When It’s Not ALS!Pure MotorSyndromes

2004 AAEM COURSE EAAEM 51st Annual Scientific Meeting

Savannah, Georgia

Richard J. Barohn, MDJonathan S. Katz, MD

David S. Saperstein, MDVinay Chaudhry, MD

American Association ofElectrodiagnostic Medicine

2004 COURSE EAAEM 51st Annual Scientific Meeting

Savannah, Georgia

Copyright © November 2004American Association of Electrodiagnostic Medicine

421 First Avenue SW, Suite 300 EastRochester, MN 55902

PRINTED BY JOHNSON PRINTING COMPANY, INC.

Richard J. Barohn, MDJonathan S. Katz, MD

David S. Saperstein, MDVinay Chaudhry, MD

When It’s Not ALS! Pure Motor Syndromes

When It’s Not ALS! Pure Motor Syndromes

Faculty

ii

Richard J. Barohn, MD

Chairman and Professor

Department of Neurology

University of Missouri – Kansas City School of Medicine

Kansas City, Kansas

Dr. Barohn is a graduate of the 6-year BA/MD program at the Universityof Missouri – Kansas City School of Medicine. He completed a medicineinternship at Wilford Hall United States Air Force Medical Center atLackland Air Force (USAF) Base in San Antonio, Texas prior to serving asGeneral Medical Officer for the USAF. He completed a neurology resi-dency there, then performed a neuromuscular fellowship at Ohio StateUniversity, and is now Chair of the Department of Neurology at theUniversity of Kansas Medical Center. Dr. Barohn is board-certified by theAmerican Board of Electrodiagnostic Medicine and the American Board ofPsychiatry and Neurology with added qualifications in clinical neurophys-iology. He is a member of many professional societies, including theAmerican Academy of Neurology, the American Neurological Association,and the AAEM. His present research focuses on myopathies, motorneuron disease, peripheral neuropathies, and myasthenia gravis. In 2000,he was awarded the Alumni Achievement Award for Medicine from theUniversity of Missouri – Kansas City.

Jonathan S. Katz, MD

Assistant Professor

Department of Neurology

Stanford University School of Medicine

Palo Alto, California

Dr. Katz is currently an assistant professor in the department of neurologyand Co-director of the Neuromuscular Disease Clinic at StanfordUniversity and the director of the EMG laboratory at the Palo Alto VAMedical Center. He is certified by the American Board of Psychiatry andNeurology, and also holds added qualifications in clinical neurophysiology.Dr. Katz is active in several organizations, including the AmericanAcademy of Neurology, the California State Myasthenia Gravis AssociationMedical Advisory Board, and the Stanford University Medical SchoolFaculty Senate. He is an ad hoc reviewer for several journals, includingNeurology, Muscle & Nerve, and Lancet. He is also a recipient of theLisia Forno Award for Outstanding Teachers.

David S. Saperstein, MD

Assistant Professor

Department of Neurology

University of Kansas Medical Center

Kansas City, Kansas

Dr. Saperstein earned his medical degree from Boston University School ofMedicine, and performed both his internal medicine and neurology resi-dencies at Wilford Hall Medical Center. He is currently an assistant pro-fessor in the Department of Neurology, and in the Department ofPathology and Laboratory Medicine at the University of Kansas MedicalCenter. His academic interests include the clinical aspects of managementof neuromuscular disorders with a special interest in the classification andidentification of chronic acquired demyelinating polyneuropathies. In ad-dition to membership in the AAEM, Dr. Saperstein is also a member ofthe Peripheral Nerve Society, the American Academy of Neurology, andthe World Muscle Society.

Vinay Chaudhry, MD

Professor

Department of Neurology

Johns Hopkins School of Medicine

Baltimore, Maryland

Dr. Chaudhry is currently a professor of neurology and Director of theNeuromuscular Division at the Johns Hopkins University School ofMedicine in Baltimore. In addition, he is Co-Director of the NeurologyEMG Laboratory and Program Director of the clinical neurophysiologyresidency there. Dr. Chaudhry received his bachelor of medicine and bach-elor of surgery degrees from the All India Institute of Medical Sciences inNew Delhi, and went on to study internal medicine in the UK. At theUniversity of Alabama at Birmingham’s School of Medicine, Dr.Chaudhry studied neurology and became Neurology Chief Resident. Dr.Chaudhry is certified by many organizations, including the AmericanBoard of Psychiatry and Neurology (Neurology and Neurology with addedqualifications), the Royal College of Physicians, and the ABEM. He is a re-viewer for several journals and is on the Editorial Board of Neurologistand Muscle & Nerve.

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.

Authors had nothing to disclose.

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 thejudgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particulardevice or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of thedevice 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 1Richard J. Barohn, MD

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

Pure Motor Neuron Syndromes 15David S. Saperstein, MD

Multifocal Motor Neuropathy and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy 21Vinay Chaudhry, MD

CME Self-Assessment Test 33

Evaluation 35

Future Meeting Recommendations 37

O B J E C T I V E S —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 variantmultifocal 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 toMMN and ALS, and treatment implications; (5) describe pure lower motor neuron syndromes such as progressive muscular dystrophy (andits relationship to ALS), juvenile monomelic amyotrophy in teenagers and young adults, and adult “distal” spinal muscular atrophy (orhereditary motor neuropathy); and (6) describe the pure or predominant upper motor neuron disease primary lateral sclerosis and its rela-tion to ALS.

P R E R E Q U I S I T E —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX consultantsat 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.

AC C R E D I TAT I O N S TAT E M E N T —The AAEM is accredited by the Accreditation Council for Continuing Medical Education toprovide continuing medical education (CME) for physicians.

CME C R E D I T —The AAEM designates attendance at this course for a maximum of 3.5 hours in category 1 credit towards the AMAPhysician’s Recognition Award. This educational event is approved as an Accredited Group Learning Activity under Section 1 of theFramework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal Collegeof Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he/she actually spent in the activity. TheAmerican Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMAPMR category 1 credit.

vi

Thomas Hyatt Brannagan, III, MDNew York, New York

Kimberly S. Kenton, MDMaywood, Illinois

Dale J. Lange, MDNew York, New York

Andrew Mazur, MDPortsmouth, Rhode Island

Christopher J. Standaert, MDSeattle, Washington

T. Darrell Thomas, MDKnoxville, Tennessee

Bryan Tsao, MDShaker Heights, Ohio

2003-2004 AAEM PRESIDENT

Lois Margaret Nora, MD, JDRootstown, Ohio

2003-2004 AAEM COURSE COMMITTEE

Kathleen D. Kennelly, MD, PhDJacksonville, Florida

Primary Lateral Sclerosisand the Differential of the “Pure” Upper

Motor Syndrome

Richard J. Barohn, MD

Professor and ChairmanDepartment of Neurology

University of Kansas Medical CenterKansas City, Kansas

INTRODUCTION

Motor neuron disorders can be considered a clinical spectrumfrom pure lower motor neuron (LMN) disorders (progressivemuscular atrophy [PMA] and spinal muscular atrophy) to pureupper motor neuron (UMN) disorders (primary lateral sclerosis[PLS]). Amyotrophic lateral sclerosis (ALS) falls in the middleand has features of both upper and lower motor neuron dys-function (Figure 1).

Primary lateral sclerosis is considered a progressive disorder ofeither corticospinal or corticobulbar UMN dysfunction forwhich no etiology is found. There continues to be an ongoingdebate regarding the existence of PLS as a separate diseaseprocess distinct from ALS or whether it is simply a predomi-nantly UMN manifestation of ALS. Several factors cause diffi-culties in definitively answering this question. The underlyingetiology of ALS and PLS is unknown, and there is no specific di-agnostic marker for either. In addition, there are only a handful

UPPER MOTOR NEURONLOWER MOTOR NEURON

Sporadic

Progressive MuscularAtrophy

AmyotrophicLateral

Sclerosis

Primary Lateral Sclerosis

Hereditary

Spinal Muscular Atrophy Hereditary SpasticParaplegia

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 determineif the pathology is indeed restricted to the UMN system.Therefore in practical terms, while the patient is alive, the dis-tinction between these motor neuron disorders is based on phe-notype recognition, natural history, and the indirect testscurrently employed to implicate involvement of upper and lowermotor neurons. As some patients with ALS ultimately are foundto have another diagnosis, perhaps PLS should be considered asyndrome composed of heterogenous diseases, some of whichmay become apparent over time. On the other hand, the use ofPLS as a diagnostic disease category is useful in approaching apatient with a progressive UMN disorder, particularly in regardsto determining prognosis.

