van den Berg LH, Gibson A, Kappelle LJ, help in diagnosing CIDP. Pure motor asymmetric disorders may Venables GS, Wokke JH. Multifocal motor neuropathy. J Neurol raise the possibility of both MMN and the progressive muscular 1997;244:143-152. atrophy variant of ALS. Once peripheral motor nerve demyeli- 10. Bouche P, Le Forestier N, Maisonobe T, Fournier E, Willer JC. nating features have been clearly identified, the diagnosis of Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy. J Neurol 1999;246:520-525. MMN is not difficult. The demyelinating features in patients 11. Bouche P, Moulonguet A, Younes-Chennoufi AB, Adams D, with MMN are recognizable if the correct nerves, including Baumann N, Meininger V, Leger JM, Said G. Multifocal motor neu- proximal segments, are studied. The diagnosis of ALS is also rel- ropathy with conduction block: a study of 24 patients. J Neurol atively straightforward in patients without demyelinating fea- Neurosurg Psychiatry 1995;59:38-44. tures, but clear pyramidal signs at several levels (bulbar, cervical, 12. Carpo M, Cappellari A, Mora G, Pedotti R, Barbieri S, Scarlato G, thoracic, and lumbosacral).1 Difficulty may arise in those cases Nobile-Orazio E. Deterioration of multifocal motor neuropathy after plasma exchange. Neurology 1998;50:1480-1482. where the patient has a pure LMN syndrome, but no obvious 13. Chad DA, Hammer K, Sargent J. Slow resolution of multifocal weak- demyelinating physiology. In these cases, careful follow-up at 3- ness and fasciculations: a reversible motor neuron syndrome. 6 month intervals will show the disorder either evolving with Neurology 1986;36:1260-1263. diffuse widespread denervation, or developing pyramidal signs 14. Charles N, Vial C, Benoit P, Bierme T, Bady B. Intravenous im- confirming ALS. On the other hand, MMN does not change munoglobulin treatment in multifocal motor neuropathy. Lancet 1992;340:182. significantly over this time period. High titers of serum IgM 15. Chaudhry V, Corse A, Skolasky RL Jr. Surface electromyographic anti-GM1 antibodies should also lead the physician to reevalu- recording of volitional activity: a technique to detect partial motor ate the diagnosis of a progressive muscular atrophy variant of conduction block. Muscle Nerve 2003;27;590-594. ALS. 16. Chaudhry V, Corse AM, Cornblath DR, Kuncl RW, Drachman DB, Freimer ML, Miller RG, Griffin JW. Multifocal motor neuropathy: Several questions regarding the pathogenesis of these rare disor- response to human immune globulin. Ann Neurol 1993;33:237- 242. ders remain unanswered, including the possible pathogenic role 17. Chaudhry V, Corse AM, Cornblath DR, Kuncl RW, Freimer ML, of anti-GM1 antibodies, the reason for the multifocal selective Griffin JW. Multifocal motor neuropathy: Etectrodiagnostic features. affection being limited to upper limbs, the role of myelin versus Muscle Nerve 1994;17:198-205. axon, motor versus sensory fibers, and the persistence of PMCB 18. Criteria for diagnosis of amyotrophic lateral sclerosis. A workshop on over several years. clinical limits of ALS. Escorial, Spain, May 26-28, 1989. World Neurol 1990;5:12. 19. Comi G, Amadio S, Galardi G, Fazio R, Nemni R. Clinical and neu- rophysiological assessment of immunoglobulin therapy in five pa- REFERENCES tients with multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 1994;57:35-37. 1. Adams RD, Asbury AK, Michelsen JJ. Multifocal pseudohyper- 20. Cornblath DR, Sumner AJ, Daube J, Gilliatt RW, Brown WF, Parry trophic neuropathy. Trans Am Neurol Assoc 1965;90:30-32. GJ, Albers JW, Miller RG, Petajan J. Conduction block in clinical 2. Alaedini A, Sander HW, Hays AP, Latov N. Antiganglioside antibod- practice. Muscle Nerve 1991;14:869-871. ies in multifocal acquired sensory and motor neuropathy. Arch 21. Corse AM, Chaudhry V, Crawford TO, Cornblath DR, Kuncl RW, Neurol 2003;60:42-46. Griffin JW. Demyelinating pathology in sural nerves in multifocal 3. Amato AA, Jackson CE, Kim JY, Worley KL. Chronic relapsing motor neuropathy. Ann Neurol 1996;39:319-325. brachial plexus neuropathy with persistent conduction block. Muscle 22. Dalakas M. Mechanism of action of intravenous immunoglobulin Nerve 1997;20:1303-1307. and therapeutic considerations in the treatment of autoimmune neu- rologic diseases. Neurology 1998;51:S2-S8. 30 Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy AAEM Course

