Motor Neuron Disease

Lewis P. Rowland, MD Robert H. Brown, MD, DPhil Eric J. Sorenson, MD Jeremy M. Shefner, MD, PhD Lisa S. Krivickas, MD Robert G. Miller, MD

2008 Plenary AANEM 55th Annual Meeting Providence, Rhode Island

Copyright © September 2008 American Association of Neuromuscular & Electrodiagnostic Medicine 2621 Superior Drive NW Rochester, MN 55901 Printed by Johnson Printing Company, Inc. ii Motor Neuron Disease

Faculty Lewis P. Rowland, MD Eric James J. Sorenson, MD Professor of Neurology Associate Professor Columbia University Medical Center Department of Neurology New York, New York Mayo Clinic Dr. Rowland is Professor of Neurology at Columbia University. Dr. Rochester, Minnesota Rowland received both his bachelor of science and his medical degree from Dr. Sorenson received his medical degree and completed his residency in Yale University. He was trained in biochemistry and is known for research neurology at Mayo Clinic, Rochester, Minnesota. A fellowship in neuro- in neuromuscular diseases and age-related neurodegenerative diseases, muscular diseases was completed in 1996 at the University of Michigan especially amyotrophic lateral sclerosis (ALS). He has written many papers Medical Center and he also received a master’s degree in clinical research on ALS and edited two books on that disease. He was the Editor-in Chief from the Mayo Graduate School of Medicine. He is currently a consultant of Neurology, 1977-1987, and has been a member of the editorial boards in the Department of Neurology at Mayo Clinic and an associate professor of other journals, including the New England Journal of Medicine, Medical at the Mayo Clinic College of Medicine. Dr. Sorenson is board certified by Letter and the Journal of Neurological Sciences. Since 2001, he has been chief the American Board of Electrodiagnostic Medicine and American Board editor of another official publication of the American Academy of Neurology of Psychiatry and Neurology. His interests include neuromuscular diseases (AAN), a bi-weekly newspaper called Neurology Today. He has been editor with an emphasis on amyotrophic lateral sclerosis. of Merritt’s Textbook of Neurology editions 7-11 and is now, with Timothy A. Pedley, co-editor of the forthcoming 12th edition. Jeremy Shefner Dr. Rowland has been President of the Association of University Professors of Professor and Chair Neurology (1977-1978), President of the American Neurological Association Department of Neurology (1980-1981), President of the AAN (1989-1991), and Chairman of the Academy’s Education and Research Foundation (1996-1999). As Chairman SUNY Upstate Medical University of two departments of neurology, as an officer of these organizations, and as a Syracuse, New York member of committees of the NINDS, Dr. Rowland has focused on training Dr. Shefner received a PhD in experimental psychology from the University in clinical neurology and research. He is currently President of the Parkinson’s of Illinois in 1976, and was a National Reasearch Service Award Research Disease Foundation and a member of the Institute of Medicine. Fellow from 1977 to 1979. He then pursued medical training; following graduation from medical school at Northwestern University, he completed neurology training at the Harvard Longwood Neurological Training Robert H. Brown, Jr, MD, DPhil program, and a fellowship in clinical neurophysiology and neuromuscular Professor disease at the Brigham and Women’s Hospital. He spent 6 years on the faculty of Harvard Medical School and the Brigham and Women’s Hospital, Department of Neurology and moved to State University of New York Upstate Medical University in Harvard Medical School 1996, where he is now Professor and Chair of Neurology. Boston, Massachusetts Dr. Brown graduated from Harvard Medical School and completed his doctoral Dr. Shefner founded the Northeast ALS Clinical Trials Consortium training in neurophysiology at Oxford University. Dr. Brown trained in neurol- (NEALS) in 1995, and now serves as co-chair. NEALS is the largest ogy at Massachusetts General Hospital (MGH) in Boston, Massachusetts. In academic clinical trials consortium in the United States, and has completed 1984, he founded The Day Laboratory for Neuromuscular Research at MGH 6 multicenter ALS trials since 2003. Upon moving to SUNY, he established to investigate neuromuscular diseases, including Miyoshi myopathy and amyo- the multidisciplinary ALS clinic there, and has held leadership positions in trophic lateral sclerosis (ALS). many National Institute of Health and industry-supported clinical trials. He has published more than 100 peer reviewed scientific articles, recently Dr. Brown is currently Professor of Neurology at Harvard Medical School completed a term as Associate Editor of Muscle & Nerve, is Neuromuscular and Director of the Day Neuromuscular Research Laboratory. He is Section Editor of UpToDate, and serves on the editorial board of Clinical renowned for his work on the inherited basis of neurodegenerative and Neurophysiology and the ALS Journal. He is also Chair of the ALS neuromuscular diseases and has a record of significant discoveries in ALS Research Group. and neuromuscular disorders, like hyperkalemic periodic paralysis and some types of muscular dystrophy. In 1993, Dr. Brown and colleagues defined mutations in the gene encoding SOD1 as one cause of familial ALS.

Authors had nothing to disclose. Plenary Chair: John E. Chapin, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. Reference to commercial products herein are for illustrative purposes only and should not be interpreted as an AANEM endorsement. Lisa S. Krivickas, MD Robert G. Miller, MD Director of Electrodiagnostic Medicine California Pacific Medical Center Spaulding Rehabilitation Hospital San Francisco, California Associate Chief of PM&R Dr. Miller is a Clinical Professor of Neurology at the University of Massachusetts General Hospital California, San Francisco (UCSF), Clinical Professor of Neurology and Associate Professor of PM&R Neurological Sciences at Stanford University Medical School, the Director Associate Chair of Academic Affairs of the Forbes Norris Amyotrophic Lateral Sclerosis (ALS) Research Center, and Chairman of the Department of Neurosciences at the California Harvard Medical School Pacific Medical Center in San Francisco. Dr. Miller received his medical Dr. Krivickas is Associate Professor of Physical Medicine and Rehabilitation degree from Weill Medical College of Cornell University, completed his (PMR) at Harvard Medical School, Associate Chair of Academic Affairs, residency at UCSF Medical Center & University of California San Diego Associate Chief of PMR at Massachusetts General Hospital, Director Medical Center, and completed a fellowship at the National Hospital of the Muscle Cell Physiology Laboratory at Spaulding Rehabilitation Queen’s Square. Hospital, and Director of EMG at Spaulding Rehabilitation Hospital. She received a bachelor of science in mechanical engineering from Cornell Dr. Miller chairs the medical advisory board of the ALS Care Program University and her medical degree from Harvard Medical School. She designed to improve database outcomes for North American patients with completed a residency in PMR at University of Medicine and Dentistry ALS. He was the lead author of the American Academy of Neurology of New Jersey, New Jersey Medical School and Kessler Institute of evidence-based practice parameters for managing ALS and he is leading Rehabilitation, and a fellowship in electromyography and neuromuscular an effort to revise and update the practice guidelines. He has been active disease in the Department of Neurology at the Cleveland Clinic. She has in ALS clinical trials and is the Chair of the Western ALS Study Group, authored over 70 publications and serves on the editorial board of several an organization that has carried out numerous clinical trials in ALS. He scientific journals. Dr. Krivickas’ current research involves the study of chairs the World Federation of Neurology ALS Research Group, and is muscle physiology in neuromuscular disorders and aging, investigation of involved with several collaborative efforts to find better markers for disease new electrophysiologic techniques for the assessment of neuromuscular progression and better treatments for ALS. disorders, and clinical trials for ALS. She is a director for the American Board of Electrodiagnostic Medicine and a member of the Neuromuscular Dr. Miller was President of the American Association of Neuromuscular & Medicine Examination Committee of the American Board of Psychiatry Electrodiagnostic Medicine (AANEM) from 1986-1987 and has served on and Neurology. She also served a term on the Board of Trustees of the numerous committees, and task forces for the association American College of Sports Medicine 2003-2006. She received the 2006 Young Academician Award from the Association of Academic Physiatrists. iv

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 specific 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 indi- cated 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. v Motor Neuron Disease

Contents

Faculty ii

Objectives v

Program Committee vi

Progressive Muscular Atrophy and Other Lower Motor Neuron Syndromes of Adults 1 Lewis P. Rowland, MD

Genetics and Biology of Amyotrophic Lateral Sclerosis 5 Robert H. Brown, MD, DPhil

Neurophysiology of Amyotrophic Lateral Sclerosis 19 Eric J. Sorenson, MD

Clinical Trials in Anterior Horn Cell Disease: What Have We Learned? 25 Jeremy M. Shefner, MD, PhD

Rehabilitation of Amyotrophic Lateral Sclerosis 31 Lisa S. Krivickas, MD

Treatment for Amyotrophic Lateral Sclerosis - Evidence Based Management 39 Robert G. Miller, MD

CME Activity and Faculty Evaluation 47

O b j e c t i v e s —The goal of this didactic session is to allow physicians involved in neuromuscular diseases and electromyography a better understanding of diseases affecting the anterior horn cell, especially amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). At the end of this session participants should have an increased awareness of basic features and new advances in (1) those disorders characterized by death of the lower motor neuron, (2) the pathobiology and genetics of anterior horn cell diseases, (3) electrophysiology of anterior horn cell disorders, (4) success and failure in clinical trials for ALS and SMA, (5) what rehabilitation offers patients with ALS, and (6) improving quality and quantity of life of those with ALS. P rerequisite —This course is designed as an educational opportunity for physicians. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM is accredited by the ACCME to provide continuing medical education (CME) for physicians. TM The AANEM designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s) . Each physician should only claim credit commensurate with the extent of their participation in the activity. This event is an Accredited Group Learning Activity as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada. CME for this activity is available 9/08 - 9/11. vi Motor Neuron Disease AANEM Course

2007-2008 AANEM PROGRAM COMMITTEE John E. Chapin, MD, Chair Albuquerque, New Mexico

Segun Toyin Dawodu, MD James M. Gilchrist, MD Christina M. Marciniak, MD Bowie, Maryland Providence, Rhode Island Chicago, Illinois

Nayan P. Desai, MD Ghazala Riaz Hayat, MD Elizabeth A. Sekul, MD San Diego, California St. Louis, Missouri Augusta, Georgia

Lawrence W. Frank, MD Shashi B. Kumar, MD Jeffrey A. Strommen, MD Elmhurst, Illinois Tacoma, Washington Rochester, Minnesota

Eric P. Gierke, MD Robert T. Leshner, MD Jay M. Weiss, MD Everett, Washington Washington, DC Levittown, New York

2007-2008 AANEM PRESIDENT Peter D. Donofrio, MD Nashville, Tennessee 1

Progressive Muscular Atrophy and Other Lower Motor Neuron Syndromes of Adults

Lewis P. Rowland, MD Professor of Neurology Columbia University Medical Center New York, New York

INTRODUCTION Table 1 Lower motor neuron syndromes

Controversies about progressive muscular atrophy (PMA) begin Hereditary Disorders with its name. Though it was once called progressive spinal muscu- lar atrophy, it was decided that the use of the word ‘spinal’ in the 1. Spinal muscular atrophies (SMAs) of childhood name could lead to confusion with the childhood disease, spinal (SMN-gene linked, types 1-3) muscular atrophy (SMA). 2. X-Linked infantile spinal muscular atrophy (XL-SMA). 3. Hereditary spinal muscular atrophy of adults (SMA Type 4). More important controversies focus on the concept of the 4. Familial progressive muscular atrophy disease itself. In theory, PMA is a disease of the lower motor neurons (LMNs) as diagnosed clinically and proven at 5. X-linked spinobulbar muscular atrophy (Kennedy-Alter-Sung Disease). postmortem examination. 6. LMN-dominant familial amyotrophic lateral sclerosis(ALS) Diagnostic requirements for PMA have been difficult to meet 7. Distal spinal muscular atrophy (Spinal Charcot-Marie-Tooth, for several reasons.20 Most importantly, within months after hereditary motor neuropathy). symptom onset, occasionally the clinical evidence of LMN disease Sporadic Disorders is complicated by new upper motor neuron (UMN) signs. This leads to a diagnosis of amyotrophic lateral sclerosis (ALS). Even 1. Progressive muscular atrophy (progressive spinal when no UMN signs are seen in living patients, autopsy shows muscular atrophy) involvement of the corticospinal tract in 50% to 66% of patients 2. Brachial amyotrophic diplegia 8,19 given a clinical diagnosis of PMA. Again, the actual diagnosis 3. Monomelic muscular atrophy (Hirayama syndrome, arm or leg) is ALS. 4. Post-polio syndrome What often appears to be PMA may introduce a differential 5. Post-radiation muscular atrophy diagnosis with other conditions (Table 1).25 Among cases of pure or 6. Multifocal motor neuropathy dominant LMN clinical manifestations there are some with SOD1 7. Slowly progressive distal muscular atrophy of upper limbs mutations.4,18,21 (O’Sullivan-McLeod Syndrome)

SOD1 mutations are not the sole cause of familial motor neuron Modified from Van den Berg-Vos, Van den Berg LH, Visser J, de Visser M, (MN) syndromes. Dynactin mutations cause an autosomal domi- Franssen H, Wokke HJH. The spectrum of lower motor neuron disorders. J Neurol nant syndrome of LMN signs including the unique manifestation 2003;250: 1279-52.24 of laryngeal paralysis.17 LMN = lower motor neuron, SMN = survival motor nerve 2 Progressive Muscular Atrophy and Other Lower Motor Neuron Syndromes of Adults AANEM Course