HISTORY

The earliest reported cases of possible PLS have been attributedby Erb in 1875.17 In 1902, he reviewed 10 autopsied cases andused the terms “spinal” or “spasmodic” paralysis.16 However, 4 ofthe 10 cases were familial and therefore the cases probably fellinto the hereditary spastic paraplegia category. Charcot, who de-scribed the first cases of ALS,12 wrote a long discussion regardingErb’s early cases and described several of his own and preferredthe term “spasmodic tabes dorsalis.” He was not prepared toconsider PLS a distinct disease entity at that time, pendinganalysis of further cases. A long excerpt from one of Charcot’stranslated lectures13 is still instructive:

Nevertheless, gentlemen, it is not uncommon clinicallyto meet with a certain number of cases in which symp-toms of spasmodic paralysis ... occur unaccompanied ...by any other symptoms. ... The affection is especiallycharacterized also by its slow evolution, and by amarked tendency to progressive invasions of the upperextremities. To some physicians, of whom I am one,this spasmodic paraplegia seems to be a special variety,so that we are led to think that these are not commoncases of transverse myelitis accidentally deprived of theirusual features. … But it is believed that the affection inquestion is peculiar, autonomous, and probably depen-dent on a specially localized lesion. Erb was the first toput forward this opinion in 1875. I soon followed him,as my lectures in 1876 testify. This alleged special affec-tion was designated by Erb spasmodic spinal paralysis.… I proposed the name of spasmodic tabes dorsalis,since the term ‘spasmodic paralysis’ represents only asymptom common to several spinal diseases. The de-scription given by Erb differs, however, in no essentialfeature from that which I subsequently traced ... I ob-served that all cases of symmetrical sclerosis withoutparticipation of the anterior grey cornua were of olddate. ‘It would be necessary,’ I remarked, ‘to revivepartly effaced remembrances. We must therefore,

before we express an opinion on this matter, await themodifying influence of new observations.’ Up to thepresent time, gentlemen, as I shall show shortly patho-logical investigation has not yet furnished any proof,and hence the solution of the problem remains in sus-pense. Meanwhile the clinical description deserves toexist alone.

Throughout the first half of the 20th century, a number ofothers attempted to address the PLS issue.9,47,48,49,51,57 Wilson, inhis authoritative textbook of neurology, was unconvinced thatPLS was a distinct entity.58 He stated:

Divergent views are still held in regard to so-calledprimary lateral sclerosis, the ‘spastic spinal paralysis’ ofErb. Some consider it belongs to a separate class fromCharcot’s disease, taking presence or absence of muscu-lar atrophy for the criterion; but since ‘pure’ atonicatrophy often co-exists with slight pyramidal lesionsonly disclosed after death, spasticity without wastingmight well represent the opposite extreme of the samecondition. Types of Charcot’s disease pass by easy gra-dations from almost monosymptomatic muscularatrophy to spastic weakness with little sign of the other,notably at an earlier period; to go a step farther in eitherdirection would seem not only allowable but requisite.If this is permitted, ‘primary lateral sclerosis’ becomes avariant of the disease without involvement of lowerneurons, and ‘nuclear amyotrophy’ another, with intactcorticospinal paths … for these several reasons the con-ception of ‘pure’ spastic paralysis caused by progressivedecay in corticospinal neurons, of endogenous sourcealone, and rigidly confined to that system has little tosubstantiate it. At least some examples are eventuallyproved to belong to the group of Charcot’s disease, andthis may well be true of all.

Rowland44 and Swash52 consider the modern era of PLS litera-ture to begin with the paper by Fisher in 1977.19 Fisher describedan autopsied case of presumed PLS and found degeneration ofthe corticospinal tracts. Since that paper, there has been a height-ened interest in the controversial topic of PLS. However, to alarge extent, medicine is no closer to solving the dilemmaCharcot and Wilson described in the late 19th and early 20thcenturies.

EPIDEMIOLOGY AND DEMOGRAPHICS

How Often is Primary Lateral Sclerosis Diagnosed?

Primary lateral sclerosis is an uncommon diagnosis. The bestway to get an idea of how often PLS is diagnosed is to look atthe larger retrospective series. In the Canadian series by Pringle

and colleagues,42 of 500 motor neuron disease patients, 8 pa-tients were diagnosed with PLS over a 10-year time span (ap-proximately 1.6%). Le Forestier and colleagues34 reported 20PLS patients out of 450 motor neuron disease patients over 5years (4.4%), and in this author’s Texas series, 13 PLS and 572ALS patients were diagnosed over 5 years (2%).31 Therefore,from this small number of series, it appears that between 2% and4% of patients seen in adult motor neuron disease clinics will bediagnosed with PLS.

Age of Onset

The typical age of onset of PLS is in the late 40s to early 50s,similar to ALS. In this author’s series, mean age of onset was 46.3years (range 36-73 years).31 In the Pringle series, mean age ofonset was 50.4 years (range 35-66 years).42 In the SalpetriereParisian series, mean age of onset was 53.4 years (range 26-64years). In a large National Institute of Health (NIH) series of 25patients, mean age of onset was 45.4 years.63

Gender

Some series show a male predominance8,31,33,34,62 while in others,both genders are equally affected.22,42,45,63 In the French series, 15out of 20 cases were male.34 The Dutch series described 9 malesand 1 female.33 This author’s Texas series of 13 patients had 9men and 4 women.31 The Canadian and NIH series both had50% male to female ratio, while the Marseilles series by Gastauthad 2 males and 3 females.22,42,63

CLINICAL FEATURES

The two most common presentations in patients diagnosed withPLS are spastic bulbar palsy, and leg weakness with spasticity.The syndrome of slowly progressive leg weakness and spasticityis more common and accounted for in 56% of the presentationsin the NIH series.63 In the Salpetriere series, 50% (10 out of 20)had bulbar onset. However in the Canadian series of Pringle,42

only 1 out of 8 had bulbar onset, and in the Dutch series 9 outof 10 had limb onset.33 This author’s Texas series was similar inthat 12 had leg onset, 1 had bulbar onset, and of the limb onsetpatients, only 1 progressed to bulbar symptoms.31 The syndromecan progress from bulbar to limb involvement or from limb tobulbar. In the limbs, leg onset is by far more common thanarm/hand onset, which, while rare, does occur.33,42,63 Patients canhave long periods of plateau in one region with nonprogressionto other regions. Rarely patients can present with a progressivehemiparesis (arm and leg) before progressing to the opposite sideor to the bulbar region.23,63

In the leg onset syndrome, symptoms usually begin in one legand then spread to the opposite leg so that patients have a para-plegia for a period of time before further progression.31,34,63 In

some patients, simultaneous bilateral leg onset or simultaneouslimb and bulbar onset is reported. Spasticity accounts for themost of the limb dysfunction in the early stages, as opposed toweakness; in ALS weakness is usually more prominent than spas-ticity.31,34,35 Therefore, patients may not complain of weakness,but notice stiffness, clumsiness, or poor coordination and dex-terity as the initial limb symptoms. When limb weakness occursit is usually in a UMN dysfunction pattern, as described later.Some authors have described cases with slow progression frombulbar involvement to leg or from leg to bulbar without men-tioning significant arm involvement.42 However, even in thesecases, brisk reflexes and other UMN signs are noted in the armsimplicating arm involvement.

Bulbar symptoms consist of dysarthria initially, then dysphagia,and are often associated with emotional lability, and eventuallyinappropriate laughing or crying, which is labeled “pseudo-bulbar” affect. Because the dysarthria is predominantly UMNand not associated with tongue atrophy or fasciculations, somerefer to all of the bulbar symptoms as pseudo-bulbar. Thedysarthria can progress to anarthria. Dysphagia can progress in away that the patient requires a feeding tube even before there issignificant limb involvement. In the Salpetriere series, theauthors found the dysphagia often remained moderate.34 It is in-teresting that some patients who become anarthric can stillswallow. However, this is unusual and in this author’s experiencemost bulbar patients eventually require mechanical feeding.

The recent NIH series provides the most detailed informationabout the timing of progression.63 In this series, 14 out of 25 pa-tients presented with spasticity of the legs and they were labeledthe “ascending group.”63 Symptoms spread to the second leg onaverage within 1.7 years after the first leg (range 1-4 years) andto the hands in 3.6 years later (range 1-6 years) and to the bulbarregion 1.5 years (range 0.5-5 years) after arm symptoms.

While most cases of limb onset eventually progress to bulbar andmost cases of bulbar onset eventually progress to limb, there areprobably cases that remain restricted to these regions for as longas the patient is followed.22,31 How often this occurs is unknown.