23. Dalakas MC. Intravenous immunoglobulin in autoimmune neuro- 43. Krarup C, Stewart JD, Sumner AJ, Pestronk A, Lipton SA. A syn- muscular diseases. JAMA 2004;291;2367-2375. drome of asymmetrical limb weakness and motor conduction block. 24. Donaghy M, Mills KR, Boniface SJ, Simmons J, Wright I, Gregson Neurology 1990;40:118-127. N, Jacobs J. Pure motor demyelinating neuropathy: deterioration 44. Lange DJ, Trojaborg W, Latov N, Hays AP, Younger DS, Uncini A, after steroid treatment and improvement with intravenous im- Blake DM, Hirano M, Burns SM, Lovelace RE, and colleagues. munoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778-783. Multifocal motor neuropathy with conduction block: is it a distinct 25. Drachman DB, Jones RJ, Brodsky RA. Treatment of refractory myas- clinical entity? Neurology 1992;42:497-505. thenia: “rebooting” with high-dose cyclophosphamide. Ann Neurol 45. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann 2003;53;29-34. N. Intravenous immunoglobulin therapy in multifocal motor neu- 26. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, ropathy: a double-blind, placebo-controlled study. Brain Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted 2001;124:145-153. therapy with rituximab in patients with rheumatoid arthritis. N Engl 46. Leger JM, Younes-Chennoufi AB, Chassande B, Davila G, Bouche P, J Med 2004;350;2572-2581. Baumann N, Brunet P. Human immunoglobulin treatment of mul- 27. Elliott JL, Pestronk A. Progression of multifocal motor neuropathy tifocal motor neuropathy and polyneuropathy associated with mon- during apparently successful treatment with human immunoglobu- oclonal gammopathy. J Neurol Neurosurg Psychiatry 1994;57:46-49. lin. Neurology 1994;44:967-968. 47. Levine TD, Pestronk A. IgM antibody-related polyneuropathies: B- 28. Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. cell depletion chemotherapy using Rituximab. Neurology Multifocal motor neuropathy improved by IVIg: randomized, 1999;52;1701-1704. double-blind, placebo-controlled study. Neurology 2000;55:1256- 48. Lewis RA. Multifocal motor neuropathy and Lewis Sumner syn- 1262. drome: two distinct entities. Muscle Nerve 1999;22:1738-1739. 29. Feldman EL, Bromberg MB, Albers JW, Pestronk A. 49. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between Immunosuppressive treatment in multifocal motor neuropathy. Ann chronic familial and acquired demyelinative neuropathies. Neurology Neurol 1991;30:397-401. 1982;32:592-596. 30. Ge XX, Spector GJ, Carr C. The pathophysiology of compression in- 50. Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demyeli- juries of the peripheral facial nerve. Laryngoscope 1982;92:S1-S15. nating neuropathy with persistent conduction block. Neurology 31. Gibbels E, Behse F, Kentenich M, Haupt WF. Chronic multifocal 1982;32:958-964. neuropathy with persistent conduction block (Lewis-Sumner syn- 51. Magistris M, Roth G. Motor neuropathy with multifocal persistent drome). A clinico-morphologic study of two further cases with review conduction blocks. Muscle Nerve 1992;15:1056-1057. of the literature. Clin Neuropathol 1993;12;343-352. 52. Mann DL, Read-Connole E, Arthur LO, Robey WG, Wernet P, 32. Gorson KC, Ropper AH, Weinberg DH. Upper limb predominant, Schneider EM, Blattner WA, Popovic M. HLA-DR is involved in the multifocal chronic inflammatory demyelinating polyneuropathy. HIV-binding site on cells expressing MHC Class II antigens. J Muscle Nerve 1999;22:758-765. Immunol 1988;141:1131-1136. 