Determining which patients with PMA actually have UMN MMNCB is therefore related to both chronic inflammatory dysfunction has become the focus of a flourishing industry of brain demyelinating polyneuropathy (CIDP) and MN disease from imaging including diffusion tensor imaging, diffusion weighted which it is differentiated primarily by nerve conduction studies. imaging, positron emission tomography scanning, magnetic reso- If untreated, the condition can cause serious disability12, but nance spectroscopy, measurement of cortical thickness, and tran- improvement has been seen in most patients with intravenous scranial magnetic stimulation. The profusion of these different immunoglobulin (IVIg) therapy.23 One patient with a PMA- methods suggests that no single method is yet sufficiently sensitive like syndrome of the hands responded to IVIg therapy after or specific for diagnosis. 39 years of weakness.10 Additionally, patients with typical clinical findings may respond to this therapy even if CB is not found.9 Although prednisone or other steroid therapy is effec- CLINICAL MANIFESTATIONS OF PMA tive in CIDP, motor neuropathies do not respond. Because it is not a fatal disease, there have been few postmortem studies In a series of autopsy patients with MN diseases, Ince and col- of MMN. leagues8 included 63 patients with ALS; 10 patients had PMA from symptom-onset until their death, and 6 initially had X-linked Spinobulbar Muscular Atrophy (Kennedy-Alter- symptoms of PMA, but UMN signs appeared before death.8 Sung Disease) The age at onset was similar in all three groups, and the male- female ratio was close to 50:50. Disease duration, however, X-linked spinobulbar muscular atrophy syndrome was one of the varied from about 16 months in PMA, to 25.7 months in those first diseases attributed to mutations in triplet repeats, disrupting converting to ALS, and 22.5 months for those with ALS.8 the androgen receptor. The clinical picture is distinct with onset after age 40, starting with dysarthria and dysphagia, proximal Seventeen patients with LMN signs were studied by de Carvalho limb weakness delayed for years, fasciculation in limb muscles and and colleagues; 10 did not develop UMN signs in 1 year of fol- also in facial muscles around the lips, gynecomastia, and low-up, but 7 others did change to ALS within 1 year.5 Patients hyperCKemia. Laryngospasm seems to be a common report of with either rapid or slow progression were described in the study. patients who are asked directly about their symptoms. Inheritance Symptom duration in some patients was as long as 16 or 19 years, is X-linked. UMN signs are usually lacking, but the syndrome or as short as 1 year.21,22 This reflects the lack of consistency in the may resemble ALS. Needle electromyography may indicate rate of disease progression. One patient studied had experienced mixed myopathic and neurogenic patterns. symptoms for 25 years.7 Other than corticospinal tract pathology (or lack of this pathology), the hallmarks of postmortem diagnosis Monomelic Muscular Atrophy (Hirayama syndrome) are not only degeneration and disappearance of MNs in cases of PMA, but also the presense of Bunina bodies and ubiquitinated Monomelic muscular atrophy disorder primarily affects men inclusions, as also seen in typical ALS. These findings provide rather than women and its onset is seen around age 20. It affects yet another reason for considering PMA to be a form of ALS. one arm more often than a leg; progresses for a year or two, Although PMA is almost always sporadic, familial PMA has been and then becomes stable. Hirayama described the syn- recorded.1 In Brazil, some familial cases of late onset SMA or ALS drome and attributed it to an anomaly of the dural sac, have been associated with mutations in the gene for vesicle-as- but surgery does not seem to offer a solution. Although sociated membrane protein/synaptobrevin-associated membrane cases have been seen elsewhere, Japan appears to have the protein B (VAPB). 4 However, the mutation of this gene is rarely highest reported incidence of this syndrome. Fasciculation is associated with PMA or ALS.11 not common.

Post-Radiation Muscular Atrophy DIFFERENTIAL DIAGNOSIS OF PMA Multifocal Motor Neuropathy Weakness, wasting, andfasciculation have followed radiation for thyroid and other cancers near the cervical spinal cord. However, once post-radiationmuscular atrophy was recognized, precautions Multifocal Motor Neuropthy (MMN) is the most important were taken to prevent this type of neurological injury and now it LMN syndrome to differentiate from other diseases because, is rarely seen. unlike PMA, it often responds to immunotherapy. Evolution of this concept probably started in 1982 with a study by Lewis Slowly Progressive Distal Muscular Atrophy of the Upper and colleagues of patients who had persistent conduction block Limbs (O’Sullivan-McLeod syndrome) (CB) in a sensorimotor syndrome that caused weakness of the hands more than the legs and sometimes improved with steroid O’Sullivan-McLeod syndrome is characterized by the therapy.13 Shortly thereafter, purely motor disorders with CB name of the condition.15 Although it is often sporadic, a that also affected primarily the arms and hands were described.2,16 case was examined that involved three sisters who all had Visible fasciculation emphasized the similarity to PMA and, weak hands for as long as they could remember. Their in some cases, preservation of tendon reflexes suggested ALS. symptoms began at age 20 and continued for an additional 20 AANEM Course Motor Neuron Disease 3 years. Visible fasciculation and cramps were not described. It is REFERENCES not clear whether the condition differs from PMA. However, IVIg therapy led to improvement in one patient. 1. Cervenakova L, Protas II, Hirano A, Votiakov VI, Nedzved MK, Kolomiets ND, Taller I, Park KY, Sambuughin N, Gajdusek DC, Hereditary Spinal Muscular Atrophy of Adults (SMA Type Brown P, Goldfarb LG. Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS). J Neurol Sci. 2000 4) (OMIN #271150) Aug 15;177(2):124-30. 2. Chad DA, Hammer K, Sargent J. Slow resolution of multifocal Compared to the usual childhood forms of SMA, Type 4 starts weakness and fasciculation: a reversible motor neuron syndrome. after age 30 and is as mild as type 3. It may be allelic to type 3, Neurology. 1986; 36:1260-3. with deletions in the same MN survival gene found in child- 3. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, hood versions of SMA. The complexity of these syndromes is Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach emphasized by the similarity of SMA-4 to ALS-4, which is clini- M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman cally similar in causing distal limb weakness of slow progression V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations but differs in the presence of pyramidal signs, juvenile onset, in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J and mutations in senataxin.3 Postmortem examinations have not Hum Genet. 2004 Jun;74(6): 1128-35. Epub 2004 Apr 21. been reported. 4. Cudkowicz ME, McKenna-Yasek D, Chen C, Hedley-Whyte ET, Brown RH Jr. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc Hereditary Motor Neuropathy superoxide dismutase gene. Ann Neurol. 1998 Jun; 43(6):703-10. 5. de Carvalho M, Scotto M, Swash M. Clinical patterns in progressive The ”neuronal form” of Charcot-Marie-Tooth (CMT) muscular atrophy (PMA): a prospective study. Amyotroph Lateral disease is identified by normal nerve conduction charac- Scler. 2007 Oct;8(5):296-9. teristics. Some are sensorimotor, while others are purely 6. Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, motor. “Distal hereditary motor neuropathy” was first divided Merlini L, Van den Bergh P, Rasic VM, Robberecht W, Fischer into seven types that were based on age at onset, mode D, Morales RJ, Mitrovic Z, Seeman P, Mazanec R, Kochanski A, of inheritance, proximal or distal limb weakness, or other Jordanova A, Auer-Grumbach M, Helderman-van den Enden AT, features. With the advent of molecular genetics, mutations Wokke JH, Nelis E, De Jonghe P, Timmerman V. Relative contribu- have been found in eight different genes, including heat shock tion of mutations in genes for autosomal dominant distal hereditary proteins, glycyl-tRNA synthetase (GARS), dynactin, sena- motor neuropathies: a genotype-phenotype correlation study. Brain. 2008 May;131(Pt 5):1217-27. Epub 2008 Mar 5. taxin, and others. GARS mutations have also been found 6 7. Forman M, Trojanowski J, Hays AP, Rowland LP. Progressive mus- in sensorimotor hereditary neuropathies. The close similar- cular atrophy for 27 years before autopsy. In preparation. ity of a motor neuropathy to a “neuronopathy” (disorder of 8. Ince PG, Evans J, Knoop M, Forster G, Hamdalla HHM, Wharton the cell body) is noted and increases the level of similarity SB, Shaw PJ. Corticospinal tract degeneration in the progressive mus- to PMA. cular variant of ALS. Neurology 2003; 60: 1252-8. 9. Katz JS, Barohn RJ, Kojan S, Wolfe GI, Nations SP, Saperstein DS, Amato AA. Axonal multifocal motor neuropathy without conduc- AN OVERALL VIEW tion block or other features of demyelination. Neurology. 2002 Feb 26;58(4):615-20. Two challenges arise in the classification of “neuronopathies”, 10. Kawano Y, Nagara Y, Murai H, Kikuchi H, Ohyagi Y, Kira J. Slowly diseases that affect the cell body of a MN (rather than the axon). progressive distal muscular atrophy of the bilateral upper limbs (O’Sullivan-McLeod syndrome) partially alleviated by intravenous One is the overlap with ALS (when, in addition to LMN signs, immunoglobulin therapy. Intern Med. 2007;46(8):515-8. Epub 2007 pyramidal signs are present in life or the corticospinal tracts Apr 17. are abnormal at autopsy). The second problem is the overlap 11. Landers JE, Leclerc AL, Shi L, Virkud A, Cho T, Maxwell MM, with “motor neuropathies” (neuronal CMT) which are linked Henry AF, Polak M, Glass JD, Kwiatkowski TJ, Al-Chalabi A, Shaw to CMT because the legs may be more affected than the hands CE, Leigh PN, Rodriguez-Leyza I, McKenna-Yasek D, Sapp PC, and because of the striking appearance of distal muscle wasting Brown RH Jr. New VAPB deletion variant and exclusion of VAPB and pedal deformities with high arches and hammer-toes. mutations in familial ALS. Neurology. 2008 Apr 1;70(14):1179-85. However, nerve conduction characteristics are normal. The Epub 2008 Mar 5. question as to whether or not motor neuropathies should be 12. Lange DJ, Weimer LH, Trojaborg W, Lovelace RE, Gooch CL, classified with PMA or with peripheral nerve disorders remains Rowland LP. Multifocal motor neuropathy with conduction block: unclear. Some inherited or familial forms have been linked to spe- slow but not benign. Arch Neurol 2006; 63:1778-81. 13. Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demy- cific mutations, but many are sporadic and of uncertain causation. elinating neuropathy with persistent conduction block. Neurology. Eight different genes have been identified. This kind of molecular 1982 Sep;32(9):958-64. identification seems to be more important than clinical features, 14. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton which can even include UMN signs. Research progress is accelerat- S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, ing and the more knowledge that is gained about PMA, the sooner Zatz M. A mutation in the vesicle-trafficking protein VAPB causes will come understanding and effective treatment for the killer late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. disease ALS. Am J Hum Genet. 2004 Nov;75(5):822-31. Epub 2004 Sep 15. 4 Progressive Muscular Atrophy and Other Lower Motor Neuron Syndromes of Adults AANEM Course

15. O’Sullivan DJ, McLeod JG. Distal chronic spinal muscular atrophy 21. Suzuki M, Irie T, Watanabe T, Mikami H, Yamazaki T, Oyanagi K, involving the hands. J Neurol Neurosurg Psychiatry. 1978 Jul;41(7): Ono S. Familial amyotrophic lateral sclerosis with Gly93Ser mutation 653-8. in Cu/Zn superoxide dismutase: A clinical and neuropathological 16. Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy study. J Neurol Sci. 2008 May 15;268(1-2):140-4. Epub 2008 Jan 14. masquerading as motor neuron disease. Muscle Nerve. 1988;11(2): 22. Tsuchiya K, Sano M, Shiotsu H, Akiyama H, Watabiki S, Taki K, 103-7. Kondo H, Nakano I, Ikeda K. Sporadic amyotrophic lateral sclerosis 17 . Puls I, Oh SJ, Sumner CJ, Wallace KE, Floeter MK, Mann EA, of long duration mimicking spinal progressive muscular atrophy Kennedy WR, Wendelschafer-Crabb G, Vortmeyer A, Powers R, exists: additional autopsy case with a clinical course of 19 years. Finnegan K, Holzbaur EL, Fischbeck KH, Ludlow CL. Distal spinal Neuropathology. 2004: Sep;24(3):228-35. and bulbar muscular atrophy caused by dynactin mutation. Ann 23. Van Asseldonk JT, Franssen H, Van den Berg-Vos RM, Wokke JH, Neurol. 2005 May;57(5):687-94. Van den Berg LH. Multifocal motor neuropathy. Lancet Neurol. 18. Restagno G, Lombardo FL, Sbaiz L, Mari C, Gellera C, Alimonti, 2005 May;4(5):309-19. Calvo A, Tarenzi L, Chiò A. The rare G93D mutation causes a slowly 24. Van den Berg-Vos, Van den Berg LH, Visser J, de Visser M, Franssen progressing lower motor neuron disease. Amyotroph Lateral Scler H, Wokke HJH. The spectrum of lower motor neuron disorders. J 2008; 9: 35-9. Neurol 2003;250: 1279-52. 19. Rowland, LP: Clinical aspects of sporadic ALS/MND. In Shaw PJ, 25. Visser J, de Jong V, de Visser M. The history of progressive muscular Strong MJ eds, Motor neuron disorders. Butterworth-Heinemann, atrophy. Neurology 2008; 70: 723-7. London, 2003, pp 111-141. 20. Rowland LP, Leung D, Hays AP: A clinically pure lower motor neuron syndrome. In Schapira AHV, Rowland LP eds. Clinical cases in neurology, Butterworth-Heinemann, Oxford, 2001, pp 47-54. 5 Genetics and Biology of Amyotrophic Lateral Sclerosis

Robert H. Brown, Jr, DPhil, MD Professor of Neurology Harvard Medical School Director Day Neuromuscular Research Laboratory Department of Neurology Massachusetts General Hospital Boston, Massachusetts