While cramps, fasciculations, and atrophy are usually believed tobe signs of LMN dysfunction and therefore incompatible withpure PLS, some authors report these symptoms and signs intheir patients. Le Forestier and colleagues34,35 reported 9 out of20 patients had fasciculations and cramps, supporting their ar-gument that PLS is similar to ALS.

As a result of corticospinal and corticobulbar involvement, pa-tients will demonstrate UMN signs consisting of spasticity, slowmovement of limbs and tongue, hyperreflexia with reflex spread(to finger flexors; crossed adductors), brisk jaw reflex, corneal-mandibular reflex, Hoffman’s signs in the fingers, extensorplantar responses, and weakness in a UMN pattern.

AAEM Course When It’s Not ALS! Pure Motor Syndromes 3

4 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

Sensory symptoms and signs should prompt a search for anotherdiagnosis. Patients do not complain of visual symptoms, al-though some authors have reported abnormal visual sac-cades.34,42 Some patients complain of urinary urgency orincontinence, and several report this more frequently—50% (4out of 8) in the Canadian series, 65% (13 out of 20) in theSalpetriere, and 3 out of 5 in the initial report of the Texas pa-tients.34,42,59 These usually occur a number of years after onset ofsymptoms. In the Canadian series, bladder symptoms first ap-peared in four out of eight patients at 5, 8, 9, and 24 years afteronset.42 In most of the early reports, cognition was reported asnormal.42 However, Le Forestier and colleagues reported 16 outof 20 patients had errors on frontal lobe function testing. Othershave reported frank frontal lobe dementia syndrome in PLS pa-tients.10,14,53 This is consistent with the recent increasing aware-ness of frontal lobe dementia in 10-20% of ALS patients39,40

DURATION AND PROGNOSIS

Primary lateral sclerosis patients have a slowly progressive diseasewhich distinguishes them from typical ALS patients. In most ofthe published cases and series the patients are reported as beingalive, and there have been only a small number of autopsiedcases. There is no good data to tell physicians what the averagelife expectancy is for patients with PLS. There is data from nu-merous papers in the modern era on the duration of symptomsat the time patients were either diagnosed or reported. In theCanadian series, median disease duration at the time of thereport was 19 years and the mean was 14.5 years (range 4-34years).42 In the Salpetriere series, mean disease duration at firstexamination was 8.5 years (range 4-14 years).34 Disease progres-sion as reported as slow with half of the patients experiencingperiods of stabilization lasting months. Follow-up on 19 patientsshowed 5 could walk unaided, 5 used a walker, and 10 neededa wheelchair after 4-6 years duration. In the NIH series, the pa-tients had symptoms present for 7-8 years at the time of diag-nosis.63 Similarly, the 10 patients in the Dutch series hadsymptoms from 6-35 years. In the Texas series, the average du-ration of illness was 4.75 years (range 4-15) in 13 patients. Allfour of Russo’s patients had symptoms more than 5 years withfollow up from 25-42 months.45 The Columbia Universitygroup’s three patients who had died had symptoms 1, 6, and 8years, and their six living patients had symptoms for 2-12years.62 The five cases of Gastaut and colleagues had symptomsfor 5, 10, 12, and 28 years.22

A few cases that were initially diagnosed as PLS eventually hadthe diagnosis changed to ALS due to progression of thedisease.8,34,62 Bryun and colleagues described three patients whohad a pure PLS picture until 7.5 years, and 27 years into the

disease had fasciculation, atrophy, and a worsening needle elec-tromyography (EMG), at which point ALS was diagnosed.8

LABORATORY FINDINGS

Creatine Kinase

Serum creatine kinase (CK) results are often elevated in ALS(usually less then two times normal), and when this occurs it isprobably a reflection of denervation from LMN involvement.Creatine kinase levels are usually not mentioned in publishedPLS cases. In the Texas series, serum CK was slightly elevated intwo out of nine patients.31 Similarly, in the Dutch series, 4 outof 10 had slightly elevated serum CK levels.33

Electromyography

Most of the smaller reports in the modern era argued thatnormal nerve conduction studies and needle EMG proved thepatients studied had PLS.2,22,23,45 However, in most of the largerseries, subtle but definite abnormalities on needle EMG are re-ported. In this author’s series, 7 out of 13 patients had featuresof mild active denervation in one or more muscles consisting ofincreased insertional activity (5 out of 7), grade 1+ fibrillationsor positive sharp waves in (4 out of 7), or fasciculations (4 outof 7). Decreased recruitment of motor units (fast firing) was seenin three out of seven although motor unit morphology wasnormal. No patients had sufficient abnormalities on EMG tomake a diagnosis of ALS. In the Salpetriere study, 6 out of 20patients had either denervation activity at rest or denervationpotentials with decreased recruitment, but did not meet criteriafor definite, probable, or possible ALS.34 During subsequent ex-aminations, of the 14 who initially had a normal needle EMG,5 developed denervation or decreased motor unit recruitment.Most patients had multiple needle EMGs and at the time of thelast evaluation, three fulfilled electrophysiologic criteria of prob-able ALS, but without clinical evidence of disease progression. Inthe Dutch study, 4 out of 10 patients had enlarged motor unitaction potentials, but none had spontaneous denervation.33 Allof these authors argued that because of the mild needle EMGabnormalities, there is some evidence of LMN dysfunction andtherefore that many cases of PLS are on a spectrum with ALS.In the Columbia Medical Center series, seven cases were ex-cluded because there was evidence of denervation on needleEMG—these cases were referred to as “PLS with EMG dener-vation.”62 One of these cases also developed clinical evidence ofLMN disease on follow-up and was diagnosed with ALS. In ad-dition, one of their autopsied cases previously had a needleEMG showing fasciculations in multiple muscles in at least twolimbs. Interestingly, in the Canadian series where the authors

argued that PLS is a discrete disorder separate from ALS, two outof eight patients had occasional fibrillations and positive sharpwaves which were considered “indicators of a relatively minordegree of denervation ... restricted to a few muscles” that ap-peared late in the course.42 In the proposed diagnostic criteria bythis group, they allow for “occasional fibrillation and increasedinsertional activity in a few muscles (late and minor).”42

Therefore, if one looks at the existing published literature, theconclusion is that mild needle EMG abnormalities can be foundin cases that clinically appear to have a pure slowly progressivePLS syndrome. In rare cases, follow-up needle EMGs can showprogression and ultimately change the diagnosis to ALS.8,34,62

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) studies in several largeseries are typically abnormal.6,33,34,63 Brown and colleaguesstudied TMS in seven PLS cases and all had central conductionabnormalities. The “ascending” group of Zhai and colleaguesshowed that motor evoked potentials could not be evoked fromhand muscles despite maximal stimulation, and this was inter-preted as decreased cortical excitability.63 The Dutch group alsohad difficulty obtaining responses with TMS, but when theywere obtained, the central motor conduction time (CMCT) wassignificantly prolonged (2-3 times normal). This is in contrast toALS patients in which CMCT is normal or only slightlydelayed.33 The Salpetriere group could not obtain responses in12 out of 20 patients in either upper and lower limbs, and onlyin the lower limbs in two patients. In six patients CMCTs wereprolonged.34 Of the two patients reported by Swash and col-leagues, one had prolonged CMCTs to the lower extremities,and one had borderline findings.52

Somatosensory Evoked Potentials

Somatosensory evoked potentials (SEPs) (visual, brainstem,median, and tibial somatosensory) were performed in six pa-tients in this author’s series and were all normal.31 However, inthe Salpetriere series, abnormalities in visual (prolonged P100),median (prolonged N20 and N13-20 interval, and tibial (pro-longed P40 and P22-40) SEPs were found in over half of their20 patients.34 The abnormalities were presumably compared tonormal control values at their institution. No comparison wasmade with ALS patients. Their findings are unexpected, partic-ularly since this group argues that PLS frequently has subtleLMN findings and should be considered on spectrum with ALS.In the Dutch series, prolonged latencies were also documentedon median and peroneal SEPs in several patients.33

Muscle Biopsy

This author biopsied one patient and found rare angulated fiberssuggesting denervation.31 In the Salpetriere series, all 20 patientsunderwent a deltoid muscle biopsy and signs of denervation orreinnervation was seen in 13 patients; 7 were normal.34

Therefore, muscle biopsy can often be useful in finding evidenceof LMN pathology in patients who clinically appear to have apure UMN syndrome.

Neuroimaging

Routine computerized tomography and magnetic resonanceimaging (MRI) brain imaging is typically normal or shows non-specific changes.31,34,52,63 However, atrophy of the precentralgyrus has been reported in some series.33,34,42 A single report ofserial MRI scans over a 9-year course showed progressive atrophyof premotor, parietal, and primary sensorimotor cortex, withsparing of the temporal lobe, occipital lobe, and cerebellum.46

Magnetic resonance spectroscopy in some series has shown re-duction of N-acetylaspartate/creatinine in the motor cortex,63 afinding that also has been shown in some ALS patients.