33. Harvey GK, Toyka KV, Zielasek J, Kiefer R, Simonis C, Hartung HP. 53. Martina IS, van Doorn PA, Schmitz PI, Meulstee J, van der Meche Failure of anti-GM1 IgG or IgM to induce conduction block follow- FG. Chronic motor neuropathies: response to interferon-beta1a after ing intraneural transfer. Muscle Nerve 1995;18:388-394. failure of conventional therapies. J Neurol Neurosurg Psychiatry 34. Hirota N, Kaji R, Bostock H, Shindo K, Kawasaki T, Mizutani K, 1999;66;197-201. Oka N, Kohara N, Saida T, Kimura J. The physiological effect of 54. Maurer M, Stoll G, Toyka KV. Multifocal motor neuropathy pre- anti-GM1 antibodies on saltatory conduction and transmembrane senting as chronic progressive proximal leg weakness. Neuromuscul currents in single motor axons. Brain 1997;120:2159-2169. Disord 2004;14;380-382. 35. Jaspert A, Claus D, Grehl H, Neundörfer B. Multifocal motor neu- 55. Meucci N, Cappellari A, Barbieri S, Scarlato G, Nobile-Orazio E. ropathy: clinical and electrophysiological findings. J Neurol Long term effect of intravenous immunoglobulins and oral cy- 1996;243:684-692. clophosphamide in multifocal motor neuropathy. J Neurol 36. Kaji R. Physiology of conduction block in multifocal motor neu- Neurosurg Psychiatry 1997;63:765-769. ropathy and other demyelinating neuropathies. Muscle Nerve 56. Nagale SV, Bosch EP. Multifocal motor neuropathy with conduction 2003;27;285-296. block: current issues in diagnosis and treatment. Semin Neurol 37. Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, Kimura J. 2003;23;325-334. Pathological findings at the site of conduction block in multifocal 57. Nemni R, Santuccio G, Calabrese E, Galardi G, Canal N. Efficacy of motor neuropathy. Ann Neurol 1993;33:152-158. cyclosporine treatment in multifocal motor neuropathy. J Neurol 38. Kaji R, Shibasaki H, Kimura J. Multifocal demyelinating motor neu- 2003; 250;1118-1120. ropathy: Cranial nerve involvement and immunoglobulin therapy. 58. Nobile-Orazio E. Multifocal motor neuropathy. J Neuroimmunol Neurology 1992;42:506-509. 2001;115:4-18. 39. Katz JS, Saperstein DS. Asymmetric acquired demyelinating 59. Nobile-Orazio E, Meucci N, Barbieri S, Carpo M, Scarlato G. High- polyneuropathies: MMN and MADSAM. Curr Treat Options dose intravenous immunoglobulin therapy in multifocal motor neu- Neurol 2001;3:119-125. ropathy. Neurology 1993;43:537-544. 40. Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn RJ. 60. Oh SJ, Claussen GC, Kim DS. Motor and sensory demyelinating Electrophysiologic findings in multifocal motor neuropathy. mononeuropathy multiplex (multifocal motor and sensory demyeli- Neurology 1997;48:700-707. nating neuropathy): a separate entity or a variant of chronic inflam- 41. Kiernan MC, Guglielmi JM, Kaji R, Murray NM, Bostock H. matory demyelinating polyneuropathy? J Peripher Nerv Syst Evidence for axonal membrane hyperpolarization in multifocal 1997;2;362-369. motor neuropathy with conduction block. Brain 2002;125;664-675. 61. Olney RK, Lewis RA, Putnam TD, Campellone JV Jr. Consensus cri- 42. Komiyama A, Toda H, Hasegawa O, Kuroiwa Y. Multifocal motor teria for the diagnosis of multifocal motor neuropathy. Muscle Nerve neuropathy. Neurology 1998;50:314-315. 2003;27;117-121. AAEM Course When It’s Not ALS! Pure Motor Syndromes 31