INTRODUCTION Table 1 Inherited disorders of the upper and lower motor neuron Over the last 15 years, several lines of investigation have provided fresh insights into the molecular basis for many of the neurodegenerative disorders. This manuscript will concentrate on Disease Defective Locus Reference lessons that are emerging from studies of inherited forms of motor Protein neuron disease (MND), including familial amyotrophic lateral Upper and Lower Motor Neurons sclerosis (FALS). It will emphasize some general principles that Amyotrophic lateral sclerosis may encompass several categories of neurodegenerative disorders. Dominant Genetic loci have now been described for several types of familial Autosomal - adult onset Superoxide 21q [9] MND (Tables 1-3). Knowledge of the molecular lesions that dismutase 1 trigger motor nerve death in FALS improve our understanding of the pathophysiology of all MNDs (both familial and sporadic) and Neurofilament 11 [95] subunit H of neurobiological properties of this cell. Dynactin 2 [71] DISORDERS OF THE UPPER AND LOWER Vesicle-associated 20q [94] MOTOR NEURONS binding protein TDP-43 1p36 [6] Dominantly Inherited, Adult-onset Amyotrophic Autosomal - juvenile onset Senatxin 9q [130] Lateral Sclerosis (helicase) Amyotrophic lateral sclerosis (ALS) is a lethal,paralyzing dis- Autosomal – juvenile onset Neuron target 12p [140] order of motor neurons in the brain, brainstem, and spinal esterase cord. Its onset, typically in the 50’s, is age-dependent; X-linked - adult onset Xcent [210] mean onset is at 55, and mean survival is 3-5 years.About Autosomal - adult onset with dementia 9q [211] 5-10% of cases are transmitted as an autosomal dominant Autosomal – adult onset with amyotrophy, 1 trait (FALS) . dementia, PD Tau protein 17q [212]

When lower motor neurons die, patients develop weakness Recessive Juvenile onset GEF-family protein 2q33 [135,213] with muscle wasting. The disease begins insidiously with “alsin” distal, focal weakness, sometimes accompanied by musclecramp- 15q [133] ing and spontaneous twitching (fasciculations). When den- ervation involves bulbar muscles, the complaint is difficulty The hallmark of ALS at autopsy is atrophy and loss of motor chewing, swallowing, and speaking. Rarely, ALS presents as neurons, sometimes with gliosis. ALS motor neurons show primary respiratory failure. When the disorder begins in cor- cytoskeletal aberrations such as axonal “spheroids,”2,3,4 and fila- ticospinal motor neurons, the clinical manifestation is weak- mentous aggregations within the cell bodies. The latter may be ness with spasticity. There is no loss of sensory, sphincteric, or positive for ubiquitin, sometimes in thread-like “skein” structures. cognitive function. It is now recognized that a major component of the ubiquitinated 6 Genetics and Biology of Amyotrophic Lateral Sclerosis AANEM Course protein complex in motor neurons with early involvement in ALS type and mutant form.29 Indeed, in neurons in cell culture, zinc- is a 43 kd protein (TDP-43) that is critical in ribonucleic acid deficient apoprotein is as toxic as the zinc deficient mutant protein; (RNA) splicing and trafficking; abnormal cytoplasmic distribu- when fully zinc loaded, neither form of the protein is toxic in this tions of TDP-43 are seen in many cases of sporadic ALS (SALS).5 system. Another hypothesis is that nitration of critical tyrosine Moreover, it is now recognized that rare cases of FALS are caused residues is a key event.30,31 High performance chromatography by germline mutations in the TDP-43 gene.6 and immunochemical studies indicate that levels of nitrotyrosine are augmented in human and mouse ALS brains.17,32,33 A fourth On clinical and pathological ground, FALS is indistinguishable hypothesis is that the mutant SOD1 protein has an enhanced 34,35,36,37 from SALS. This strongly suggests that these diseases involve ability to act as a peroxidase with H2O2 as a substrate. This similar pathogenic mechanisms. In a subset of FALS pedigrees, mutations in the gene for cytosolic, copper/zinc superoxide dis- mutase (SOD1) were identified in a subset of FALS pedigrees.7,8,9 To date, more than 100 SOD1 mutations have been detected in such families. SOD1 is a homodimeric enzyme of 153 amino acids that has been highly conserved during evolution. It is a member of a family of related proteins including a manganese dependent SOD expressed in mitochondria (SOD2), and an extracellular form (Cu/Zn dependent, SOD3). SOD1 catalyzes the conver- sion of superoxide anion O2 to hydrogen 2 peroxide H2O2 (Figure 1a). H2O2is then converted to H2O by catalase or glutathione peroxidase.10 These facts suggests that free radical toxicity might be implicated when SOD1 is mutated, although this hypothesis remains controversial.

There is a reduction of total brain SOD1 activity in some FALS patients with SOD1 mutations, but not in SALS patients or FALS patients without SOD1 mutations.11 Some SOD1 muta- tions reduce SOD1 activity in red blood cells and lymphoblastoid lines.12,13,14,15,16

Several markers of oxidative injury (to proteins, lipids, and deoxy- ribonucleic [DNA]) are increased in ALS tissues. These include carbonyl proteins, and markers both lipid peroxidation11,17,18 and oxidatively modified DNA.19 Moreover, there are also indications that one can detect rather striking oxidative markers in ALS spinal fluid.20 These reports documenting that SOD1 activity is decreased in tissues of patients with SOD1-associated FALS raise the possibil- ity that motor neuron death is a direct consequence of this loss of SOD1 function. For example, as reviewed below, studies of motor neurons in vitro show that diminished superoxide activity initiates programmed cell death of neurons.21,22,23 It is also likely that the mutant SOD1 protein has acquired properties that are lethal for the motor neuron. Strong support for this view is the observation Figure 1a Selected reactions of cytosolic Cu, Zn superoxide dismutase (SOD1) that SOD1 knock-out mice do not develop motor neuron cell SOD1 catalyzes the conversion (dismutation) of superoxide anion (O2.-) to 24 hydrogen peroxide (H O ) H O is converted to water by catalase and glutathione death in the first few months of life. Oppositely, over-expression 2 2 2 of FALS-related mutant SOD1 protein (with FALS mutations) peroxidase. Superoxide anion can combine non-catalytically with nitric oxide (NO) causes a lethal, paralytic disorder in mice beginning at 3-5 months to form peroxynitrite (ONOO-). Peroxynitrite and hydrogen peroxide can interact with reduced 2+1+metals such as Feor Cu to hydroxyl radicals. of age.25 Figure 1b Putative reactions of mutant Cu/Zn SOD1. (1) FALS-associated mu- These considerations indicate that the mutant SOD1 molecule tations may lessen the affinity of SOD1 for copper and zinc. (2) Nitronium anions is cytotoxic. While the basis for this novel activity is not yet well may be formed more rapidly by the reaction of ONOO- with mutant SOD1 in the established, several possible adverse functions for the mutant presence of FALS mutations; this may accelerate transfer of nitrate groups to 2+ molecule have been proposed (Figure 1b). One is that metal tyrosines. (3) familial amyotrophic lateral sclerosis (FALS)-associated mutations binding properties of some mutants (e.g., G85R and G93A) are may favor the reduction of Cu, enhancing the ability of SOD1 to reduce substrates like H O and thereb y act as a peroxidase. (4) In the 2+ absence of zinc, ox ygen abnormal, and that either copper or zinc acts as a toxin for motor 2 2 neurons.26,27,28 More recently, it has been reported that deficiency can reduce Cu in SOD1 to produce superoxide anion within the active ch annel; this can potentially interact with nitric oxide to form perox ynitrite. (5) Mutant SOD1 of zinc from SOD1 enhances its potential toxicity, both in the wild- may be unstable and aggregate, both with itself and with wild-type SOD1. AANEM Course Motor Neuron Disease 7

Figure 2 Mutations in SOD1 impair multiple functions in motor neurons.The abundant, mutant SOD1 protein is capable of aberrant redox reactions that generate free radical species and is also prone to misfold. The misfolded SOD1 protein is presumed to be toxic either via a micro-aggregate (e.g., a pore-like structure) or a macro-aggregate. These events are correlated with multiple types of cellular dysfunction includeincomplete buffering of intracel- lular calcium, leading to heightened free calcium and mitochondrial calcium levels. Secondarily, there is a reduction in ATP generation. There is also impairment of axonal transport. Adverse consequences of mutant SOD1 are also exerted on cells such as astrocytes (e.g., causing subnormal glutamate uptake). Both astrocytes and microglia are activated, secreting factors that affect motor neuron viability, with both beneficial and adverse consequences. ALS = amyotrophic lateral sclerosis; ATP = adenosine triphosphate hypothesis is consistent with recent reports that levels of produc- larger, microscopically visible microaggregates.43 Such aggregates tion of hydroxyl radicals are increased in ALS mice.38 might be directly injurious; they might also act by impairing normal endogenous mechanisms for protein reutilization.44 It is Distinct from the foregoing proposals is the alternative sugges- proposed that through one or more of these adverse biochemi- tion that the critical effect of mutations in this abundant SOD1 cal reactions, the mutant SOD1 protein is directly or indirectly protein (up to 0.5% of intracellular proteins) is to cause misfold- toxic to the cell. Whether oxidative pathology is critical for the ing, leading to the accumulation of unstable, mutant protein, cytotoxic effects of mutant SOD1 is still not clear. An elegant perhaps as insoluble toxic aggregates. It has been clear for some study has documented that elimination in the ALS mice of a time that the stability of many of the mutant SOD1 proteins protein responsible for loading copper into the active site of are reduced when expressed in COS cells.39 More recent studies SOD1 does not ameliorate the disease; this has been interpreted now document that most, if not all, of the mutant SOD1 pro- as excluding a role for copper-mediated oxidative pathology45; teins are unstable either at baseline or with minimal physiologi- however, this view has been challenged on the grounds that there cal stresses.40,41,42 With little provocation, most mutant forms may be residual copper associated with the SOD1 molecule of SOD1 protein can be induced to form aggregates that may either in the normal active site or at an atypical, but potentially potentially be toxic, either as mini- or proto-aggregates, or as toxic site.46 8 Genetics and Biology of Amyotrophic Lateral Sclerosis AANEM Course

It is clear that there are several possible targets for this toxicity. One and a propensity to excitotoxicity, in part because of a persistent, target that has been intensively studied in recent years is the astro- incompletely activating Na current.54,55,56 A third important target glial glutamate transporter, EAAT2 or GLT1. This protein has been is the Na/K pump; a recent report documents a marked reduction extensively implicated as a factor in ALS pathogenesis both because in subunits of this G93A pump in spinal cords of mice expressing glutamate toxicity has generally been incriminated in the disease high levels of mutant SOD1.57 and because studies have documented a decrease in both astroglial glutamate transport activity47 and levels of EAAT2 protein.48 It has At the level of sub-cellular organelles, it is clear that another im- been suggested that the latter might be a consequence of altered portant target of mutant SOD1 protein are mitochondria. High splicing of the RNA transcript for EAAT2.49 Recent studies show levels of the protein, as expressed in different lines of transgenic that EAAT2 is susceptible to inactivation by mutant SOD1, par- ALS mice, trigger striking morphological changes in mitochondria 50 58,59 ticularly in the face of oxidative challenge by H2O2 or iron. This selectively in motor neurons. It is now clear that high levels may be because the transporter has a caspase-sensitive site whose of both wild-type and mutant SOD1 are evident in mitochon- cleavage leads to truncation of the transport protein, and the forma- dria.60 Moreover, mutant SOD1 is apparently more toxic when tion of abnormal protein adducts of the truncated fragments.51,52 localized to mitochondria than in other organelles.61 The mutant Another molecular target of mutant SOD1 protein is the voltage- SOD1 protein within mitochondria disrupts electron transport sensitive sodium (Na) channel, which shows diminished Na current and adenosine triphosphate (ATP) generation at the time of disease and a depolarizing shift of the voltage-dependence of activation in onset but not in presymptomatic stages.62 Why SOD1, usually the presence of mutant SOD1.53 Indeed, studies now indicate that considered to be cytosolic, is found in mitochondria is not clear, motor neurons from ALS mice (below) show hyperexcitability although it is intriguing that studies find a direct binding interac-