Positron emission tomography (PET) has shown a regional de-crease in fluorodeoxygluse uptake.42 In cerebral blood flow(rCBF) a decrease using flumazenil as a marker (an index ofsynaptic brain function) and regional density of benzodiazepinereceptors (BZRs) decrease (a putative index of cortical neuronaldensity)35 in the precentral gyrus regions. Again, these PETimaging findings may not distinguish PLS from ALS.35,42

More recently, diffusion tensor imaging has demonstrated de-creased image intensities reflecting decreased diffusionanisotropy in the posterior limbs of the internal capsules com-pared to normal control.55 However, that paper also indicatesthese changes can be seen in ALS patients, and therefore theybelieve this tool may be useful in distinguishing PLS from otherdisease states. It remains to be determined if this tool can be amarker for UMN pathology in both PLS and ALS, or if it trulyis more specific for these diseases.11

Pathology

There have been surprisingly few autopsy reports of PLS in themodern era since the description by Fisher.2,19,29,42,62 The consis-tent finding in the six autopsied patients described in thesestudies is the loss of myelinated fibers in the entire corticospinalsystem with sparing of the cranial nerve neurons and the

AAEM Course When It’s Not ALS! Pure Motor Syndromes 5

anterior horn cells. Most of these cases also had atrophy of thepre-central gyrus and loss of Betz cells in the motor cortex.2,19,29,42

In the case by Beal and Richardson, intracytoplasmiceosinophilic inclusion bodies were observed rarely in motorneurons (one in the hypoglossal nuclei and two in spinal cordanterior horn cells), and were suspicious for the Bunina bodiesdescribed in ALS.2

In rare cases, patients who are diagnosed with a PLS syndromeduring life can have changes more typical of ALS at autopsy. Inthe series of 45 autopsied cases of motor neuron disease byBrownell and colleagues, 3 patients who were diagnosed withPLS in life were found to have anterior horn cells affected atautopsy.7

In the recent case by Tan and colleagues, an elderly patient witha 7-year history of progressive bulbar symptoms followed byspasticity and dementia showed typical corticospinal tract in-volvement seen in PLS as well as marked frontotemporalatrophy with ubiquitin-positive staining neurons these corticalregions.53 The cortical pathology was therefore typical of fron-totemporal lobar degeneration, in addition to the pyramidalchanges of PLS. They also reported Bunina body inclusions in afew LMNs. The patient never developed significant limb weak-ness or clinical evidence of LMN dysfunction. In this paper, theyreport that seven previous autopsy cases of a PLS-like syndromewith dementia and ubiquitin immunohistochemistry had beenreported, although it appears that most of these were reportedonly in the Japanese literature.30,32,41,50,54,56,60

A patient with a 10-year history and clinical features suggestiveof PLS was found at autopsy to have diffuse Lewy body disease,but without ante-mortem clinical features of dementia orParkinsonism.28

Reports of Concurrent Diseases

There have been several reports of patients with PLS having aconcurrent medical diagnosis, but the relationship is usually un-certain. Five women were reported with breast cancer and PLS,and in three of these cases, ultimately diagnosed with ALS.20,43

One of the autopsied cases of Younger and colleagues had a smallcell lung carcinoma.62 In addition, two of the patients in theYounger and colleagues series were human immunodeficiencyvirus (HIV) positive, and one went on to develop acquired im-munodeficiency syndrome (AIDS).62 There has been an autop-sied case of multiple myeloma and a PLS syndrome in theabsence of cord infiltration by tumor.7 A patient with PLS of 7years duration has been reported to have an IgM paraproteinand elevated cerebrospinal fluid (CSF) protein.15,52

Differential Diagnosis and Work-up

The differential diagnosis for the progressive corticospinal andcorticobulbar syndrome is outlined in Table 1. This is an inclu-sive table and most of the disorders probably do not need to beseriously considered when evaluating a patient for possible PLS.

While some consider PLS a diagnosis of exclusion, this can besaid for most sporadic degenerative conditions for which no di-agnostic test is available. In reality, if a patient presents with apure progressive spastic bulbar and limb syndrome, the differen-tial diagnosis is limited. Most of the conditions listed in Table 1have either sensory symptoms or evidence ofinvolvement ofanother neurologic system, such as cerebellar. Also, a number ofthe disorders in the degenerative group have a hereditary basisand therefore should have a history of other affected familymembers.

The hereditary spastic paraparsis (HSP) disorders deserve partic-ular consideration.18 These hereditary conditions have previouslybeen referred to as Strumpell’s disease. In the last several yearsthere has been an explosion in the molecular genetic identifica-tion of a number of genes responsible for HSP. Hereditaryspastic paraparsis can be autosomal dominant, autosomal reces-sive, or X-linked. To date, 20 genetic loci (spastic gait loci [SPG])have been identified. The most common HSP appears to be dueto a mutation in the SPG4 gene which produces a protein calledspastin. The SPG4 gene mutations account for 40% of autoso-mal dominant HSP. Other mutations are in genes coding for at-lastin (SPG3), kinesin heavy chain (SPG10), andNIPA1(SPG6), heat shock protein 60 (SPG13) (all autosomaldominant); paraplegin (SPG7) and spartin (SPG20) (both auto-somal recessive); and L1 cell adhesion molecule (SPG1) and pto-teolipid protein (SPG2) (both X-linked). Genetic testing iscurrently available for spastin, atlastin, and NIPA1 mutations.Hereditary spastic paraparsis usually presents in the teenage yearswith symmetrical leg spasticity. While the disorder progresses,arm involvement is uncommon and bulbar involvement is ex-tremely rare. There is some range in the age of onset, and somepatients are diagnosed in middle age. Bladder symptoms arecommon and some patients exhibit mild sensory loss in the feet(vibration and proprioception deficits) suggesting posteriorcolumn involvement. Therefore, while it is probable that somepatients reported as PLS may have had one of the HSP disorders,the absence of a family history, middle or late life onset, andbulbar involvement make PLS much more likely.

With regard to familial ALS (FALS), these patients have signifi-cant UMN and LMN involvement, and therefore usually do notneed to be considered in the differential of a possible PLS

6 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

patient. In one family reported by Appelbaum, two first cousinshad either a PLS or PMA phenotype.1 However, in families withthe two identified autosomal dominant FALS mutations (SOD1mutation on chromosome 21 or the 9q34 mutation), PLS phe-notypes have not been reported. There are at least two juvenileautosomal recessive forms of ALS. In some of these kindreds, apure UMN presentation (limb and bulbar) has been describedusing the term “juvenile PLS.”3,21,25,26,27,36,61 Recently, a numberof these rare cases have been shown to be due to mutations in agene that codes for a protein called alsin.25,27,62 Many of thesechildren present in the first 1-2 years of life. Not all families havebeen shown to have the alsin mutation, and since there clearly isan overlap with HSP, this phenotype has also been referred to asinfantile ascending hereditary spastic paralysis (IAHSP).37

In a sporadic pure UMN syndrome developing in middle age orlater, the two main diseases to consider are ALS and PLS.Amyotrophic lateral sclerosis is more common than PLS andtherefore is the ultimate diagnosis in patients presenting withthis syndrome. However, if there is either minimal or no evi-dence of LMN pathology, a tentative diagnosis of PLS can bemade. In this setting, patients can be told that the prognosis isbetter compared to ALS and the progression is slow. However,they also need to be informed that they need to be followedclosely to determine if their motor neuron disease will evolveinto ALS or another diagnosis.