62. Pakiam AS, Parry GJ. Multifocal motor neuropathy without overt 78. Thomas PK, Claus D, Jaspert A, Workman JM, King RH, Larner AJ, conduction block. Muscle Nerve 1998; 21:243-245. Anderson M, Emerson JA, Ferguson IT. Focal upper limb demyeli- 63. Parry GJ. AAEM Case Report #30: multifocal motor neuropathy. nating neuropathy. Brain 1996;119:765-774. Muscle Nerve 1996;19:269-276. 79. Uncini A, Santoro M, Corbo M, Lugaresi A, Latov N. Conduction 64. Parry GJ, Clarke S. Multifocal acquired neuropathy masquerading as abnormalities induced by sera of patients with multifocal motor neu- motor neuron disease. Muscle Nerve 1988;11:103-107. ropathy and anti-GM1 antibodies. Muscle Nerve 1993;16:610-615. 65. Pestronk A, Chaudhry V, Feldman EL, Griffin JW, Cornblath DR, 80. Van den Berg LH, Franssen H, Wokke JH. Improvement of multi- Denys EH, Glasberg M, Kuncl RW, Olney RK, Yee WC. Lower focal motor neuropathy during long-term weekly treatment with motor neuron syndromes defined by patterns of weakness, nerve con- human immunoglobulin. Neurology 1995;45:987-988. duction abnormalities, and high titers of antiglycolipid antibodies. 81. Van den Berg LH, Franssen H, Wokke JH. The long-term effect of Ann Neurol 1990;27:316-326. intravenous immunoglobulin treatment in multifocal motor neu- 66. Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin ropathy. Brain 1998;121:421-428. JW, Alderson K, Adams RN. A treatable multifocal motor neuropa- 82. Van den Berg LH, Kerkhoff H, Oey PL, Franssen H, Mollee I, thy with antibodies to GM1 ganglioside. Ann Neurol 1988;24:73- Vermeulen M, Jennekens FG, Wokke JH. Treatment of multifocal 78. motor neuropathy with high dose intravenous immunoglobulins: a 67. Pestronk A, Florence J, Miller T, Choksi R, Al Lozi MT, Levine TD. double blind, placebo controlled study. J Neurol Neurosurg Treatment of IgM antibody associated polyneuropathies using ritux- Psychiatry 1995;59:248-252. imab. J Neurol Neurosurg Psychiatry 2003;74;485-489. 83. Van den Berg LH, Lokhorst H, Wokke JH. Pulsed high-dose dex- 68. Roberts M, Willison HJ, Vincent A, Newsom-Davis J. Multifocal amethasone is not effective in patients with multifocal motor neu- motor neuropathy human sera block distal motor nerve conduction ropathy. Neurology 1997;48:1135. in mice. Ann Neurol 1995;38:111-118. 84. Van den Bergh P, Logigian EL, Kelly JJ Jr. Motor neuropathy with 69. Roth G, Rohr J, Magistris MR, Ochsner F. Motor neuropathy with multifocal conduction blocks. Muscle Nerve 1989;12:26-31. proximal multifocal persistent conduction block, fasciculations, and 85. Van den Berg-Vos RM, Franssen H, Visser J, de Visser M, de Haan myokymia: evolution to tetraplegia. Eur Neurol 1986;25:416-423. RJ, Wokke JH, Van den Berg LH. Disease severity in multifocal 70. Santoro M, Uncini A, Corbo M, Staugaitis SM, Thomas FP, Hays motor neuropathy and its association with the response to im- AP, Latov N. Experimental conduction block induced by serum from munoglobulin treatment. J Neurol 2002;249:330-336. a patient with anti-GM1 antibodies. Ann Neurol 1992;31:385-390. 