Figure 3 Mutations in many genes compromise the f unction of motor neurons. Primary mutations in sev eral genes cause motor neurons to degenerate. The corresponding disorders are ALS, lower motor neuron disorders (LMN), u pper motor neuron disorders (UMN) and peripheral neuropathies (PN). Of the five gene defects associated with ALS, only two (involving SOD1 and VAPB) produce a clin ical phenotype that closely resembles ALS. The others are progress slowly and typically begin in the late juvenile or early adult years. ALS = amyotrophic lateral sclerosis; HSP = hereditary spastic paraplegia; VAPB = vesicle transport within neurons. AANEM Course Motor Neuron Disease 9 tion between SOD1 and an anti-apoptotic protein (bcl2) on the An important theme that has emerged over the last 5 years is that mitochondrial surface.63,64,65 the death process in mutant SOD1-mediated MND involves not only pathology intrinsic to motor neurons, but abnormal physi- In addition to specific molecules and sub-cellular organelles, it ological prop erties of non-neuronal cells. That this might be the is now clear that some sub-cellular processes are deficient in the case is suggested by the observations above regarding the astrocytic presence of aberrant SOD1. Important among these is axonal glutamate transporter. That this is likely is strongly argued by transport.66,67,68,69 In fact, several lines of evidence contend studies of chimeric ALS mice with varying complements of mutant that motor proteins should be considered candidate ALS genes. and wild-type cells88 and by elegant studies by Cleveland and col- Particularly persuasive are reports implicating motor proteins in leagues documenting that levels of expression of mutant SOD1 in both mouse and human MND. The former model (“legs at odd motor neurons modulates the age of onset in the mice, while the angles”) arises because of a primary defect in a gene encoding a duration of the disease, once underway, is determined in part by form of dynein.70 Very striking is the parallel observation that expression in microglial cells.89,90,91 dynactin, which complexes with dynein, is mutated in a family with a slowly progressive, bulbar-onset form of MND.71 These The role of non-neuronal cells in the demise of motor neurons has data accord well with the recent report that disruption of the been underscored in recent remarkable studies showing that motor dynactin-dynein complex in mice by manipulation of a dynami- neurons derived either from primary cultures or neural stem cells tin, a related protein, also causes a motor neuron phenotype72 by are adversely impacted by exposure to monolayers of astrocytes perturbing axonal transport. expressing mutant SOD1 protein. The nature of the factors medi- ating the cytotoxic influence is not yet established.92,93 It has become apparent from several lines of study that, whatever the specific target or mechanism of its action, mutant SOD1 While much attention has been devoted to the analysis of the prop- protein can markedly induce activity of cell death genes in neurons. erties of mutant SOD1, the search for other gene defects that can This is particularly remarkable as it has now become clear that wild- cause dominantly inherited ALS has continued. As noted above, type SOD1 is anti-apoptotic.21 The pro-apoptotic properties of mutations in the gene encoding a protein that mediates vessicle mutant SOD1 were first explored in a variety of cell types in vitro, transport within neurons (VAPB) are associated with a range of including yeast cells and diverse types of neuronal cells.73,74,75,76 In phenotypes that can mimic ALS.94 As well, mutations in the motor one model, the pro-apoptotic mutant SOD1 protein aggregates protein dynactin are also directly implicated as a cause of MND.71 within the cytosol of motor neurons.74 In N2A cells, oxidative stress can activate the cell death gene caspase-1 (interluekin-1 beta It has also been reported that mutations in the gene encoding the converting enzyme or ICE) and thereby lead to increased formation heavy subunit of neurofilament (NF-H) are present infrequently in and secretion of Il-1 ß ; this change is also seen in the spinal cords Table 2 Inherited disorders of the lower motor neuron of ALS mice.77 Subsequently, it was shown that both caspase-1 and caspase-3 are G93A activated sequentially in the spinal cords of the SOD1 mice.78,79 The activation of caspase 3 appears to invoke a Disease Defective Locus Reference pathway of programmed cell death that implicates mitochondria, Protein with increased expression of BAX, release of cytochrome c and Lower Motor Neurons 80,81,82 activation of caspase 9. As noted above, there is a direct inter- Spinal Muscular Atrophy Survival Motor 5q11 .2-13.3 [144] action of SOD1 with bcl2; when SOD1 is mutated, this produces Neuron aggregates of both proteins that may acceleration activation of GM2 Gangliosidoses apoptotic events.63,65 It is striking that the formation of aggregates Tay-Sachs disease Hex A deficiency 15q23-24 [214] of SOD1 in mitochondria is specific to mitochondria isolated from (alpha-subunit) spinal cord.63,83 Sandhoff disease Hex A+B deficiency 5q11 .2-13.6 [214] (beta-subunit) The prediction from these observations that inhibition of cas- pases might slow the MND has been tested in some experi- AB variant GM2 activator 5q [215] ments. Inactivation of caspase 1 slightly prolongs survival in protein ALS mice bearing the glycine 93 to alanine mutation.84 By the Scapuloperoneal muscular atrophy ? [187, 189] same token, over-expression of the anti-apoptotic protein bcl-2 Progressive juvenile bulbar paralysis ? [181] 85 slows the onset of the disease in these mice. Moreover, infu- Fazio-Londe sion of tetra-peptide pan-caspase inhibitors into the spinal fluid Arthrogryposis 9 [184] of ALS mice prolongs survival by about 25%.78 Analogous, treat- ment with minocycline is also beneficial.86 These findings are of X-linked rather general interest in understanding cell death in neurode- Spinal muscular atrophy Xp generative disorders, as activation of caspase-1 and elevation of Spino-bulbar Il-1 ß levels have also been detected in the brains of patients with muscular atrophy Androgen receptor Xq11 [160] Huntington’s disease.87 Arthrogryposis Xp11-q11 [185] Scapuloperoneal muscular atrophy X [189] 10 Genetics and Biology of Amyotrophic Lateral Sclerosis AANEM Course some individuals with SALS95; in two larger studies, these muta- 96,97 Table 3 Inherited disorders of the upper motor neuron including tions were not detected in SALS or FALS. Moreover, these mu- the hereditary spastic paraplegias tations do not clearly co-migrate with the disease trait in large ALS pedigrees showing a dominant inheritance pattern, suggesting that the mutations may define risk factors for the disease. In the same Disease Locus Defective Protein Selected Features Reference vein, a single patient has been detected with SALS and a mutation Dominant in a glycosylation site of EAAT298; it is now clear that this mutation SPG3 14q GTPase (atlastin) 9% of HSP [216] results in reduced surface expression and reduced glutamate trans- SPG4 2p Spastin 42% of HSP 1ST decade [174] port by EAAT2.99 As well, several patients have been identified SPG6 15q NIPA1 Adult [217] with variants in the targeting sequence of the mitochondrial form SPG8 8q Adult of SOD (manganese SOD or SOD2).100 SPG9 10q SPG10 12q KIF5A Childhood [218] SPG12 12q APPROACHES TO TREATMENT OF ALS 19q SPG13 2q HSPD1 HSP + amyotrophy Adult [219] SPG17 11q BSCL2 Silver Syn [220] Regrettably, there is no therapy that substantially augments survival SPG18 101,102 in ALS. Riluzole, which is believed to act primarily but not SPG19 9q exclusively through inhibition of glutamate, has repeatedly been Recessive documented to prolong survival in ALS by approximately 10-15% or so.103 The availability of mouse and now cell-based models SPG1 Xq LI-CAM Infantile [178] SPG2 Xq Proteolipid protein Infantile [177] for cytotoxicity by mutant SOD1 protein should accelerate the SPG5 8q search for effective therapies. An extensive series of compounds SPG7 16 Paraplegin 1ST decade [221] and manipulations have proven statistically, if not biologically sig- SPG11 15q Most AR HSP nificant in extending the lifespan of the ALS mice. A partial list SPG14 3q now includes the following categories of compounds: anti-oxidants SPG15 14q 2ND decadend (Vitamin E104, buckminsterfullerine105, lyophilized red wine106, SPG20 13q Spartin [222] gingseng root107); copper chelating agents (d-penicillamine108, SPG21 15q Maspardin trientine, and ascorbate109); anti-glutamate compounds (riluzole, SPG23 1q gabapentin104), and agents that augment cellular energy production SPG24 13q (coenzyme Q10110, creatine111). SPG25 6q SPG26 12p SPG27 10q Beneficial genetic approaches to ameliorating the disease in mice have SPG28 14q included over- expression of the major astroglial glutamate trans- AMN Xq ABCD1 1ST, 2NDdecade [179] porter, EAAT2, and forced expression of two compounds that inhibit 85 84 apoptosis: bcl-2 and a dominant negative inhibitor of caspase-1. 2B KIF5A = kinesin heavy chain; 5A L1CAM = L1 cell adhesion molecule; AMN = As noted above, infusion of tetra-peptide inhibitors of caspases also adrenomyeloneuropathy; BSCL2 = Bernadelli-Seip congen lipodystrophy; NIPA1 = 78 slowed the course of the disease in the mice. Particularly exciting Non-imprinted Pradi-Willi/Angelman locus 1; SPG = spastic gait has been the observation that activity of the enzyme cyclooxygenase-2 is elevated in spinal cords of ALS patients and in ALS mice.112 This NF-H should reduce axon NF burden (and axonal caliber) without has a direct implication for therapy, as potent cyclooxygenase inhibi- causing NF accumulations in the cell body. If it is the NF aggre- tors are already in widespread use in such disorders as arthritis. The gates that protect the G37R mice, then these mice should have the observation that the cyclooxygenase inhibition can slow the course of typical, shorter survival of the unmanipulated G37R mice. On MND in ALS mice 113 led to a multi-center human trial of this drug the other hand, if the critical factor is the diminution in axonal in ALS which unfortunately showed not benefit. NF burden, these mice should have enhanced survival. When this painstaking experiment was completed, it favored the former Several genetic manipulations that alter levels of expression of view. The resulting mice had no accumulation of NF protein in subunits of neurofilaments in the motor nerve axons have also the motor neuron cell body, and they showed no prolongation in had significant impacts on the survival of the transgenic ALS survival.116 Confounding this interpretation are recent studies mice. For example, expression of high levels of the heavy neuro- demonstrating that elimination of the heavily phosphorylated tails filament subunit, NF-H, increases the lifespan of the G37R mice of both NF-M and NF-H in the SOD1 does prolong survival, by approximately 65%.114 Analogously, blocking expression of again without accumulations of NF in the cell bodies.117 This any axonal neurofilament subunits by knocking out the light NF recent result underscores the possibility that some aspect of NF subunit also prolongs survival.115 This apparent paradox may be burden within the axon, related to the phosphorylated tails, does resolved by the observation that in both of these strains of mice adversely impact the disease, perhaps by slowing axonal transport. there is accumulation of neurofilament aggregates within the soma Elimination of the tails is established to enhance transport and of the motor neuron. The prediction of this finding is that genetic presumably thereby augment motor neuron viability. The aggre- manipulations that stoichiometrically reduce NF-L, NF-M, and gated NF protein in the cell body might partially rescue the ALS AANEM Course Motor Neuron Disease 11 phenotype is not clear, although studies in progress suggest the a survival of several decades. This “juvenile ALS” appears to be accumulated proteins may act as a sink or buffer for one or more recessively inherited. Most affected individuals have limb atrophy, adverse substances.117 reflecting both disuse and some degree of denervation. In two small families, the disease is predominantly due to degeneration of Still other strategies for treating the ALS mice have been the corticospinal and corticobulbar tracts; these features have sug- attempted. Gene therapy has been attempted with cautiously gested this disorder should be designated juvenile primary lateral encouraging results. Two groups have shown a modest benefit sclerosis. In some families, this disorder is mapped to chromosome from administration of the neurotrophic factor, GDNF. When 2q33131,132; in others the disorder maps to chromosome 15q.133 myoblasts transduced with GDNF ex vivo are implanted in the The 2q33 locus has now been fully cloned; several candidate genes ALS mice, a modest but statistically significant benefit resulted.118 within it have been identified.132 Recently, the gene defect in Intramuscular, segmental administration of GDNF via adenoviral these families has been attributed to mutations in gene encoding a vectors also produced a modest survival benefit in the ALS mice.119 protein with domains that show homology to guanine nucleotide Most striking in the gene therapy studies is the observation that in- exchange factors.134,135 This gene is therefore believed to regulate tramuscular injection of adeno-associated virus expressing insulin- activity of one or more GTPases. Mutations of this protein are like growth factor I (AAV-IGF) substantially prolongs survival of uncommon in routine series of ALS cases; in an initial study, there the SOD1 mice, presumably a G9 3A consequence of retrograde was no association between polymorphic haplotypes in this gene transport of the virus and enhanced expression of IGF1 in motor and sporadic ALS.136 The most common phenotype associated neurons.120 Cell therapy has been proposed as the only therapeutic with alsin mutations is slowly progressive, infantile or juvenile approach that will allow reconstitution of the motor neuron pool. onset spastic paraplegia.137 Mouse models of alsin deficiency have While the translation of this approach into practical therapy is not now bee reported, with evidence of subtle central nervous system close at hand, several developments suggest this concept has merit. neurodegeneration.138,139 Recently, rare cases with predominant Motor neuron stem cells have now been isolated121 and shown to be corticospinal features (resembling hereditary spastic paraparesis) capable of forming functional neuromuscular junctions with skel- have been associated with mutations in the gene encoding target etal muscle122; moreover, data now indicate that implanted motor neuronal esterase.140 neurons can send axonal processes out from an injured spinal cord to make functional neuromuscular synapses, provided that signals that inhibit axonal sprouting are blocked123. Others have proposed DISORDERS OF THE MOWER MOTOR NEURON that stem cells derived from umbilical cord cells may also be thera- Spinal Muscular Atrophy peutic in ALS.124,125