All patients should have standard brain and spinal cord MRIimaging and EMG/nerve conduction studies. Further tests suchas evoked potentials and muscle biopsies are determined on acase-by-case basis. Blood work in these patients routinely in-cludes serum CK and human T-lymphotropic virus 1 (HTLV-1)antibodies. This author also obtains serum B12, rapid treponinetest and fluorescent antibody test (for syphilis), and serumprotein electrophoresis/immunofixation electrophoresis, butwithout sensory symptoms or signs, the yield on these studies isnegligible. If there is absolutely no evidence of a LMN process,CSF studies should be obtained as part of a multiple sclerosisevaluation. If nerve conduction studies indicate an unsuspectedsensorimotor neuropathy, this author checks for long-chain fattyacids. Antibodies for HIV are tested in at-risk patients. If thereare no bulbar features, one can check for the commercially avail-able genetic mutations for HSP (SPG4, SPG3A, SPG6), butwithout an autosomal dominant family history, the yield is prob-ably extremely low. This author has not been routinely checking

AAEM Course When It’s Not ALS! Pure Motor Syndromes 7

Table 1 Differential diagnosis of the progressive corticospinaland corticobulbar dysfunction syndrome

Sporadic motor neuron disease

Primary lateral sclerosis (PLS)

Amyotrophic lateral sclerosis (ALS)

Structural lesions

Cervical spondylytic myelopathy

Other causes of spinal cord compression

Tumor, arteriovenous malformation, disc

Syringomyelia

Foramen magnum tumor

Arnold-Chiari malformation

Hydrocephalus

Degenerative and hereditary diseases

Hereditary spastic paraplegia

Spinocerebellar ataxias

Diffuse Lewy body disease

Leukodystrophies (adrenoleukodystrophy,adrenomyeloneuropathy, metachromate leukodystrophies

Vitamin E deficiency

Familial ALS (FALS); juvenile FALS

Dysimmune disease

Multiple sclerosis

Infection

*HTLV-1 myelopathy (tropical spastic paraplegia)

**HIV-related vascular myelopathy

Neurosyphilus

Metabolic, nutritional, toxic disorders

Cobalamin (Vitamin B12) deficiency

Vitamin E deficiency

Copper deficiency

Lathyrism

Vascular

Lacunar state

* HTLV1 – human T-lymphotropic virus 1

** HIV – human immunodeficiency virus

molecular genetic mutations for the spinocerebellar ataxia genesunless there is ataxia, family history, or other evidence to suggestinvolvement outside of the corticospinal/corticobulbar system.

DIAGNOSTIC CRITERIA

The most recent proposed diagnostic criteria for PLS have beenthose of Pringle and colleagues in 1992 and are outlined in Table2.42 Interestingly, a pure UMN syndrome in two regions of thebody can fulfill the El Escorial research criteria for clinically pos-sible ALS as originally proposed in 1994.4 If one finds evenminimal needle EMG abnormalities in two limbs to the degreethat has been reported in some PLS publications, this wouldmeet the revised El Escorial criteria for clinically probable labo-ratory supported ALS.5

TREATMENT

Treatment is symptomatic and directed toward the spasticity,usually with baclofen or tizanidine.63 Rarely dantrolene can beused. However, with the advent of the baclofen pump, this isprobably a better alternative than dantrolene in difficult tocontrol patients. Excessive drooling can be treated with a varietyof oral anti-cholingergic medications (amitriptyiline,hyoscyamine, benztropine mesylate, glycopyrrolate, or scoal-palamine patches). The tricyclic antidepressants can also beuseful for emotional lability associated with the pseudobulbarcondition. There is some preliminary data indicating that botu-linum toxin injections into the submandibular glands may de-crease saliva production24,38

At this point, there is no data to indicate that riluzole is of benefitin PLS patients as all of the data pertains to typical ALS. Thisauthor has treated some PLS patients with riluzole, but thepatient needs to be aware that the benefit is unknown in thissetting. As with all of this author’s ALS patients, patients areplaced on high-dose antioxidant vitamin C, E, and beta-carotene, although no good clinical data is available regardingthe benefit of this approach. It is preferable for the patient to be

8 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

Table 2 Proposed diagnostic criteria by Pringle andcolleagues42

Clinical

1. Insidious onset of spastic paraesis, usually beginning in lower ex-tremities but occasionally bulbar or in an upper extremity

2. Adult onset, usually fifth decade or later

3. Absence of family history

4. Gradually progressive course (i.e., not step-like)

5. Duration > 3 years

6. Clinical findings limited to those usually associated with corti-cospinal dysfunction

7. Symmetrical distribution, ultimately developing severe spasticspinobulbar paresis

Laboratory (help in exclusion of other diseases)

1. Normal serum chemistry including normal vitamin B12 levels

2. Negative serologic tests for syphilis (in endemic areas, negativeLyme, and HTLV-1 serology

3. Normal CSF parameters, including absence of oligoclonal bands

4. Absent denervation potentials on EMG or at most, occasional fib-rillation and increased insertional activity in a few muscles (lateand minor)

5. Absence of high signal lesions on MRI similar to those seen in MS

Additionally suggestive of PLS

1. Preserved bladder function

2. Absent or very prolonged latency on cortical motor evoked re-sponses in the presence of normal peripheral stimulus-evokedmaximum compound muscle action potentials

3. Focal atrophy of precentral gyrus on MRI

4. Decreased glucose consumption in pericentral region on PET scan

HTLV-1 = human T-lymphotropic virus 1; MRI = magnetic resonance imaging;MS = multiple sclerosis; PET = positron emission tomography; PLS = primarylateral sclerosis.

(Used with permission, Oxford University Press.)42

managed in a multi-disciplinary ALS clinic so that their multi-ple needs can be addressed—equipment, speech, pulmonary,physical, and dietary, as well as having access to social workers,counselors, and occupational therapy professionals.

SUMMARY

Primary lateral sclerosis remains a difficult diagnosis to make. Tosome extent, some of the same issues that Charcot, Erb, andWilson faced, are still being struggled with today; particularly re-garding whether or not PLS is a distinct entity. Interestingly,there has been a renewed focus on PLS in the neuromusculardisease literature in the last 2 decades, probably because these pa-tients continue to challenge clinicians. While there remain manyunanswered questions regarding diagnosis and nosology, it is be-lieved that PLS is a useful concept which carries implications forprognosis that differ from other categories of motor neurondisease.

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25. Gros-Louis F, Meijer IA, Hand CK, Dube MP, MacGregor DL, SeniMH, Devon RS, Hayden MR, Andermann F, Andermann E,Rouleau GA. An ALS2 gene mutation causes hereditary spastic para-plegia in a Pakistani kindred. Ann Neurol 2003;53:144-145.

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28. Hainfellner JA, Pilz P, Lassmann H, Ladurner G, Budka H. DiffuseLewy body disease as a substrate of primary lateral sclerosis. J Neurol1995;242:59-63.

29. Hudson AJ, Kiernan JA, Munoz DG, Pringle CE, Brown WF, EbersGC. Clinicopathological features of primary lateral sclerosis are dif-ferent from amyotrophic lateral sclerosis. Brain Res Bull1993;30:359-364.

30. Imai H, Furukawa Y, Sumino S, Mori H, Ueda G, Shirai T, KondoT, Mizuno Y. [A 65-year old woman with dysarthria, dysphagia,weakness, and gait disturbance.] No To Shinkei 1995;47:399-410.

31. Kojan S, Goodwin WE, Bryan WW, Nations SP, Burns DK, BarohnRJ, Wolfe GI. Clinical and laboratory features of primary lateral scle-rosis. J Child Neurol 2000;15:200.

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32. Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y.Upper motor neuron predominant degeneration with frontal andtemporal lobe atrophy. Acta Neuropathol 1998;96:532-536.

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34. Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier-BuchmanL, Salachas F, Pradat PF, Lacomblez L, Meininger V. Does primarylateral sclerosis exist? Brain 2001:124:1989-1999.

35. Le Forestier N, Maisonobe T, Spelle L, Lesort A, Salachas F,Lacomblez L, Samson Y, Bouche P, Meininger V. Primary lateral scle-rosis: further clarification. J Neurol Sci 2001:185:95-100.

36. Lerman-Sagie T, Filiano J, Smith DW, Korson M. Infantile onsethereditary ascending spastic paralysis with bulbar involvement. JChild Neurol 1996;11:54-57.

37. Lesca G, Eymard-Pierre E, Santorelli FM, Cusmai R, Di Capua M,Valente EM, Attia-Sobol J, Plauchu H, Leuzzi V, Ponzone A,Boespflug-Tanguy O, Bertini E. Infantile ascending hereditary spasticparalysis (IAHSP):clinical features in 11 families. Neurology2003;60:674-682.

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50. Sugihara H, Horiuchi M, Kamo T, Fujisawa K, Abe M, Sakiyama T,Tadokoro M. A case of primary lateral sclerosis taking a prolongedclinical course with dementia and having unusual dendritic balloon-ing. Neuropathology 1999;19:77-84.

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10 Primary Lateral Sclerosis and the Diffferential of the “Pure” Upper Motor Syndrome AAEM Course

11

Brachial Amyotrophic Diplegia andMultifocal Acquired Motor Axonopathy

Jonathan S. Katz, MD

Stanford University Medical CenterDepartment of Neurology

Stanford, California

INTRODUCTION

The goal of this manuscript, other than to describe brachialamytrophic diplegia (BAD) and multifocal acquired motor ax-onopathy (MAMA), is to discuss why these definitions need toexist. These terms are used to demonstrate practical problemsthat 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-derlying reasoning process in this domain.