86. Van Den Berg-Vos RM, Franssen H, Wokke JH, van den Berg LH. 71. Saperstein DS, Amato AA, Wolfe GI, Katz JS, Nations SP, Jackson Multifocal motor neuropathy: long-term clinical and electrophysio- CE, Bryan WW, Burns DK, Barohn RJ. Multifocal acquired de- logical assessment of intravenous immunoglobulin maintenance myelinating sensory and motor neuropathy: the Lewis-Sumner syn- treatment. Brain 2002;125:1875-1886. drome. Muscle Nerve 1999;22:560-566. 87. Van den Berg-Vos RM, Franssen H, Wokke JH, van Es HW, van den 72. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of Berg LH. Multifocal motor neuropathy: diagnostic criteria that chronic acquired demyelinating polyneuropathies. Muscle Nerve predict the response to immunoglobulin treatment. Ann Neurol 2001;24;311-324. 2000;48:919-926. 73. Takigawa T, Yasuda H, Kikkawa R, Shigeta Y, Saida T, Kitasato H. 88. Van den Berg-Vos RM, van den Berg LH, Franssen H, Van Doorn Antibodies against GM1 ganglioside affect K+ and Na+ currents in PA, Merkies IS, Wokke JH. Treatment of multifocal motor neuropa- isolated rat myelinated nerve fibers. Ann Neurol 1995;37:436-442. thy with interferon-beta1A. Neurology 2000;54:1518-1521. 74. Tan E, Lynn DJ, Amato AA, Kissel JT, Rammohan KW, Sahenk Z, 89. Van den Berg-Vos RM, van den Berg LH, Franssen H, Vermeulen M, Warmolts JR, Jackson CE, Barohn RJ, Mendell JR. Witkamp TD, Jansen GH, van Es HW, Kerkhoff H, Wokke JH. Immunosuppressive treatment of motor neuron syndromes. Multifocal inflammatory demyelinating neuropathy: a distinct clini- Attempts to distinguish a treatable disorder. Arch Neurol cal entity? Neurology 2000;54:26-32. 1994;51:194-200. 90. Van Den Berg-Vos RM, van den Berg LH, Visser J, de Visser M, 75. Taylor BV, Dyck PJ, Engelstad J, Gruener G, Grant I, Dyck PJ. Franssen H, Wokke JH. The spectrum of lower motor neuron syn- Multifocal motor neuropathy: pathologic alterations at the site of dromes. J Neurol 2003; 250:1279-1292. conduction block. J Neuropathol Exp Neurol 2004;63;129-137. 91. Van Es HW, Van den Berg LH, Franssen H, Witkamp TD, Ramos 76. Taylor BV, Wright RA, Harper CM, Dyck PJ. Natural history of 46 LM, Notermans NC, Feldberg MA, Wokke JH. Magnetic resonance patients with multifocal motor neuropathy with conduction block. imaging of the brachial plexus in patients with multifocal motor neu- Muscle Nerve 2000;23:900-908. ropathy. Neurology 1997;48:1218-1224. 77. Teunissen LL, Notermans NC, Franssen H, van der Graaf Y, Oey PL, 92. Yuki N. Possible mechanism of intravenous immunoglobulin treat- Linssen WH, van Engelen BG, Ippel PF, van Dijk GW, Gabreels- ment on anti-GM1 antibody-mediated neuropathies. J Neurol Sci Festen AA, Wokke JH. Differences between hereditary motor and 1996;139:160-162. sensory neuropathy type 2 and chronic idiopathic axonal neuropathy. A clinical and electrophysiological study. Brain 1997;120:955-962. 32 AAEM Course AAEM Course 33 When It’s Not ALS! Pure Motor Syndromes

CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

1. All of the following diseases should be considered in a patient 6. Reasons for missing conduction block in patients with a with a progressive upper motor neuron syndrome EXCEPT: multifocal motor presentation might include: A. Primary lateral sclerosis (PLS). A. Lesions are too proximal. B. Amyotrophic lateral sclerosis (ALS). B. Lesions may be “burnt out.” C. Progressive muscular atrophy. C. Lesions may actually affect only axons. D. Hereditary spastic paraplegia (HSP). D. Conduction block is dynamic. E. Multiple sclerosis. E. All of the above.

2. The first author to report cases that are probably PLS was: 7. An exhaustive domain is one: A. Erb. A. Where you have to think so hard it makes you tired. B. Charcot. B. Where the likelihood of all diseases considered adds up C. Wilson. to 100%. D. Barohn. C. Where you need to be on the lookout for patterns that E. Fisher. do not fit any of the disorders on the list of possibilities. D. That characterizes the field of diagnosis in motor disor- 3. The duration of symptoms at the time of diagnosis for most ders. PLS patients is approximately: E. None of the above. A. 3 weeks. B. 3 months. 8. The reason 2 years is used as the minimal time needed to di- C. 1 year. agnose brachial amyotrophic diplegia (BAD) is: D. 5 years. A. It seemed like a good idea. E. 30 years. B. Amyotrophic lateral sclerosis always becomes clear before 2 years. 4. HSP patients can be distinguished from PLS patients on the C. All patients who showed spread beyond the arms before basis of all of the following EXCEPT: 2 years had a poor prognosis. A. Younger age of onset in HSP. D. All cases that remained static for at least 2 years re- B. Absence of bulbar symptoms in HSP. mained focal permanently. C. Abnormal needle electromyography in HSP. E. All of the above. D. Abnormal molecular genetic studies in HSP. E. Family history of a similar disorder in HSP 9. Which of the following is more common to multifocal ac- quired motor axonopathy than multifocal motor neuropa- 5. The most common clinical presentations of PLS are: thy? A. Tongue and limb atrophy. A. The hands are often affected. B. Spastic bulbar palsy and leg weakness with spasticity. B. There is an absence of proximal involvement. C. Arm and leg fasciculations. C. Onset is before age 30. D. Diplopia and dysphagia. D. GM-1 antibodies are present. E. Paraplegia with a thoracic sensory level. E. There is conduction block. 34 CME Self-Assessment Test AAEM Course

10. Cases of BAD that seemed to remain focal over time: 15. Each of the following is associated with prolonged survival A. Tended to begin in the hands. EXCEPT: B. Tended to affect the shoulders and biceps maximally. A. Upper motor neuron signs. C. Always remained limited to one or two myotomal dis- B. Symmetrical, proximal weakness. tributions over time. C. Weakness restricted to the proximal upper arms. D. Were usually women. D. Purely lower motor neuron findings. E. Responded to immune therapy. E. None of the above.

11. Which of the following statements about progressive mus- 16. All of the following diseases should be considered in a patient cular atrophy (PMA) is FALSE? with a progressive asymmetric weakness EXCEPT: A. Patients with PMA may have undetected upper motor A. Lewis-Sumner syndrome. neuron findings. B. ALS. B. Overall, the patients with PMA have longer survival C. Multifocal motor neuropathy (MMN). compared to those with ALS. D. Mononeurits multiplex. C. There are reliable clinical means for reliably distinguish- E. Chronic inflammatory demyelinating polyneuropathy ing PMA from ALS. (CIDP). D. Many patients who appear to have PMA may meet di- agnostic criteria for ALS later in their course. 17. Conduction block can be seen in all of the following E. All of the above. EXCEPT: A. ALS. 12. Which of the following statements about monomelic amy- B. MMN. otrophy is true? C. Lewis-Sumner syndrome. A. This entity affects predominantly young males. D. CIDP. B. The proximal upper limbs are preferentially affected. E. Guillain-Barré syndrome (GBS). C. This entity is treatable with immunosuppressive med- ications. 18. Most patients with MMN respond dramatically to: D. Cervical spine magnetic resonance imaging (MRI) does A. Steroids. not show any specific diagnostic findings. B. Intravenous immunoglobulin (IVIg). E. None of the above. C. Azathioprine. D. Plasma exchange. 13. Which test would be the most useful for the evaluation of a E. All of the above. 40-year-old man with symmetrical proximal arm and leg weakness, dysarthria, dysphagia, decreased deep tendon re- 19. MMN is different from Lewis-Sumner syndrome in the fol- flexes, and normal sensation? lowing: A. Genetic testing for a survival motor neuron deletion on A. Conduction block. chromosome 5. B. Asymmetrical distal involvement. B. Genetic testing for expanded trinucleotide-repeat ex- C. Predominant upper limb involvement. pansion repeats in the androgen receptor gene on chro- D. Absence of sensory findings. mosome X. E. Response to IVIg. C. Diffusion tensor MRI imaging. D. Cervical spine MRI taken with the neck flexed. 20. MMN is characterized by all of the following EXCEPT: E. None of the above. A. IVIg response. B. Progressive asymmetric involvement. 14. A 68-year-old Caucasian man has severe, right greater than C. Myokymia. left, proximal arm weakness. There are prominent fascicula- D. Invariably fatal course. tions and decreased reflexes in the arms. Strength is normal E. Conduction block. in bulbar and leg muscles. Sensation is normal. His symp- toms began 2 years ago. Which of the following statements is most accurate? A. The patient will likely die within 1-2 years. B. The patient will likely have a prolonged survival. C. The patient has Hirayama’s disease. D. The patient is likely to have gynecomastia. E. The patient is likely to have Stukenlaken’s disease. AAEM Course 35 When It’s Not ALS! Pure Motor Syndromes