The most dramatic benefit in the ALS mice to date has been The spinal muscular atrophies (SMAs) are characterized by pro- the use of methods to inactivate the mutant SOD1 gene and gressive death of lower motor neurons in the brainstem and spinal prevent expression of the mutant SOD1 protein. Initial studies cord. SMA is inherited as an autosomal recessive trait. Type I demonstrated that mutant SOD1 toxicity can be ameliorated in SMA (Werdnig-Hoffmann disease) begins very early (and may be vitro using inhibitory RNA.126 It was recently reported that early evident in utero as diminished fetal movement in the weeks prior to intramuscular administration (day 7) of inhibitory RNA, also birth). Werdnig-Hoffmann infants are weak, floppy, and suck and directed against SOD1, prolonged the life of the SOD1 mice to cry quite feebly. They never develop enough strength to sit up and more than 200 days, compared G9 3A with the expected death at they rarely survive beyond 2 years. SMA I is relatively common, approximately130 days.127 Efforts are now underway to translate affecting up to 1/20,000 babies. The carrier frequency for SMA this for the treatment of human SOD1-mediated ALS as rapidly I is 1/80.141 Type II SMA begins clinically prior to 18 months (and safely) as possible. By the same token, anti-sense oligo- of age but is associated with long-term survival. Unlike SMA I nucleotides administered intrathecally are also beneficial in rodent patients, those with SMA II can sit but they cannot stand or walk. models of mutant SOD1-mediated ALS and are being advanced to Patients with SMA III, which begins after 18 months, are able to clinical trials.128 walk. In late-onset SMA (Kugelberg-Welander disease), weak- ness may be more evident proximally than distally; often the legs Dominantly Inherited, Juvenile-onset ALS are more severely involved than the arms. The hallmark of SMA microscopically is lower motor neurons cell death. Genetically, A large family with a slowly evolving disorder of both upper and all forms of SMA are linked to chromosome 5.142,143 The critical lower motor neurons has recently been mapped to a single a large gene appears to be a novel protein of 294 amino acids designated pedigree with this disease to chromosome 9.129 The causative gene “survival motor neuron” or SMN.144 The locus encoding SMN and generates a protein, senataxin, that functions as a helicase and is neural apoptosis inhibitory protein (NAIP) is complex; it is dupli- implicated in DNA metabolism, functioning as a helicase.130 cated such that there are at least two copies SMN (telomeric or centromeric) These copies differ only in that one exon (exon 7) is Recessively Inherited, Juvenile-onset ALS spliced out of the centromeric copy. SMN has been localized both to the nucleus and cytoplasm in cells in vitro.145 Its function is not In recessively inherited juvenile ALS, there is very slowly progres- entirely clear although several elegant studies have documented that sive degeneration of both upper and lower motor neurons and it complexes with several ribonuclear proteins in spliceosomes and 12 Genetics and Biology of Amyotrophic Lateral Sclerosis AANEM Course may be important in the shuttling of RNA between the nucleus be a pivotal element in the pathogenesis of the disease; forced and cytoplasm.146,147,148 The fundamental defect in SMA may expression of CRB can correct the neurotoxicity of the expanded involve berrant splicing and trafficking of messenger RNA species. androgen receptor glutamine repeat domain.165 The availability of The telomeric copy of SMN is deleted in 98% of SMA patients. transgenic mice with expanded androgen receptor polyglutamine In the remaining 2% or so, it has undergone gene conversion such tract should facilitate studies of pathogenesis and therapy of that it has the sequence of the centromeric copy of the protein.149 X-SBMA.166 The severity of SMA is probably modified by several factors includ- ing the overall level of expressed SMN150, the number of intact copies of SMN151 and the presence or absence oft neighboring DISORDERS OF THE UPPER MOTOR NEURON genes that are commonly deleted with SMN. These include an Primary Lateral Sclerosis anti-apoptotic protein (NAIP)152 and a second protein even more closely associated with SMN designated 4F5.153 Recently, three mouse models of SMA have been developed. Two entail dual Primary lateral sclerosis (PLS) is a disorder that selectively targets genetic manipulations: (1) knocking out the single native SMN the upper motor neuron. It usually occurs as a sporadic disease. Its gene in mice (a change that, by itself, is lethal because mice have main clinical feature is slowly progressive weakness without atrophy only one copy of SMN), and (2) expressing a transgenic copy of but with marked limb spasticity. Laboratory studies (electromyo- the human centromeric SMN gene.154,155 The third involves a graphy, muscle biopsies) do not detect denervation of muscles. motor-neuron specific deletion of exon 7 from the endogenous While long-term survival is reported in PLS, the disease may run SMN gene.155,156 The phenotype of the resulting animals rather its course aggressively with 3 or 4 year survival from onset to death. closely resembles SMA. At autopsy there is loss of pyramidal cells in the motor cortex with corresponding degeneration of the corticospinal and corticobulbar Adult-onset Tay Sach’s Disease projections. Early PLS raises the diagnostic possibility of multiple sclerosis or other demyelinating diseases, although these diagnoses Infrequently, patients with GM2 gangliosidosis develop a slowly are usually clarified over time. progressive motor neuropathy157 characterized by life-long motor clumsiness and later development of frank proximal muscle weak- Hereditary Familial Spastic Paraplegia ness. These individuals may also manifest some upper motor neuron signs, cerebellar features and behavioral features such as Hereditary familial spastic paraplegia (HSP) is an autosomal an altered attention span or even psychotic episodes.158 Bulbar dominant trait with a clinical picture marked by spastic weakness features such as dysphagia and some dysarthria may become ap- beginning in the distal legs. The crucial neuropathological abnor- parent. The critical defect in Tay-Sach’s disease is an accumula- mality is corticospinal tract degeneration that is more pronounced tion of GM2 ganglioside that develops because of deficiency caudally.167,168 In “complicated” HSP progressive spasticity is ac- of activity of the proteins that metabolize GM2 ganglioside: companied by findings not confined to the corticospinal tract. N-acetyl-hexosaminidase A and B. These dimeric enzymes These include amyotrophy, mental retardation, optic atrophy, and consist of an alpha and a beta subunit (hexosaminidase A), or two sensory neuropathy; the corresponding pathology is not confined beta subunits (hexosaminidase B). Each dimer is complexed with to the corticospinal tracts. In the more common, “uncomplicated” a third protein, GM2 activator, which modulates the activity of form, HSP is purely a corticospinal disease. Fortunately, genetic both enzymes. studies are now illuminating some of these clinical distinctions. Multiple loci for HSP are known (Table 1). An early onset pedigree X-linked Spinal Bulbar Muscular Atrophy with spastic gait, relatively little weakness, and a very slow disease course, it maps to chromosome 14q.169 A large family with un- X-linked spinal bulbar muscular atrophy (X-SBMA) is a slowly complicated HSP has also been linked to chromosome 15q.170 progressive, familial motor neuropathy that is affects only males.159 This family has a more variable age of onset and a more aggressive In addition to motor weakness, there may be subtle gynecomastia course than the 14q family.171 Both early and late onset families and testicular atrophy, as well as low-grade sensory findings. The map to a third HSP locus on chromosome 2p.172,173 The defective molecular defect in X-SBMA is an expansion of a CAG repeat gene at this locus has recently by identified and termed “spastin”; in exon 1 of the androgen receptor gene.160 This produces an this protein may play a role in the metabolism of nucleoproteins.174 expanded polyglutamine tract within the receptor. In general, Other HSP genes are noted in Table 1. A recent summary esti- the longer the tract of repeated CAGs, the more seere the mated that uncomplicated HSP is distributed among these loci illness.161, 162 The mechanism of neurotoxicity of the CAG’s as follows: 2p 45%, 14q 6%, 15q 3%, other 45%.175 It is clear is not known, although recent data suggest that the expanded that there is extensive genetic heterogeneity in dominantly inher- polyglutamine tract may aggregate to form nuclear inclusions ited, uncomplicated HSP. Moreover, other HSP loci remain to in these CAG-expansion diseases.163 In neurons in cell culture, be identified. expanded polyglutamine tracts induce apoptosis through activa- tion of a specific cell death gene, caspase 8.164 Data now suggest There are early onset forms of recessively inherited HSP. One that in X-SBMA and other CAG repeat diseases, accumulation of locus, on chromosome 16, has been found to encode a novel gene, CREB-binding protein (CRB) in the intranuclear aggregates may “paraplegin,” whose gene product is believed to function within mi- AANEM Course Motor Neuron Disease 13 tochondria and to have homology to a yeast ATPase. A locus for with an increased rate of progression.200 The foregoing possible uncomplicated, recessive HSP has been reported on chromosome risk factors were selected because of their obvious importance as 8q.176 X-linked recessive forms are also reported. One is caused determinants of motor neuron viability. Presumably, it will also be by mutations in the gene encoding proteolipid protein (PLP). It informative to study variants in genes that are important in coping is intriguing that other mutations within this gene cause the more with environmental toxins. Although the field of environmental fulminant Pelizaeus-Merzbacher disease.177 Another type of com- genetics or genotoxicology, is nascent, the concept has recently plicated, infantile-onset HSP is caused by mutations in the gene been applied to ALS; the observation that blood and bone levels of encoding the adhesion molecule L1CAM.178 Finally, there are rare lead are increased in a cohort of ALS patients201 is being elucidated cases of adult-onset, X-linked HSP-like disorders that are allelic through the analysis of polymorphisms in serum proteins that forms of adrenoleukodystrophy.179 bind lead. Along these lines, it is also of potential interest that there have been several recent papers incriminating variants in par- Miscellaneous oxonase, an esterase enzyme that detoxifies exogenous toxins such as sarin, as ALS risk factors, although the findings do not cleanly Other inherited MNDs are recognized. Some affect only the cross validate one another.202,203,204,205 Vascular endothelial growth motor system; others are complex, multi-system degenerations. factor (VEGF) has been proposed to be another risk factor in ALS. Fazio-Londe disease (progressive juvenile bulbar palsy) is a bulbar This hypothesis was generated by the observation that mice that motor neuronopathy that begins before the third year.180,181 The have mutations in the VEGF gene promoter that reduce sensitiv- arthrogryposes are a complex set of disorders with contractures at ity to hypoxia develop a slowly progressive motor neuropathy. A birth from motor neuron cell loss. These may be either sporadic large consortium of European ALS centers tested this hypothesis or inherited as autosomal recessive182, autosomal dominant183,184, by studying single nucleotide polymorphisms (SNP) in the VEGF or X-linked185 traits. In the scapuloperoneal muscular atrophies gene in ALS patients. This group concluded that ALS patients there is neuropathic weakness in the shoulders muscles and in the homozygous for a specific VEGF haplotype defined by three SNPs peroneal groups. This disease also shows considerable diversity had nearly a two-fold higher risk of developing ALS, and that this with dominantly inherited (mid-life onset186 and early-onset187,188 correlated with lower circulating levels of VEGF.206 The study also and possible X-linked forms.189 documented that reduction in gene dose of VEGF was a risk factor for increased disease severity in G93A ALS mice.206 ALS Risk Factors: A Bridge Between Inherited and Sporadic ALS Finally, a potentially fruitful avenue to identification of susceptibil- ity variants in SALS has been the application of unbiased, whole While most cases of ALS are not familial, it remains plausible that genome analyses. Briefly, this approach asks whether commonly many individuals with SALS may have heightened susceptibility to occurring genetic variants, which are normally occurring poly- factors such as environmental insults and the consequences of aging morphisms, are statistically over- or under-represented in ALS as that challenge and ultimately disrupt motor neuron function and compared to controls. To date three such initial studies have iden- viability. Many such putative ALS risk factors have been consid- tified some potential candidate ALS-associated variants; while these ered. The status of polymorphisms in ApoE has been investigated have not cross-confirmed one another, efforts now underway to because the ApoE4 allele confers a distinct risk for early onset in complete meta-analyses of these studies to provide enough genetic Alzheimer’s disease. 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Neurophysiology of Amyotrophic Lateral Sclerosis

Eric J. Sorenson, MD Associate Professor Department of Neurology Mayo Clinic Rochester, Minnesota

INTRODUCTION capacity to identify atypical features suggestive of an alternative diagnosis, and in some instances, may provide prognostic informa- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenera- tion. Currently, there are novel neurophysiology techniques under tive disorder that results in progressive weakness and death in the investigation. majority afflicted. The disease has an annual incidence rate of approximately 2 cases per 100,000 person-years38 with a median CONFIRMING THE DIAGNOSIS survival of approximately 2 years from diagnosis.36 The effects of ALS are devastating for the patients and their caregivers. The ALS typically begins as a focal disorder in one of the limbs or clinical manifestations of the disease result from the pathological bulbar muscles that generalizes with time. The findings on nerve loss of the large cortical motor neurons (MNs) and the anterior conduction studies (NCSs) and needle electromyography (EMG) horn cells of the spinal cord. are reflective of this. Abnormalities on NCSs and needle EMG examination are largely driven by the loss of the spinal cord ante- This pattern of neuronal loss gives a characteristic clinical pre- rior horn cells. Abnormalities noted on NCSs in ALS are limited sentation. The classical findings of upper motor neuronal loss to the motor NCSs. One recent study noted that when compared include: hyperreflexia and the Babinski response, spasticity, and to control subjects, sensory nerve action potentials (SNAPs) are 16 slowness of movements. The findings of lower motor neuronal relatively reduced, particularly in the younger age groups. Rarely loss include weakness, atrophy, and fasciculations. These findings does this manifest itself clinically, and in nearly all cases, the SNAPs typically present in a focal, asymmetrical pattern which generalize remain normal in absolute terms. over time. Most commonly, onset occurs in one limb or the bulbar muscles.25,38 Progressive findings in the absence of pain, sensory Early in the course, ALS may have little effect on the motor NCSs. loss, or other neurological dysfunction are highly suggestive of Unless the loss of the anterior horn cells is particularly rapid, ALS. In most cases, the presentation is so characteristic that one there is compensatory reinnervation of the denervated muscle may question the need for additional diagnostic testing. Given the fibers and the compound muscle action potential (CMAP) will prognosis of ALS, ancillary testing is advisable to increase diag- remain preserved. With progressive or rapid loss of the anterior nostic certainty. Because of its poor prognosis, clinicians are often horn cells, reinnervation cannot compensate, and the number of reluctant to discuss ALS with the patients and family members denervated muscle fibers begins to increase. As the denervation until they are confident of the diagnosis. to the muscle increases, the CMAP will diminish proportion- ally. Because the distal latency and the conduction velocity is With the exception of genetic testing in familial forms of measured from the onset of the CMAP, these two parameters are ALS, there is currently no single test that is diagnostic of ALS. reflective of the fastest conducting motor neurons (MNs). As Neurophysiology testing remains a cornerstone in the evaluation the fastest MNs succumb, there may be a modest slowing of the of ALS, and serves a number of functions. In the proper setting, CMAP distal latency and conduction velocity measurements. F electrodiagnostic (EDX) testing will confirm a diagnosis, it has the waves remain generally unaffected and are not altered beyond 20 Neurophysiology of Amyotrophic Lateral Sclerosis AANEM Course the minimal change incurred, due to the modest slowing of the are the most widely accepted criteria for the diagnosis of ALS.3 conduction velocity and distal latency. If the CMAP amplitude The El Escorial criteria is named after the city in Spain that drops substantially, then one may fail to elicit an F wave when hosted the consensus conference of ALS investigators who were stimulating that MN. trying to standardize patient populations entered into ALS clinical research. This was believed to be necessary because the histori- The findings on needle EMG depend upon the stage of the illness. cal criteria, established by Dr. Edward H. Lambert in the 1950s, Classically, long duration, high amplitude motor unit action poten- were believed to be too stringent.21 The El Escorial criteria have tials (MUAPs) are identified with increased complexity and poor subsequently become the standard by which the diagnosis of ALS stability along with fibrillation and fasciculation potentials in affected is made. muscles. Recently, one group of investigators has shown that in the transgenic SOD mice, there is a dying back process of the nerve The El Escorial criteria allow for a level of diagnostic certainty terminals prior to the death of the anterior horn cell.31 This work ranging from suspected ALS to definite ALS (Table 1). The clas- concurs with the earliest needle EMG findings of reduced motor sification system is based upon the presence of progressive upper unit (MU) stability, occurring at a time when other MU changes MN findings (clinically) and lower MN findings (clinically or are not appreciable.8 With reinnervation following the dying back electrophysiologically) in four body regions: bulbar, cervical, tho- of the terminal branches, this early MUAP instability is followed racic, and lumbosacral. If upper MN findings and lower MN by an increased fiber density, as measured by single-fiber EMG.7 findings are present (in more than one myotome) in three or These two changes, MUAP instability, and increased fiber density, more of the body regions, the illness is classified as definite. ALS may occur at a time when other classical changes in the MUAPs are is probable if the findings are in two regions, and ALS is possible if not appreciated. the findings are in one region. Suspected ALS includes only lower MN findings regionally. Fasciculations are highly prevalent in ALS. While not universal, it is rare to see a patient that has no fasciculations clinically or Table 1 El Escorial diagnostic criteria electrophysiologically. Fasciculations, however, are not specific to ALS. They can occur in any of the MN diseases and in fact, occur in nearly all normal individuals from time to time. There Suspected Pure lower motor neuron syndrome is, however, a strong association between fasciculations and ALS. The generator for fasciculations remains debated with Possible Upper motor neuron and lower motor evidence for both central and peripheral derivation.19,20 There neuron findings concurrently in is increasing evidence of mitochondrial dysfunction in ALS.17 one region* The mitochondria play an important role in buffering systems or for excessive calcium and moderating the apoptotic balance, Lower motor neuron findings in one both thought to be relevant to the pathogenesis of ALS. The region rostral to upper motor neuron mitochondria also play the central role in energy balance of the findings in another region* metabolically demanding MNs. It has been shown that one Probable Upper motor neuron findings in at least of the earliest abnormalities in the transgenic SOD mice is an one region* rostral to lower motor neuron impairment in the oxidative respiratory chain of the MN’s mito- findings in two regions* 12 chondria which leads to energy failure within the cell. Because Classified as Probable - laboratory maintaining the resting membrane potentials below threshold is supported if the lower motor neuron adenosine triphosphate (ATP) dependent, it is likely that at times findings are identified by needle of reduced ATP availability, the resting membrane potential may EMG only be subject to drift. This drifting membrane potential may reach Definite Upper motor neuron findings and lower threshold and randomly trigger an action potential, leading to motor neuron findings in at least a fasciculation. three regions*