There are three aspects of neuromuscular diseases that, at times,can make practicing in this area particularly daunting. These are:

1. Complexity (making numerous observations about eachpatient).

2. Lack of exhaustiveness (the nomenclature is too small toaccount for every presentation).

3. No gold standard tests (physicians are left to rely on theirobservations for diagnosis).

COMPLEXITY

There are at least nine basic features used to describe any givenpure motor presentation (Table 1). Although this may not soundlike a lot, consider that this means there are at least 29 possiblepatterns derived from these observations (actually some featureshave three or more choices and some have continuous rather

than discrete variables, making it even far more complex). Thismeans a minimum of over 500 potential presentations.

Since no individual observation can prove or disprove the pres-ence of a disease by itself, physicians must rely on summationsof findings, or “the patterns.” For example, amyotrophic lateralsclerosis (ALS) is a pure motor, chronic, asymmetrical disorderwith upper motor neuron (UMN) signs. It often presentswithout antibodies, sometimes with a family history, and withaxonal pathophysiology. It is virtually always progressive.Knowledge about these “clusters” of observations is at the root ofpattern recognition. The complexity becomes evident because

Table 1 Nine observations for motor presentations

1. Proximal or distal muscles affected

2. Symmetric or asymmetric

3. Multifocal, generalized, or regional

4. Upper limbs, lower limbs, neck, trunk involved

5. Upper motor neuron signs present or not

6. Acute, subacute, or chronic

7. Hereditary or sporadic

8. Axonal or demyelinating

9. Antibody against nerve is present

some ALS patients never develop observable UMN signs. Here,a slightly different pattern has been created, but one which stillhandles the logic that UMN signs may not be evident.

Now consider two cases; one where the weakness remains largelyconfined to one region (like the arms for long periods of time)and lacks UMN signs, the other with rapidly progressing weak-ness, involvement of all four distal limbs at the time of initialpresentation, and clear UMN signs. When do these patternsbecome so different that a physician cannot be confident theseare the same condition? Going a step further, when is it useful tothink about these presentations as though they are two differentdisorders? The discussion of BAD will be a practical approach tothese questions.

LACK OF EXHAUSTIVENESS

Many physicians practice in a way that assumes every disease hasactually been named. It should be understood that this assump-tion might be incorrect. Without a deeper understanding ofpathophysiology, it might be assumed that there is more thanone way that a motor nerve might die, and differences in pre-sentations may signal different underlying mechanisms.

From a practical standpoint, physicians clearly see presentationsthat do not fit neatly into a diagnostic “pigeon hole.” These casescan be dealt with by applying the designation variant (ALSvariant, etc.). Practicing as though an exhaustive universe existssimplifies the reasoning process. Focusing on a single technologyhas the same effect. Splitting cases simply by the presence orabsence of conduction block (CB), no matter what the pheno-type, can cut the number of diseases down to only two.

At the same time, the possibility that atypical patterns could rep-resent an as-yet unnamed disease is often neglected. Table 2points out one situation where physicians are forced to considerthe nonexhaustive universe.

Since ALS presents with diffuse weakness and is axonal, andmultifocal motor neuropathy (MMN) is multifocal but de-myelinating, it is quickly apparent that one box is unfilled. It isclear that not every case will fit into the rubric of motor neurondisease or motor neuropathy, as they are defined. While cases inthe upper right corner are rare, they do exist and they might bestbe reasoned about as a discrete clinical entity. The situation of ex-haustiveness becomes obvious when situations with more thantwo observations are considered. The only solution is to keep anopen mind on how to manage these cases, to think about theirpathophysiology, and to move forward with the reasoningprocess.

GOLD STANDARDS

Finally, there are few “gold standards” or simple diagnostic teststo aid physicians in diagnosis. In most cases the existence of agiven diagnosis can never absolutely be proven. With no tests, acomplex reasoning domain, and the absence of exhaustivenaming, physicians are left with pattern recognition as the maindiagnostic tool. It is inevitable that they will meet circumstancesof real uncertainty. It might be wise to coin the term “nonevi-dence-based medicine” as the science behind creating rules formanaging this area.

MULTIFOCAL ACQUIRED MOTOR AXONOPATHY

In the early 1990s after MMN was described and physicians hadno experience with its diagnosis, there were several cases carryingthe diagnosis of ALS or atypical motor neuron disease makingthe rounds through this author’s clinic. Before physicians wereable to diagnose these cases correctly, they had to overcome acognitive dilemma. Specifically, they needed to reconsider therole of CB in the diagnosis of MMN since, at that time, the dis-order carried the label of “multifocal motor neuropathy withCB.” Through a series of discussions (in Texas at the time) thisauthor’s group began to think of the condition by its phenotyperather than by electrodiagnostic (EDX) testing. Multifocalmotor neuropathy became a phenotype marked by the presenceof distal, asymmetric, primarily upper limb and stepwise weak-ness, with absence of retained reflexes.3

This relatively simple change in the way the disease was viewedled to a new set of conclusions about the nature of the condition.It followed that only about 40% of MMN patients diagnosedthis way actually fulfilled standard EDX criteria for CB. While asmall number of cases had multiple pure CBs, these were the ex-ception and made up approximately 10% of the phenotypiccaseload. Instead, the most salient feature was the presence ofother evidence of demyelination (temporal dispersion of wave-

12 Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy AAEM Course

Table 2

Axonal NCS/EMG Demyelinating NCS

Multifocal phenotype ? MMN

Diffuse weakness ALS/PMA Pure Motor CIDP?

ALS = amyotrophic lateral sclerosis; CIDP = chronic inflammatory demyelinatingpolyneuropathy; EMG = electromyography; MMN = multifocal motor neuropathy;NCS = nerve conduction study; PMA = progressive muscular atrophy.

forms without changes in area, conduction slowing, and pro-longed distal latencies) in virtually all patients. Moreover, inweak nerve distributions, individual nerves often showed axonalmanifestations only (low compound muscle action potential[CMAP] amplitude denervation potentials) with no evidence ofdenervation. Overall, the complete picture of EDX testing inMMN that emerged was a mixture of features, with axonal find-ings predominate in some affected nerves, obvious CB at othersites, and a combination of other demyelinating findings. It fol-lowed that the same underlying pathophysiologic process causeddifferent electrophysiological manifestations.

From here, it was only a short step to the concept of MAMA. Ofthis author’s initial 19 cases, 1 patient had no EDX evidence ofdemyelination at all. After several more years, eight similar caseswere identified with multifocal involvement clinically, a lack ofprogression, and axonal-appearing EDX testing. It made littlesense to diagnose these patients with motor neuron disease basedon the EDX testing since this implied progression with time andsince motor neuron disease is not supposed to have such clearmultifocal involvement. It was further reasoned that if somenerve territories had no evidence of demyelination in MMN, itwas plausible that in some patients every affected nerve wouldlack evidence of demyelination, if not by chance alone. It fol-lowed that the same neuropathy would, at times, show up elec-trodiagnostically as an axonal disorder.

In the initial report of MAMA,1 and in subsequent letters to theeditor, it was postulated that several mechanisms for a purelyaxonal motor neuropathy.4 First, this may simply be a variant ofMMN where the nerve lesions may be too proximal. In this sce-nario, a physician would only be able to find secondary axonalloss since the demyelinating lesions are in a segment where theconduction abnormalities cannot be easily identified (withoutroot stimulation). F waves may also miss a very proximal lesionif there is slowing over only a short segment of nerve or if thereis only a partial block of conduction. Second, the lesions mightbe too distal. Conduction block in the terminal segment of anerve fiber may be incorrectly interpreted as axonal loss. Third,the injury may actually be directed against the axon. Even usingthe most common hypotheses—that MMN is an antibody me-diated disorder, marked by an immunological attack directedagainst myelin, myelin/axonal interactions, or ion channels inthe axonal membrane—it follows that the same antibodiesmight actually damage the axon through an inflammatoryprocess without causing much in the way of conduction abnor-malities. A related method would be a chronic immune attackagainst a nerve, where the demyelinating features become“hidden” because there is severe damage of the underlying axonover time. Fourth, if there are few nerves injured or if the injurednerves are difficult to study, or simply not studied on routinetesting (anterior interosseous, musculocutaneous, or sciatic) thechances of discovering a demyelinating lesion are reduced simplybecause the opportunity is lost. Last, others have suggested a

dynamic CB, which cannot be discovered with routine testing.Here antibodies are able to cause weakness via CB that occursonly during volleys of nerve action potentials, but not at baselinewith a single stimulus, as is the case with standard testing.