EVALUATION

Select ANY of the answers that indicate your opinions. Your input is needed to critique our courses and to ensure that we use the best faculty instructors and provide the best course options in future years. Please use the computer form to answer the following questions. For the purpose of tabulating evaluations, please enter the last 4 digits of your telephone number in the ID NUMBER box beginning with the left column and fill in the appropriate ovals below each number. Make additional comments or list suggested topics or faculty for future courses on the comment form provided at the end. 21. How would you rate the quality of instruction received 25. How would you rate the quality of instruction received during Dr. Barohn’s presentation? during Dr. Saperstein’s presentation? A. Best possible. A. Best possible. B. Good. B. Good. C. Average. C. Average. D. Fair. D. Fair. E. Worst possible. E. Worst possible.

22. Select any item(s), that, if changed, would have appreciably 26. Select any item(s), that, if changed, would have appreciably improved Dr. Barohn’s presentation: improved Dr. Saperstein’s presentation: A. Quality of slides. A. Quality of slides. B. Quality of handout. B. Quality of handout. C. Amount of clinically relevant information in the presen- C. Amount of clinically relevant information in the presen- tation. tation. D. Amount of scientific content in the presentation. D. Amount of scientific content in the presentation. E. Other: please explain on the comment form at the back E. Other: please explain on the comment form at the back of this handout. of this handout.

23. How would you rate the quality of instruction received 27. How would you rate the quality of instruction received during Dr. Katz’s presentation? during Dr. Chaudhry’s presentation? A. Best possible. A. Best possible. B. Good. B. Good. C. Average. C. Average. D. Fair. D. Fair. E. Worst possible. E. Worst possible.

24. Select any item(s), that, if changed, would have appreciably 28. Select any item(s), that, if changed, would have appreciably improved Dr. Katz’s presentation: improved Dr. Chaudhry’s presentation: A. Quality of slides. A. Quality of slides. B. Quality of handout. B. Quality of handout. C. Amount of clinically relevant information in the presen- C. Amount of clinically relevant information in the presen- tation. tation. D. Amount of scientific content in the presentation. D. Amount of scientific content in the presentation. E. Other: please explain on the comment form at the back E. Other: please explain on the comment form at the back of this handout. of this handout. 36 Evaluation AAEM Course

29. As a result of your attendance at this course, did you learn 31. Should this topic be presented in the future by a different anything that will improve the care of your patients? method of presentation. A. Yes, substantially. A. No, the topic of presentation should remain as a course. B. Yes, somewhat. B. Yes, the topic should be presented as a dinner seminar. C. Not sure. C. Yes, the topic should be incorporated into the plenary D. Probably not. session. E. This course was not applicable to my patients. D. Yes, the topic should be discussed during a breakfast session. 30. Select ALL items where improvement was needed. E. Yes, the topic should be organized as a special interest A. The accuracy of advance descriptions of this course. group. B. The specific topics selected for presentation. C. The number of speakers in this course. D. The amount of time allotted for discussion in this course. E. Other: please add other areas and outline specific rec- ommendations for areas needing improvement on the comment form at the back of this handout. AAEM Course 37 FUTURE MEETING RECOMMENDATIONS

Select ANY of the answers that indicate your opinions. The following questions are included with all dinner seminar, course, and plenary session evaluations. It is only necessary to answer these questions once during the course of the entire meeting.