Fasciculations can be detected a number of ways clinically and electrophysiologically. Neurophysiology methods include surface *Regions include: bulbar, cervical, thoracic, and lumbosacral segments and intramuscular needle EMG recordings. The method which EMG = electromyography has the highest sensitivity and specificity for fasciculations remains debated.26 EXCLUDING MIMIC DISEASES El Escorial Diagnostic Criteria Neurophysiology testing can be valuable in identifying mimickers Because ALS is a diffuse disorder, it is anticipated that abnor- of ALS. These conditions range from motor predominate neuropa- malities will be identified diffusely on needle EMG. However, thies to myopathic disorders to non-ALS MN diseases. For each of how widespread must the findings be before concluding that the these, NCSs and needle EMG examination may provide invaluable process is diffuse? Currently, the El Escorial diagnostic criteria clues as to the correct diagnosis. AANEM Course Motor Neuron Disease 21

Neuropathic Disorders spinal muscular atrophy). Hirayama’s disease is a rare disorder with the literature limited to isolated case reports and small case Motor predominate neuropathies may be mistaken for ALS. series. It is thought to be a focal disorder of the lower cervi- Similarities include focal weakness, atrophy, and fasciculations. A cal cord which may or may not be related to epidural venous notable difference includes the absence of upper MN features. A congestion or intermittent cervical cord trauma from repeated typical presentation of multifocal motor neuropathy may bear a strik- flexion and extension injury.7 The disease typically presents in ing resemblance to ALS. This disorder has a predilection to affect young, athletic men and is unilaterally or markedly asymmetri- the radial motor nerve.35 An asymmetrical lower MN presentation cally in the distal upper extremity.18 There are no specific EDX favoring the radial nerve distribution should result in a physician features for Hiryama’s disease. While some have reported ab- considering this disorder. Motor predominate neuropallnes can normalities on somatosensory evoked potentials, this has not be be diagnosed by NCSs if the conduction block is identified in an confirmed independently.27,29 affected motor nerve. When considering this disorder, stimula- tion of the ulnar and radial motor nerves (two nerves commonly Chronic inflammatory demyelinating polyradiculoneuropathy affected by this disorder) should be extended proximally with (CIDP) typically presents as a motor predominate, symmetrical stimulation of the plexus at Erb’s point. Stimulation of the C8 root, ascending disorder that would not ordinarily be mistaken for through a monopolar cathode needle, can also be performed. By ALS. There are, however, rare focal manifestations of CIDP doing so, evidence of conduction block may be identified in these with only segmental slowing or conduction block. NCSs may proximal segments (Figure 1). be helpful in localizing these disorders (Figure 2). In contrast to ALS, these focal forms of CIDP are not diffuse and the findings Stimulation at these proximal sites is technically more diffi- are restricted to the distribution of the lesion. If successfully lo- cult. It must be accepted that while increasing sensitivity, some calized, imaging of the affected area may also lead to the correct false positive studies will also occur. Due to this risk,physicians diagnosis (Figure 3). should pay particular attention to technique and thoroughly troubleshoot any abnormalities encountered. It should be noted that not all cases of multifocal motor neuropathy will have an identifiable conduction block.13 Antiganglioside antibodies also have a low sensitivity. In the absence of an identifiable conduc- tion block or a high titer of anti-ganglioside antibodies, it may be difficult to distinguish this disorder from another ALS mimic syndrome, Hirayama’s monomelic MN disease (a.k.a. segmental

Figure 2 Prolonged tibial motor F wave with a latency of 71.5 ms (F estimate was 56 ms) indicative of marked proximal slowing. Magnetic resonance imaging scan of the lumbosacral plexus from this case is seen in Figure 3.

Myopathic Disorders

While in most cases, myopathic disorders and neurogenic disorders can be easily distinguished by needle EMG, inclusion body myositis (IBM) is an exception. Needle EMG testing in IBM may be misleading with mixed patterns of large and small MUAPs.4 As a result, IBM is commonly mistaken for ALS.9 Despite this, there is little evidence of an actual neurogenic component to IBM.24 Helpful clinical features differentiating IBM from ALS include the absence of fasciculations and upper MN findings in IBM, and the relative symmetry of IBM. IBM Figure 1 Ulnar motor conduction study in multifocal motor neuropathy usually demonstrates a characteristic distribution of weakness demonstrating conduction block between stimulation at Erb’s point (fourth with early weakness of the quadriceps and deep finger flexors, tracing) and the upper arm (third tracing). in particular.1,5 22 Neurophysiology of Amyotrophic Lateral Sclerosis AANEM Course

PROGNOSIS

Information gained from NCSs and needle EMG examinations may be helpful in providing prognostic information for those with ALS. It has been convincingly shown that the level of di- agnostic certainty by the El Escorial criteria at presentation is in- versely proportional to overall survival.39 The prognosis for those subjects meeting three affected regions at presentation is poor when compared to those with one or two affected regions. The use of needle EMG to delineate affected and unaffected regions is important in assisting with this prognostication.

Figure 3 Magnetic resonance imaging flair sequence demonstrat- ing increased T2 signal and mass effect arising within the lumbosacral plexus. This mass did not enhance and proved to be an inflammatory reaction to a focal inflammatory demyelinating neuropathy.

Non-ALS Motor Neuron Diseases

Spinal and bulbar muscular atrophy (SBMA or Kennedy’s disease) is a distinct spinal muscular atrophy arising from a trinucleotide repeat within the androgen receptor protein located on the Figure 4 Median sensory nerve action potential from a patient with 27 X-chromosome. SBMA commonly presents with progressive X-linked spinal and bulbar muscular atrophy (Kennedy’s disease). weakness, atrophy, and fasciculations in a distribution similar to ALS, including prominent bulbar weakness. Helpful clinical features to distinguish SBMA from ALS include the absence of upper MN features and the presence of endocrine abnormalities Motor Unit Number Estimation including gynecomastia and testicular atrophy. An X-linked in- heritance pattern may be suggestive as well if this can be obtained. Motor unit number estimation (MUNE) is a term applied Because the endocrine abnormalities are variably present, genetic to a number of techniques used to estimate the number testing of men with only lower MN involvement is advisable. of MUs that have innervated a muscle or muscle group Sensory NCSs may be helpful in distinguishing SBMA from ALS. including: incremental technique, multi-point stimulation SBMA does not affect the anterior horn cells exclusively and there technique, F-wave technique, and the statistical method (Figure is an associated sensory neuronopathy. This is often apparent on 5). Each of these offers advantages and has limitations. Common NCSs by identifying reduced amplitude SNAPs (Figure 4).28,40 to all of the techniques is the determination of the size of the The long-term prognosis of spinal and bulbar muscular atrophy average single MU potential (SMUP). Once derived, the am- is only modestly diminished when compared to normal age plitude of the average SMUP is divided into the supramaximal matched control30 subjects, and offers a prognosis that is much CMAP amplitude, resulting in a unitless number representing better than ALS. the number of MUs innervating that muscle or muscle group. For obvious reasons, the ability to quantitate the number of MUs The spinal muscular atrophies (SMA) are a heterogenous is attractive in studying MN diseases. It has been shown that group of genetic disorders affecting the anterior horn cells the rate of decline in the MUNE values correlates with the rate of the spinal cord. The most common forms are the proxi- of disease progression and may be useful in prognostication.30,33 mal SMAs that are associated with deletions within the The rate of decline in the MUNE value has also been used as survival MN gene on chromosome 5.23 These typically present an outcome measure in ALS clinical trials.32,34 The utility of with symmetrical proximal weakness in childhood or young MUNE in routine clinical practice remains debated and this adulthood, and in their classical presentations are rarely confused technique has not become a routine standard of care in most with ALS. EDX laboratories. AANEM Course Motor Neuron Disease 23

accepted diagnostic criteria for ALS. Neurophysiology testing may also provide important clues pointing towards an alternative diag- nosis. The EDX physician should examine each patient carefully looking for clinical evidence of the mimicking syndromes. The patients should be examined for evidence of motor conduction block suggestive of multifocal motor neuropathy; abnormal SNAP amplitudes in a male may suggest X-linked SBMA; a needle EMG with mixed large and SMUPs may suggest a diagnosis of IBM. The neurophysiology community awaits further confirmation of the value of the newly described techniques and whether or not they will emerge into routine clinical practice.

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13. Delmont E, Azulay JP, Giorgi R, Attarian S, Verschueren A, Uzenot 28. Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic fea- D, Pouget J. Multifocal motor neuropathy with and without conduc- tures of X-linked recessive bulbospinal neuronopathy.[see comment]. tion block: a single entity?[see comment]. Neurology 2006;67(4):592- Neurology 1991;41(6):823-828. 596. 29. Restuccia D, Rubino M, Valeriani M, Mirabella M, Sabatelli M, Tonali 14. Dinca-Avarvarei L, Patrignani-Ochoa JH, Castilla-Garrido JM, P. Cervical cord dysfunction during neck flexion in Hirayama’s Jimenez-Castellano Ballesteros R, Ugarte-Monasterio J. [Single fibre disease. Neurology 2003;60(12):1980-1983. electromyography in 18 patients with amyotrophic lateral sclerosis]. 30. Sartucci F, Maritato P, Moscato G, Orlandi G, Calabrese R, Domenici Revista de Neurologia 2005;40(3):141-144. GL, Murri L. Motor unit number estimation (mune) as a quantitative 15. Esper GJ, Shiffman CA, Aaron R, Lee KS, Rutkove SB. 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Lambert EH, Mulder DW. Electromyographic studies in amyo- cal trial. Muscle & Nerve 2004;30(4):463-469. trophic lateral sclerosis. Proceedings of the Staff Meetings of the 35. Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: Mayo Clinic 1957;32(17):441-446. the diagnostic spectrum and response to treatment. Neurology 22. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. 2007;69(17):1680-1687. Androgen receptor gene mutations in X-linked spinal and bulbar 36. Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ. Amyotrophic muscular atrophy. Nature 1991;352(6330):77-79 lateral sclerosis in Olmsted County, Minnesota, 1925 to 1998.[see 23. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, comment]. Neurology 2002;59(2):280-282. Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. Identification 37. Stalberg E. Electrophysiological studies of reinnervation in ALS. and characterization of a spinal muscular atrophy-determining gene. 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Clinical Trials in Anterior Horn Cell Disease: What Have We Learned?

Jeremy M. Shefner, MD, PhD

Professor and Chair Department of Neurology SUNY Upstate Medical University Syracuse, New York