It is still unclear whether MAMA and MMN are, if fact, thesame disease, or even if MAMA represents a single underlyingdisorder. Like MMN, these cases have weakness in the distribu-tion of individual peripheral nerves. However, they tend to haveproximal involvement more commonly than MMN and onsetat a relatively young age in a few cases (around 20). Three of sixcases that this author treated responded favorably to therapy, em-phasizing the pitfalls in characterizing MAMA as a “motorneuron disease variant” based solely on needle electromyography(EMG) findings. One case of MAMA was prednisone respon-sive, a finding that differs from MMN, which responds to intra-venous immunoglobin (IVIg) but not prednisone. Finally, someof these cases have confluent or overlapping mononeuropathiesresulting in a pattern of proximal and distal weakness reminis-cent of chronic inflammatory demyelinating polyneuropathy.Thus, it is currently believed that the axonal cases are somehowdifferent.

Multifocal acquired motor axonopathy cases also generally lackGM-1 antibodies, and given that antibodies are present in atleast 35% of definite MMN cases, it is hard to understand howno antibodies were found in these first nine cases if this is simplyan MMN variant. By pure chance this would amount to a 1%chance if MAMA and MMN were the same disease. (A subse-quent case did have anti-GM1 antibodies suggesting at leastsome of these could be an MMN variant.)

BRACHIAL AMYOTROPHIC DIPLEGIA

Another group of patients examined at this author’s clinic hadbeen diagnosed with ALS but were not dying quickly nor werethey showing constant progression that is typical of that disease.Most of these cases had a specific phenotype for which the termbrachial amyotrophic diplegia (BAD) was used.2 This wasmarked by the onset of weakness of one arm that spread rela-tively quickly over periods ranging from 1-2 years to become bi-lateral, eventually reaching the point where the arms hunglimply at the patients’ sides. There was a complete absence ofweakness outside of the upper limbs, sparing the neck flexorsand extensors, breathing, bulbar muscles, and the legs. Thirteenof the first 15 patients had absent reflexes, while 2 others hadbrisk reflexes in the upper limbs.

Brachial amyotrophic diplegia, by definition, remains localizedto the arms for at least 2 years after the first onset of weakness.The rationale was that every case where weakness spread beyondthe arms earlier than 2 years, turned out to be clear ALS. Whilethis raises the possibility of a circular argument that those who

AAEM Course When It’s Not ALS! Pure Motor Syndromes 13

do not progress are the ones who do not progress, it turns outthat these patients often continue to have focal weakness for upto 5 years. More importantly, it is among this population thatthere exists a group of patients with no progression at all.

Needle EMG shows denervation in the upper limbs. Some pa-tients had a few positive sharp waves and fibrillation potentialsin the legs or paraspinal muscles, a finding suspicious for ALS,but still did not show progression with time. Creatine kinase canbe mildly elevated or normal. Magnetic resonance imaging scan-ning was nonrevealing except for nonspecific spondylosis.

This clinical presentation is important to distinguish from ALSbecause of the differences in prognosis. It should be clear thatwithin the first 2 years after onset, it is impossible to predict withaccuracy exactly how a patient with hanging arms will eventuallyprogress. However, it is clear that some of these cases ultimatelyturn out to have benign courses (except for the devastating in-volvement of the arms). This may benefit patients by offeringsome hope. In fact, 6 of this author’s 15 patients have failed todevelop any involvement outside of the arms to date, even after8 years from onset. The longest duration of static weakness inBAD is now over 30 years. From these observations, it can beconcluded that there are “benign” motor presentations.

The underlying pathophysiology of BAD is not known. Amongthis author’s patients, a specific subset had the onset of weaknessmainly in the C5 and C6 muscles, which became bilateral, re-mained asymmetric, and continued to spare the triceps, wrists,and hands. Some cases with severe involvement of the proximalarms at onset developed only mild to moderate hand involve-ment and had a benign prognosis. It might be useful to think ofsome BAD cases as a variant of juvenile monomelic amyotrophy(JMA), but with involvement of the proximal rather than thedistal limbs. In contrast to JMA, which tends to affect maleteenagers, BAD typically affects men in their late 30s or early40s. Chronic mechanical impingement of the lower cervicalspine, associated with flexing the neck, which develops during a

growth phase in teenagers is postulated to be the root cause ofJMA. One can only speculate as to whether a similar mechani-cal factor is at play in BAD.

In contrast, it should be clear that some BAD patients die ap-proximately 5-8 years from onset, with a gradually progressivecause leading to respiratory failure that is typical of ALS. Theoverall point is that BAD is actually a clinical syndrome com-prised of two types of progression. Obviously, the longer thecondition remains localized to the arms, the more hope there isthat the patient does not have a life-threatening illness.

Under any circumstance, BAD does not appear to be treatable.Several patients were treated when they failed to progress overtime, and the initial diagnosis of ALS was questioned. The ra-tionale was that if the patient did not have ALS, they could havea potentially treatable neuropathy. This is not totally unjustifiedsince reports of ill-defined lower motor neuron disorders thatrespond to IVIg exist. Given that there is no way to know aboutthe response without a trial of therapy, it made sense to givetreatment at least a resort.

Bibliography

1. Katz JS, Barohn RJ, Kojan S, Wolfe GI, Nations SP, Saperstein DS,Amato AA. Axonal multifocal motor neuropathy without conductionblock or other features of demyelination. Neurology 2002;58:615-620.

2. Katz JS, Wolfe GI, Andersson PB, Saperstein DS, Elliott JL, NationsSP, Bryan WW, Barohn RJ. Brachial amyotrophic diplegia: a slowlyprogressive motor neuron disorder. Neurology 1999;53:1071-1076.

3. Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn RJ.Electrophysiologic findings in multifocal motor neuropathy.Neurology. 1997;48:700-707.

4. Menkes DL, Ghosh A, Donaghy M, Katz JS, Barohn RJ, SapersteinD, Amato AA. Axonal multifocal neuropathy without conductionblock or other features of demyelination. Neurology 2002;59:1666 -1667.

14 Brachial Amyotrophic Diplegia and Multifocal Acquired Motor Axonopathy AAEM Course

Pure Lower Motor Neuron Syndromes

David S. Saperstein, MD

Assistant Professor of NeurologyUniversity of Kansas Medical Center

Kansas City, Kansas

INTRODUCTION

Diagnosing amyotrophic lateral sclerosis (ALS) is often difficultlargely because this disease is uncommon (with a prevalence ofapproximately 1 per 100,000). However, when both upper andlower motor neuron features are present, diagnosis is usually rel-atively straightforward. Furthermore, ALS is the most commonmotor neuron disease (MND). Diagnostic difficulty is more sig-nificant when a patient has purely lower motor neuron (LMN)involvement. This manuscript will focus on this situation. TheLMN syndromes are heterogeneous and consist of idiopathicconditions similar to ALS, inherited disorders, and—of mostinterest—immune-mediated disorders. The potentially treatabledisorders, multifocal motor neuropathy and its variants, will bediscussed elsewhere in this course. Overall, the remaining LMNdisorders progress more slowly and tend to have a better prog-nosis than ALS.

The nomenclature used for these disorders can be confusing.Patients with an idiopathic purely LMN disorder are typically re-ferred to as having progressive muscular atrophy (PMA) or pro-gressive spinal muscular atrophy (PSMA). The term PMA willbe used here. It is clear that a significant proportion of PMA pa-tients actually have ALS and lack clinical evidence of uppermotor neuron (UMN) involvement. This is supported byautopsy series showing UMN pathology in approximately 50%of PMA patients.1,12,13,19,20 Up to one-third of MND patientslack UMN signs at presentation.21 A significant proportion ofPMA patients, if followed over time, will develop UMN exami-nation findings and, therefore, can then be diagnosed with ALS.

In some cases, UMN signs may have been present before thepatient was evaluated, but subsequently became undetectabledue to progressive LMN loss. During a PMA patient’s lifetime,UMN pathology may be detected with magnetic resonanceimaging (MRI) or transcranial magnetic stimulation (TMS).26

Conventional MRI sequences may demonstrate evidence ofUMN involvement, but more specialized modalities such asmagnetic resonance spectroscopy (MRS) are usually needed.14

Opinions differ on how to refer to patients with an acquiredLMN syndrome. For patients presenting with a clinical pictureresembling ALS (asymmetrical, progressive weakness), butlacking UMN findings, many clinicians will give a diagnosis ofALS. This is based on the high incidence of UMN features thatcan be found in these patients on imaging, TMS, or autopsy.Other clinicians tell patients presenting with these symptomsthat they do not meet criteria for ALS at the time and are,instead, diagnosed with PMA. Another semantic issue involvesthe terms PMA and spinal muscular atrophy (SMA). Somephysicians use the term SMA synonymously with PMA orPSMA. Many reserve the term SMA for patients with a geneticLMN disorder. It is usually impossible to know with certainlythe cause of a particular patient’s LMN syndrome. Although apatient may have a genetic cause for his weakness, if there is nofamily history and no gene defect identified, the patient may beclassified as PMA. However, certain clinical features, such assymmetrical and proximal weakness with legs weaker than armswould favor SMA over PMA, as will be discussed later. The exactclassification is not as important; the key is arriving at the bestdetermination of clinical course, prognosis, and management.