32. Please indicate below your specialty: 38. How would you rate this meeting? A. Neurologist. A. Poor. B. Physiatrist. B. Fair. C. PhD. C. Good. D. Other. D. Very good. E. Excellent. 33. How often do you attend AAEM meetings? A. Annually. 39. Did this meeting meet your expectations? B. Every 2-3 years. A. Not at all. C. Every 4 or more years. B. Somewhat. D. This is the first AAEM meeting I have attended. C. As expected. D. Exceeded expectations. 34. With regard to this years meeting, which of the smaller E. Best ever. group sessions did you attend? (mark all that apply) A. Experts’ roundtables. 40. Was the printed program clear and easy to follow? B. Workshops. A. Yes. C. Dinner seminars. B. No. D. None of the above. 41. With regard to the meeting hotels: 35. If you answered none of the above to the previous question, A. I stayed at one of the meeting hotels. please answer the following. The reason I did not attend the B. I did not stay at one of the meeting hotels. small group sessions was due to: A. The timing of the event. 42. If you answered B to the question above, please explain why B. The cost of the event. you did not stay at one of the meeting hotels (please make C. My lack of interest in the topics offered. your comments under Comments, page 39). D. The session was full. 43. How did you first learn about the meeting? (choose the 36. Did this meeting provide information that will enhance care method where you first learned about the meeting) of your patients? A. Preliminary brochure mailing. A. Extremely. B. Registration brochure mailing. B. Somewhat. C. The internet. C. Very little. D. Email message. D. Not at all. E. From a friend.

37. With regard to the social event: 44. Did you perceive any commercial bias in any of the educa- A. I am signed up to attend the social event. tional sessions offered by the AAEM at this meeting? B. I did not sign up because of the cost of the event. A. Yes. C. I did not sign up because of the day the event was B. No. offered. D. I did not sign up because I am not interested in attend- 45. Did you attend any of the industry forums provided this ing this type of function. year? A. Yes. B. No. 38 Future Meeting Recommendations AAEM Course

46. If you answered yes to question 45 and you attended the 48. How do you prefer to learn new information? Pfizer Industry Forum, how would you rate the quality of the A. Lecture only. session? B. Lecture in conjunction with questions and answers. A. Best possible. C. Small group hands-on. B. Good. D. Small group discussion. C. Average. D. Fair. 49. I plan to attend the 2005 AAEM meeting in Monterey, E. Worst possible. California, September 21-24. On Page 39 under comments, please provide any other A. Yes, definitely. comments you have about your attendance at the Pfizer B. No, definitely. Industry Forum. C. Will wait to see the program content. D. Will wait to see if budget allows my attendance. 47. If you answered yes to question 45 and you attended the Allergan Industry Forum, how would you rate the quality of 50. I would be more likely to attend the 2005 AAEM meeting if the session? (please make your comments under Comments, page 39): A. Best possible. B. Good. C. Average. D. Fair. E. Worst possible. On Page 39 under comments, please provide any other comments you have about your attendance at the Allergan Industry Forum. COMMENTS

Given time and budget constraints, is there something we could do in terms of altering the format of the meeting that would signifi- cantly increase the likelihood of your attendance at future AAEM meetings? Explain:

Write out any additional comments about specific courses or the plenary session (please indicate which), and list suggestions for topics and speakers for future meetings. Leave at the AAEM Registration and Information Center or mail to the AAEM Executive Office at 421 First Avenue SW, Suite 300 East, Rochester, MN 55902. AAEM 421 First Avenue SW, Suite 300 East Rochester, MN 55902 (507) 288-0100 / Fax: (507) 288-1225 [email protected] www.aaem.net