INTRODUCTION possible SMA treatments is facilitated by the fact that a single gene mutation accounts for the vast majority of cases of SMA. However, “Amyotrophic lateral sclerosis (ALS) is a predominantly idiopathic, other aspects of the disease make planning experimental trials rapidly progressive, and universally fatal neurodegenerative disorder perhaps even more challenging than for ALS. with no known cure or effective disease modifying treatment.” This sentence, or a close approximation of it, is the first sentence of at Given the many potential therapeutic agents for these rare motor least 12 clinical trial protocols that have been initiated in the last neuron diseases, it is crucial that studies are performed in an decade. One could reasonably conclude from this statement that efficient and effective manner. A well-designed trial can speed there has been little progress in ALS research during this time; time to approval of a drug, and identify efficacy with the however, just the opposite is true. In recent years, much has been minimum number of patients exposed for the shortest possible learned about pathogenic mechanisms of ALS. Mitochondrial time. In contrast, a poorly designed trial can fail to show an effect dysfunction, neurofilament damage, glutamate toxicity, protein of an effective drug, can mistakenly suggest efficacy when there misfolding, and microglial activation are all mechanisms for which is no effect, can lead to patient distress and harm, or may simply there is compelling and increasing experimental support. For each delay time to approval. proposed mechanism, pharmacological manipulation is possible. Targeted drug discovery programs can lead to new compounds, and This manuscript discusses several aspects of clinical trial design reevaluation of existing drugs may suggest therapeutic possibilities that can contribute to more effective and timely clinical investiga- that may be immediately tested. Recently, a collaborative effort tion in the coming years. It also reviews recent and upcoming trials jointly funded by the National Institute of Neurological Disorders testing therapies to alter pathways that may contribute to motor and Stroke (NINDS) and the ALS Association tested more than neuron degeneration. 1000 available compounds in 29 different assays to determine activity against a variety of different aspects of neurodegenera- tion.20 Although a full description of this effort has not yet been CLINICAL TRIALS: STRUCTURAL ISSUES published, individual laboratories have further investigated drugs Drug Dose identified by this screening program, with the first of these (ceftri- axone) entering clinical trials in 2006. At this writing, there are at least 10 different compounds either in human trials or about to be Decisions regarding the dose range to be used both in preclinical tested in humans. and clinical studies are extremely important and often underem- phasized. Poor dose choices have led to problems in many previ- Equally vigorous investigation is occurring into the pathophysiol- ously published ALS trials. Dose-finding studies should start at the ogy and potential treatment of the most common pediatric motor bench; in preclinical assays, drug activity should be assessed from neuron disease, spinal muscular atrophy (SMA). Research into a no-effect level to a point at which the drug causes clear toxic- 26 Clinical Trials in Anterior Horn Cell Disease: What Have We Learned? AANEM Course ity. While drug concentrations achieved in vitro do not directly muscles and nutritional status, changes in muscle strength do not correlate to dose in either in vivo disease models or human trials, strongly predict survival.46 they do provide target tissue concentrations to which initial dosing studies should be aimed. Animal models should be used to establish Respiratory failure is the primary cause of death in ALS. Assessing maximum tolerated dose; disease-related activity must be assessed the measurements of respiratory muscle function has obvious in models that match the disease itself to the greatest extent pos- clinical relevance. Vital capacity (VC), maximal inspiratory sible. In ALS, the most commonly used model is the SOD1 trans- pressure, and expiratory mouth pressure are the methods most genic mouse 19; recently several mouse models of SMA have also commonly used. Vital capacity declines with time in patients been described.5,28,34 with ALS and is a sensitive measure of disease progression. Both the baseline VC and the rate of decline in VC are predictive of For many agents that have reached human trials, full-dose explora- survival.31,43,47 tion has not been performed on animal models.13,25,40 This may have led to clinical investigation pursuing a range of doses not optimized Functional rating scales that assess the activities of daily living for clinical effect. In a recently reported investigation of lithium in (ADL) have intuitive meaning, and can be performed without ALS models,15 the effect of lithium on motor neuron cell cultures costly equipment, sometimes even by telephone. The scale was markedly beneficial at one concentration, but had the opposite most widely accepted is the ALS Functional Rating scale effect at a concentration two-fold higher. Inadequate preclinical dose (ALSFRS).6 The ALSFRS has been revised and is now called ranging studies may have led to clinical trials that failed to show the ALSFRS-R. The ALSFRS-R is employed as a primary efficacy because of dose levels that were too low (creatine41 and cele- outcome measure in most ALS trials that do not employ sur- coxib11), or too high (topiramate10 and minocycline16). vival as the primary endpoint. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores Choice of Outcome Measures correlated with change in strength over time, as measured by MVIC,17 was closely associated with quality-of-life measures, There are currently no tissue based biomarkers able to determine and predicted survival.6,7,9,31 With appropriate training the drug activity in ALS. Thus, clinical assessment of efficacy is based ALSFRS-R can be administered with high interrater reliability and on measurement of a variety of aspects of disease. The gold stan- test-retest reliability. dard outcome for ALS trials currently remains survival. There are several reasons, however, why other measures are being sought, and None of the measures described above are perfect outcome mea- why many current trials use outcomes other than survival. First, sures; they are limited by inherent variability of measurement survival can be manipulated by many interventions that do not and do not directly reflect underlying disease processes. The ideal modify underlying disease course. Good nutrition and early use outcome measure would be a biomarker that could be easily col- of percutaneous endoscopic gastrostomy clearly prolong life.23,35,45 lected, changed as a function of a clearly important pathophysiolog- Respiratory support with noninvasive positive pressure ventilation ical decline, and was sensitive to disease modification. Physiological has been less studied, but likely also prolongs life.18,21,30,42 To the assessments such as motor unit number estimates have the potential extent that these therapies are not employed equally in treatment of achieving greater sensitivity than current measures. The search groups in a clinical trial, extraneous variability and potential con- for a fluid biomarker that reflected disease activity is under- founding may occur. In addition, the use of survival as an endpoint way2,26,38,39; the availability of such a marker could drastically alter mandates large trials that treat patients for long time periods. clinical trials in ALS. Unless patients are chosen late in the disease course, survival at one year ranges from 82% to 91% in recent studies.10,11 Thus, very Trial Design few patients will experience the event being measured. To show an 80% chance of seeing a 25% difference in mortality rate requires Phase I clinical trial design is fairly standard, and will not be dis- approximately 600 patients studied over 18 months (Schoenfeld cussed in this manuscript. Similarly, the goals of a phase III trial 2007, personal communication). Thus, there is a pressing need for require a structure that is rigidly defined. The goal of phase III more sensitive measures that may show effects in fewer patients and is to demonstrate efficacy of the therapeutic agent under study. shorter treatment periods. Issues related to trial size and duration are related to the outcome measure chosen as the primary endpoint. For survival, as previously As increasing weakness is a critical symptom of ALS, assessment noted, approximately 600 patients in 2 groups must be followed of muscle strength has clear clinical relevance. There are a variety for 18 months to have an 80% chance of detecting a true differ- of methods available to measure muscle strength. Both quantita- ence in survival rate of 25%. If multiple doses are to be studied, tive (maximum voluntary isometric contraction [MVIC]) and the required sample size would increase accordingly, requiring qualitative (Medical Research Council muscle grading) measures approximately 900 patients to be studied in 3 groups, and so on. have been employed in past trials; with careful training, both are Clearly, studies requiring this sample size are expensive, and limit sensitive indicators of disease change. Strength testing has been the number of agents that can be concurrently studied. For these validated against other measures of disease progression.10,16,32,33 reasons, the alternate endpoints of muscle strength and ALSFRS-R However, as survival primarily reflects function in respiratory have been employed. Sample size calculations depend on the rate and variability of decline for these measures; for both strength and AANEM Course Motor Neuron Disease 27

ALSFRS-R, power analyses show that 150-200 patients per group were felt possibly relevant to ALS. The compound class with the must be studied for 9-12 months to have an 80% chance of seeing highest number of “hits” were beta lactam antibiotics; ceftriaxone a 25% difference in the rate of decline of either measure. was chosen for further study because of its know ability to pen- etrate the blood brain barrier. Subsequent studies showed that In phase II trials, alternative trial designs may play an important ceftriaxone prolonged life in the transgenic SOD1 mouse model role, as the goal is to search for a suggestion of efficacy that can of ALS. It also protected against glutamate mediated toxicity in be more definitively tested in a phase III trial. One possible ap- a spinal cord slice model, most likely by increasing gene activ- proach is to apply a futility design.36,37 Rather than stating that ity for the glial glutamate transport protein EAAT2.40 A three the goal of the study is to show evidence of efficacy, the purpose phase, adaptive design clinical trial of ceftriaxone was initiated of a futility study is to determine whether it is worthwhile going in October 2006, with the first two phases devoted to obtaining forward. There are some outcomes of a small study that would halt safety and pharmacokinetic data on two dose levels of IV ceftriax- further investigation; for example, if all treated patients did worse one. The third phase was designed to assess efficacy of ceftriaxone on all measures than all placebo patients. Such results would be in 600 participants with ALS studied an average of 18 months. a demonstration of futility. Futility designs invert the traditional The long duration and large sample size are due to the fact that null hypothesis; the null hypothesis in a futility study is that it is survival was chosen as the primary outcome measure; multiple nonfutile to go forward. If the null hypothesis is rejected, futility other measures of strength and function are included so that, is proved. Demonstration of nonfutility requires far fewer subjects should the drug prove efficacious, the relative sensitivity of other than demonstration of efficacy; however, depending on the measure measures can be compared. used, nonfutility may be demonstrated even when two comparison groups are identical. R+Pramipexole

Adaptive designs are another approach to study design. In this R+pramipexole is a close relative to the dopamine agonist method, findings in the initial portion of a study are used to alter pramipexole, which is prescribed as symptomatic treatment for subsequent data collection. The design may or may not involve patients with Parkinson’s disease and restless legs syndrome. a placebo group, but compares several groups that may either The R+ enantiomer, however, has virtually no dopaminergic be given different doses of the same drug, or different drugs activity, and has been shown to have neuroprotective properties over a defined time period. At some point in the study, the best as well as positive effects on mitochondrial stability.48 A small performing group is declared the “winner” and the remainder of open label trial showed that R+pramipexole was well tolerated the study is then performed using that drug or dose and compar- in patients with ALS.48 A phase II study more fully evaluating ing it to placebo patients that have been accrued throughout. the safety of this drug is now underway, with efficacy studies The algorithm for determining the winner may be based on an being planned. efficacy signal, safety data, or drug concentration in the blood, cerebrospinal fluid, or brain. Adaptive trial designs are currently Arimoclomol being employed in clinical trials of ceftriaxone and coenzyme Q in ALS.29 In patients with SOD1 mutations and familial ALS, abnormal SOD1 structure leads to protein aggregates that can cause cell Other options for study design include the use of historical damage. There is increasing evidence that oxidation of wildtype controls rather than a placebo group in phase II studies.12 For SOD1 may lead to misfolding and act as a toxic substrate.22 this approach to be useful, the natural history of the rate of Heat shock proteins are molecular chaperones that help to reduce change of the outcome measure chosen must be well studied, protein aggregates. Protein aggregates are slightly increased in ALS. and shown to not significantly change over time or from study Arimoclomol is a heat shock protein co-inducer that penetrates to study. This requirement is clearly not met for survival studies, the blood brain barrier, is well-tolerated in humans, and which as the 1 year survival of ALS patients participating in studies has a dramatic effect on life span and motor neuron survival in from 1994-2007 has varied greatly.10,11,27 However, both MVIC the SOD1 transgenic mouse model.24 Based on these findings, a and ALSFRS-R have been quite stable over time. In a phase II phase II study of arimoclomol in ALS is currently underway in the study of coenzyme Q, rates of decline in pulmonary function United States and Canada. and ALSFRS-R closely matched that of a placebo group from a previous study.14 Talampanel

Talampanel is a noncompetitive alpha-amino-3-hydroxy-5-methyl- CURRENT AND UPCOMING TRIALS 4-isoxazolepropionate (AMPA) antagonist that has shown efficacy Ceftriaxone as an anticonvulsant in humans, and is neuroprotective in a number of animal models.1,8 It was used in a small human trial in 1999, in which 40 patients taking 50 mg 3 times daily were compared to 20 Interest in ceftriaxone in ALS originated from an NINDS spon- placebo patients. Despite the small size of the trial, most outcome sored drug screen that evaluated over 1000 available compounds measures trended positively, and ALSFRS-R neared statistical sig- on 29 different assays related to neurodegeneration, 8 of which nificance. The fact that riluzole, the only effective treatment for 28 Clinical Trials in Anterior Horn Cell Disease: What Have We Learned? AANEM Course

ALS, also likely exerts its effect on the AMPA pathway also suggests protein as well. Valproate, a histone deacetylase (HDAC) inhibitor, that other drugs affecting this pathway may be of benefit. For this has been shown to double the lifespan of mice with a severe SMA reason, a phase III trial of talampanel in ALS is in preparation in phenotype.28 Other HDAC inhibitors include hydroxyurea and the United States and Europe. sodium phenylbutyrate. All three drugs have been the subjects of small clinical trials. Lithium

In February 2007, investigators from Italy published a study of the SUMMARY effects of lithium in the SOD1 mouse model of ALS. The study showed that lithium prolonged both disease onset and survival.15 As more is learned about the pathophysiology of motor neuron dis- They attributed this result to lithium’s effect on promoting au- eases, the clinical trial sophistication must also increase to allow the tophagy, which may be an early step in the reduction of protein rapid and effective evaluation of many different agents. The drugs aggregates. They also reported the results of a small, unblended currently being evaluated may lead to more effective therapies; it is human trial, comparing 16 patients taking lithium and riluzole clear, however, that understanding of the mechanisms involved in over 15 months, to 28 patients taking riluzole only. There were motor neuron disease is increasing dramatically. Combined with no reported deaths in the lithium and riluzole treated group, while advances in trial design, the hope for better therapy for this devas- 29% of patients died in the riluzole only group. All other outcome tating class of disease is likely to be realized in the near future. measures, including ALSFRS and VC, declined markedly more slowly in the lithium group. REFERENCES Despite the obvious flaws in the human study, the magnitude of the reported effect was striking. For this reason, phase III random- 1. Belayev L, Alonso OF, Liu Y, Chappell AS, Zhao W, Ginsberg MD, ized trial of the lithium/riluzole trial in ALS is about to start. A Busto R. Talampanel, a novel noncompetitive AMPA antagonist, is nonblinded trial of 100 patients is already underway. neuroprotective after traumatic brain injury in rats. J Neurotrauma 2001;18:1031-1038. Other Agents 2. Bowser R, Cudkowicz M, Kaddurah-Daouk R. Biomarkers for amy- otrophic lateral sclerosis. Expert Rev Mol Diagn 2006;6:387-398. There are many other potentially interesting treatment pos- 3. Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve sibilities being evaluated either in clinical or preclinical settings. 2002;25:445-447. These include pharmaceutical approaches (coenzyme Q, glatiramer 4. Bromberg MB, Swoboda KJ, Lawson VH. Counting motor units in acetate, insulin-like growth factor 1, and others) as well as targeted chronic motor neuropathies. Exp Neurol 2003;184 Suppl 1:S53-57. therapy to reduce mutant proteins through ribonucleic acid inter- 5. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phe- ference or antisense oligonucleotides. notype in the SMNDelta7 mouse model of spinal muscular atrophy. Neurobiol Dis 2007;27:207-219. 6. Cedarbaum J. The amyotrophic lateral sclerosis functional rating scale THOUGHTS ON SMA (ALSFRS). Arch Neurol 1996;53:141-147. 7. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, SMA is the most common motor neuron disease of childhood. As Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale opposed to ALS, which is of unkown etiology in the vast majority that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13-21. of patients, SMA is universally caused by homozygous deletion of 8. Chappell AS, Sander JW, Brodie MJ, Chadwick D, Lledo A, Zhang the SMN1 gene, and phenotypically modified by the copy number D, Bjerke J, Kiesler GM, Arroyo S. A crossover, add-on trial of of the SMN2 gene. In concept, this known genetic lesion should talampanel in patients with refractory partial seizures. Neurology help with the design of medications to ameliorate or reverse dis- 2002;58:1680-1682. ability. In practice, however, SMA clinical research is hampered 9. Clarke S, Hickey A, O'Boyle C, Hardiman O. Assessing indi- by two problems. 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A randomized, placebo-controlled trial of disease involving predominantly static loss of motor neurons, this topiramate in amyotrophic lateral sclerosis. Neurology 2003;61:456- is a very high threshold to reach. 464. 11. Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson Medications that have shown promise in animal models act to KI, Rothstein JD, Drachman DB. Trial of celecoxib in amyotrophic increase the expression of the SMN2 gene, which produces a lateral sclerosis. Ann Neurol 2006;60:22-31. truncated form of the SMN protein, but also some full length AANEM Course Motor Neuron Disease 29