15

Several different LMN syndromes have been described.Although there is overlap, there are distinguishing aspects withregard to age of onset, etiology, site of involvement (regionalpredilections and restrictions), progression, and mortality (Table 1).

PROGRESSIVE MUSCULAR ATROPHY

Progressive muscular atrophy (also referred to as Aran-Duchenne syndrome)22 comprises approximately 10% of pa-tients with MND.31 It is slightly more common in men, with anearlier mean age of onset than ALS. Patients receiving the diag-nosis of PMA represent a mixed group—some are patients whohave ALS but lack clinical features of UMN involvement, whileothers are patients with a purely LMN disorder. Therefore, it isimpossible to know for certain the clinical course and prognosisof PMA. As a group, patients with PMA have a much betterprognosis than patients with ALS. In one series, PMA patientsshowed a 5-year survival of 56%.3 In contrast, the average 5-yearsurvival for ALS patients is approximately 25%.30

Brain MRI using conventional sequences may reveal abnormal-ities of the corticospinal tract in ALS patients. However, thislacks sensitivity and specificity.14 Magnetic resonance spec-troscopy, which permits assessment of regional brain biochem-istry, has shown mixed results in the past for detecting UMNpathology in ALS patients.14,26 Recently, Kaufmann and col-leagues16 found MRS to be 86% sensitive for identifying UMNpathology in MND patients with and without clinical UMNfindings. Autopsies performed in some patients confirmedUMN involvement. Research from German investigators sug-gests that a new MRI imaging technique called diffusion tensorMRI may be an effective way to detect UMN pathology inMND patients.26 This modality permits the estimation of theorientation of white matter on the basis of the diffusion charac-teristics of water. It showed abnormalities in 15 ALS patients, 6of whom had no UMN findings at the time of testing (but laterdeveloped UMN findings and met full diagnostic criteria forALS).26 Transcranial magnetic stimulation is another test thatmay permit the identification of UMN pathology. Studies of theusefulness TMS in ALS have provided mixed results.14,26

16 Pure Lower Motor Neuron Syndromes AAEM Course

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 Yearsover 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 SporadicAD, AR, XR (Gene unknown) (CAG repeats)

Distinct Features Gynecomastia, Male Preservation ofDiabetes, predominance respiratory and

Impotence, bulbar functionInfertility

AD = autosomal dominant; AR = autosomal recessive; CAG = cytosine-adenine-quanine nucleotidase; LMN = lower motor neuron; UMN = upper motor neuron; XR = X-linked re-cessive.

Currently, MRI and TMS are not routinely used in clinical prac-tice. The appropriate roles of these technologies in the diagnosisand management of patients with MND remains to be deter-mined.

There is no data regarding treatment of PMA, therefore, at thepresent time, these patients are managed the same as those withALS.

SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy is a diverse group of hereditary motorneuron diseases selectively involving LMNs, particularly the an-terior horn cells of the spinal cord.23 Adult-onset SMA, referredto as type IV, has several forms and usually begins over the ageof 20. The prevalence is estimated to be 0.32 per 100,000 pop-ulation and accounts for less than 10% of all SMA cases.23

Weakness is usually greater in the legs than the arms.31 The mostcommon inheritance pattern (seen in approximately two-thirdsof patients) is autosomal recessive, with a mean age of onset inthe fourth decade.25 The autosomal dominant form accounts forone-third of cases and shares a similar clinical phenotype.23 Theadult-onset disease is slowly progressive with only a small pro-portion of patients becoming wheelchair-dependent after 20years. Patients typically present with symmetrical, proximal, orgeneralized weakness, and fasciculations. Spinal muscularatrophy rarely affects bulbar muscles and respiratory musclesgenerally remain unaffected. Upper motor neuron signs areabsent. Other forms of SMA can involve predominantly distalmuscles (so-called “distal SMA”).8 Distal SMA can also be eitherautosomal recessive (two-thirds of patients) or autosomal domi-nant (one-third of patients). Although SMA types I, II, and IIIare usually caused by deletions in the survival motor neuron geneon chromosome 5, no genes responsible for SMA type IV havebeen identified.27

SPINOBULBAR MUSCULAR ATROPHY (KENNEDY’S DISEASE)

Kennedy’s disease is a form of SMA that is associated with bulbarinvolvement and X-linked recessive inheritance.17 The diseaseaffects only males, usually beginning in the third or fourthdecade of life. The initial symptoms include muscle cramps, alimb-girdle distribution of muscle weakness, and bulbar symp-toms. Distinguishing clinical features include facial and perioralfasciculations that are present in more than 90% of patients,hand tremor, and tongue atrophy associated with a longitudinalmidline furrow. There is no evidence of UMN involvement.Although sensory examination is typically normal, sensory nerveconduction studies are frequently abnormal. Other systemicmanifestations, include gynecomastia in 60-90% of patients dueto elevated gonadotropin levels associated with testicular atrophy,feminization, impotence, and infertility. Diabetes mellitus is seen

in 10-20% of patients. Genetic testing can be performed toconfirm the presence of an abnormal trinucleotide-repeat expan-sion (CAG) in the androgen receptor gene on the X chromo-some.18 In healthy individuals, the repeats range from 17-26 inthis coding area whereas, in Kennedy’s disease, the number ofrepeats range from 40-65. The number of the enlarged CAGrepeat is significantly correlated with the age of onset, but has nocorrelation with severity of weakness, degree of sensory neu-ropathy, presence of gynecomastia, or impotence.

REGIONAL VARIANTS

Regional variants of MND are disorders that are atypical pre-sentations of generalized MND due to the selected distributionof affected muscles. Several named disorders will be discussed. Itis not known whether they constitute distinct pathophysiologi-cal entities or if they are a subset of generalized MND (e.g.,PMA or ALS). Some entities do appear very distinct.Monomelic amyotrophy, for example, occurs at a young age andremains restricted to specific myotomes.

Monomelic Amyotrophy (Focal Motor Neuron Disease,Hirayama Disease)

Monomelic amyotrophy usually refers to an MND originallydescribed as juvenile muscular atrophy of the distal upper ex-tremity by Hirayama in 1959 in which muscle weakness remainslimited to several myotomes (usually C5 - T1) within a single ex-tremity.10 The mean age of onset is typically 20-35 years of agewith a male predominance (2:1). Patients demonstrate preferen-tial weakness in the hand and forearm muscles which progressesrapidly over a period of 2-3 years and subsequently remainsstable. Approximately 75% of cases involve the upper extremi-ties and the remainder involve the lower extremities. Reflexes inthe involved muscles are invariably hypoactive or absent. Thereare no UMN signs and sensory symptoms are limited to hypes-thesia to pin and touch in approximately 20% of patients. In50% of cases, the weakness remains localized to one limb, andthe other 50% of cases show clinical evidence of involvement inthe contralateral limb. Electrodiagnostic studies often show evi-dence of bilateral involvement although weakness may be clini-cally apparent in only one extremity.6

Magnetic resonance imaging may reveal a normal cervical spinalcord, but bilateral or unilateral cord atrophy is often seen.2

Hirayama and colleagues9 have suggested that this syndromemay be related to either local compression of the cervical cord orcirculatory insufficiency caused by an anterior shift of the poste-rior dura during neck flexion. Sometimes, abnormalities may beseen on MRI only when images are acquired with the neck in aflexed position (forward displacement of cervical dural sac).9

Neck flexion may also produce decreased abnormalities onsomatosensory evoked potentials.24 A recent report from Taiwan

AAEM Course When It’s Not ALS! Pure Motor Syndromes 17

describes a useful finding that can be seen in cervical spine MRIscans taken in a neutral, nonflexed position.2 These investigatorsfound that an increased separation between the posterior duralsac and adjacent lamina was a highly sensitive and specificfinding in Hirayama patients. They endorse a pathogenic theoryinvolving imbalance between the spinal cord and spinal columnthat results in a “tight dural sac.”2

The appropriate management of patients with Hirayama diseaseis unknown. Uncontrolled data from Japan sugges