12. Czaplinski A, Haverkamp LJ, Yen AA, Simpson EP, Lai EC, Appel 28. Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert SH. The value of database controls in pilot or futility studies in ALS. DD, Gavrilina TO, Xing L, Bassell GJ, Burghes AH. SMNDelta7, the Neurology 2006;67:1827-1832. major product of the centromeric survival motor neuron (SMN2) 13. Drachman DB, Frank K, Dykes-Hoberg M, Teismann P, Almer G, gene, extends survival in mice with spinal muscular atrophy and as- Przedborski S, Rothstein JD. Cyclooxygenase 2 inhibition protects sociates with full-length SMN. Hum Mol Genet 2005;14:845-857. motor neurons and prolongs survival in a transgenic mouse model 29. Levy G, Kaufmann P, Buchsbaum R, Montes J, Barsdorf A, Arbing of ALS. Ann Neurol 2002;52:771-778. R, Battista V, Zhou X, Mitsumoto H, Levin B, Thompson JL. A two- 14. Ferrante KL, Shefner J, Zhang H, Betensky R, O'Brien M, Yu H, stage design for a phase II clinical trial of coenzyme Q10 in ALS. 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Proc Natl Acad Sci U S A randomized trial of gabapentin in patients with amyotrophic lateral 2008;105:2052-2057. sclerosis. Neurology 2001;56:843-848. 16. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, 33. Miller RG, Petajan JH, Bryan WW, Armon C, Barohn RJ, Goodpasture Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto JC, Hoagland RJ, Parry GJ, Ross MA, Stromatt SC. A placebo-con- H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack trolled trial of recombinant human ciliary neurotrophic (rhCNTF) RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R. Efficacy of factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. minocycline in patients with amyotrophic lateral sclerosis: a phase III Ann Neurol 1996;39:256-260. randomised trial. Lancet Neurol 2007;6:1045-1053. 34. Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi 17. Group A-CTS. A double-blind placebo-controlled clinical trial Y, Tanaka F, Doyu M, Inukai A, Sobue G. Sodium butyrate amelio- of subcutaneous recombinant human ciliary neurotophic factor rates phenotypic expression in a transgenic mouse model of spinal (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996;46:1244- and bulbar muscular atrophy. Hum Mol Genet 2004;13:1183-1192. 1249. 35. Mitsumoto H, Davidson M, Moore D, Gad N, Brandis M, Ringel 18. Gruis KL, Brown DL, Lisabeth LD, Zebarah VA, Chervin RD, S, Rosenfeld J, Shefner JM, Strong MJ, Sufit R, Anderson FA. Feldman EL. Longitudinal assessment of noninvasive positive Percutaneous endoscopic gastrostomy (PEG) in patients with ALS pressure ventilation adjustments in ALS patients. J Neurol Sci and bulbar dysfunction. Amyotroph Lateral Scler Other Motor 2006;247:59-63. Neuron Disord 2003;4:177-185. 19. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander 36. Palesch YY, Tilley BC. An efficient multi-stage, single-arm Phase DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor II futility design for ALS. Amyotroph Lateral Scler Other Motor neuron degeneration in mice that express a human Cu,Zn superoxide Neuron Disord 2004;5 Suppl 1:55-56. dismutase mutation [see comments] [published erratum appears in 37. Palesch YY, Tilley BC, Sackett DL, Johnston KC, Woolson R. Science 1995;269:149]. Science 1994;264:1772-1775. Applying a phase II futility study design to therapeutic stroke trials. 20. Heemskerk J. High throughput drug screening. Amyotroph Lateral Stroke 2005;36:2410-2414. Scler Other Motor Neuron Disord 2004;5 Suppl 1:19-21. 38. Ranganathan S, Nicholl GC, Henry S, Lutka F, Sathanoori R, 21. Heiman-Patterson TD, Miller RG. NIPPV: a treatment for ALS Lacomis D, Bowser R. Comparative proteomic profiling of cere- whose time has come. Neurology 2006;67:736-737. brospinal fluid between living and post mortem ALS and control 22. Kabashi E, Valdmanis PN, Dion P, Rouleau GA. Oxidized/mis- subjects. Amyotroph Lateral Scler 2007;8:1-7. folded superoxide dismutase-1: the cause of all amyotrophic lateral 39. Ranganathan S, Williams E, Ganchev P, Gopalakrishnan V, Lacomis sclerosis? Ann Neurol 2007;62:553-559. D, Urbinelli L, Newhall K, Cudkowicz ME, Brown RH, Jr., Bowser 23. Kasarskis EJ, Scarlata D, Hill R, Fuller C, Stambler N, Cedarbaum R. Proteomic profiling of cerebrospinal fluid identifies biomarkers JM. A retrospective study of percutaneous endoscopic gastrostomy for amyotrophic lateral sclerosis. J Neurochem 2005;95:1461-1471. in ALS patients during the BDNF and CNTF trials. J Neurol Sci 40. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles 1999;169:118-125. DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn 24. Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuro- Greensmith L. Treatment with arimoclomol, a coinducer of heat protection by increasing glutamate transporter expression. Nature shock proteins, delays disease progression in ALS mice. Nat Med 2005;433:73-77. 2004;10:402-405. 41. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton 25. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, M, Urbinelli L, Qureshi M, Zhang H, Pestronk A, Caress J, Donofrio Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal P, Sorenson E, Bradley W, Lomen-Hoerth C, Pioro E, Rezania K, MF. Neuroprotective effects of creatine in a transgenic animal model Ross M, Pascuzzi R, Heiman-Patterson T, Tandan R, Mitsumoto H, of amyotrophic lateral sclerosis. Nat Med 1999;5:347-350. Rothstein J, Smith-Palmer T, MacDonald D, Burke D. A clinical trial 26. Kolarcik C, Bowser R. Plasma and cerebrospinal fluid-based protein of creatine in ALS. Neurology 2004;63:1656-1661. biomarkers for motor neuron disease. Mol Diagn Ther 2006;10:281- 42. 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43. Stambler N, Charatan M, Cedarbaum JM. Prognostic indicators of 46. Traynor B, Zhang H, Shefner J, Schoenfeld D, Cudkowicz survival in ALS. ALS CNTF Treatment Study Group. Neurology M. Functional outcome measures as clinical trial endpoints in 1998;50:66-72. Amyotrophic Lateral Sclerosis. Neurology 2004;63:1933-1935. 44. Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna 47. Varrato J, Siderowf A, Damiano P, Gregory S, Feinberg D, McCluskey SP, Bromberg MB. Natural history of denervation in SMA: relation L. Postural change of forced vital capacity predicts some respiratory to age, SMN2 copy number, and function. Ann Neurol 2005;57:704- symptoms in ALS. Neurology 2001;57:357-359. 712. 48. Wang H, Larriviere KS, Keller KE, Ware KA, Burns TM, Conaway 45. Thornton FJ, Fotheringham T, Alexander M, Hardiman O, McGrath MA, Lacomis D, Pattee GL, Phillips LH, 2nd, Solenski NJ, Zivkovic FP, Lee MJ. Amyotrophic lateral sclerosis: enteral nutrition provision— SA, Bennett JP, Jr. R+ pramipexole as a mitochondrially focused neu- endoscopic or radiologic gastrostomy? Radiology 2002;224:713-717. roprotectant: initial early phase studies in ALS. Amyotroph Lateral Scler 2008;9:50-58. 31

Rehabilitation of Amyotrophic Lateral Sclerosis

Lisa S. Krivickas, MD Director of Electrodiagnostic Medicine Spaulding Rehabilitation Hospital Associate Chief of PM&R Massachusetts General Hospital Associate Professor of PM&R Associate Chair of Academic Affairs Harvard Medical School

INTRODUCTION to predict how quickly the patient’s disease will progress so that the Despite the explosion of research interest in amyotrophic lateral team may stay ahead of the disease process. sclerosis (ALS) and the numerous clinical trials that have been conducted over the last decade, clinicians treating ALS still have Rehabilitation and symptom management in ALS may be ap- only one Food and Drug Administration approved drug, riluzole, proached in a problem-oriented manner. Rehabilitation problems which marginally slows disease progression. At the present time, ag- addressed below include the role of exercise in patients with ALS, gressive rehabilitation and symptom management, which includes the management of muscle weakness resulting in mobility and management of respiratory failure and dysphagia, can prolong activity of daily living (ADL) difficulties, and communication dif- life and improve the quality of life for the patient with ALS to a ficulties. Musculoskeletal pain syndromes and spasticity also are greater extent than any currently available pharmacologic interven- discussed because of their direct impact on the ability to exercise, tions.1,4,11,21,25,28,29 As researchers develop additional drugs that maintain mobility, and perform ADLs. These problems are best slow disease progression in ALS, life expectancy will increase, and handled by a multidisciplinary team which may consist of some rehabilitation will become even more important. or all of the following individuals: physiatrist, neurologist, physi- cal therapist, occupational therapist, speech therapist, nutrition- “Rehabilitation is the process of helping a person to reach the fullest ist, respiratory therapist, orthotist, social worker, and nurse. Two physical, psychological, social, vocational, avocational, and educational recent studies from the Netherlands and Ireland have shown that potential consistent with his or her physiological or anatomic impair- ALS patients cared for in a multidisciplinary clinic have a better ment, environmental limitations, and desires and life plans. Realistic quality of life, longer survival, and are more likely to use riluzole goals are determined by the person and those concerned with his care. and noninvasive positive pressure ventilation. They are also more Thus, one is working to obtain optimal function despite residual dis- likely to have the appropriate equipment and assistive devices to ability, even if the impairment is caused by a pathological process that meet their needs.32,33 cannot be reversed.”10 Rehabilitation is necessary during all stages of ALS. As the disease In ALS, the pathological process cannot be reversed and is pro- progresses, however, rehabilitation strategies and needs change. Most gressive. Comprehensive ALS care should include rehabilitation therapies will be discontinuous. For example, a patient with early that restores the patient to a level of optimal functioning in his or ALS may be referred to a physical therapist for help designing an ap- her normal societal environment and achieves the optimal quality propriate aerobic exercise and strengthening program. As increasing of life possible throughout the course of the disease. For patients spasticity develops, the patient may return to physical therapy for with ALS, rehabilitation is a fluid process because of their rapidly sessions on stretching and range of motion exercises. If a foot drop changing physical status. Consequently, rehabilitation is more develops and the patient is prescribed an ankle foot orthosis (AFO), challenging for these patients than it is for patients with static he or she may again return for gait training with the new brace. As functional deficits produced by events such as stroke or spinal cord weakness increases, additional physical therapy may be necessary to injury. One of the most difficult tasks for the rehabilitation team is teach the caregiver how to effectively transfer the patient. 32 Rehabilitation of Amyotrophic Lateral Sclerosis AANEM Course

Insurance carriers typically deny coverage of continuous physical, ness and muscle damage do not occur in muscles with greater than occupational, or speech therapy to patients with ALS because they or equal to 3/5 strength on the MRC scale, and strength gains can consider it maintenance therapy with no “improvements” expected. be achieved, although they are not as great as they would be in Healthcare providers need to educate insurers to stop this faulty subjects without a neuromuscular disorder. In general, the strength reasoning. ALS is not a static disease. As function declines, patients gain is proportional to the initial muscle strength, suggesting that develop the need for new treatment interventions, and additional a strengthening program should be initiated as early as possible therapy is often required. In addition, therapy is sometimes re- in the course of the disease. High-resistance eccentric exercise quired in order for the patient to maintain function or to slow should be avoided as it may produce muscle damage. The ability decline in function. to extrapolate these findings to patients with ALS needs to be demonstrated in well controlled randomized trials. Furthermore, no studies of strength training in neuromuscular patients have EXERCISE demonstrated translation of the modest strength gains achieved into improved function in ADL or slowing of the overall course of Rehabilitation should begin early in the course of ALS so that it the disease. may be used to prevent or delay the onset of disability. This concept is known as “prehabilitation” because it is a preventive form of re- For patients with ALS, the recommendation is to begin a habilitation. One important method of prehabilitation is exercise. strengthening program as soon as possible after diagnosis. The There are three types of exercise that are important for all individu- objective of such a program is to maximize the strength of unaf- als, whether or not they have ALS; flexibility or stretching exercises, fected or mildly affected muscles in an attempt to delay the time strengthening or resistance exercises, and aerobic exercise. at which function becomes impaired. For example, if an elderly patient must use 90% of the strength of his or her leg muscles Flexibility training involves stretching and range of motion to rise from a chair before developing ALS, he or she will be (ROM) exercises. While there is a paucity of scientific literature unable to arise from a chair after losing only 10% of his or her on the role of flexibility training in patients with ALS, it is widely motor units. If another individual requires only 50% of his or accepted that this form of exercise helps prevent the develop- her maximal leg strength to arise from a chair before developing ment of painful contractures and nonpharmacologically decreases ALS, even if the disease progresses at the same pace as in the previ- spasticity and aborts painful muscle spasms. Loss of ROM can ous individual, he or she will remain independent much longer. result in a painful adhesive capsulitis and even complex regional Weight training or strengthening exercise should be performed pain syndrome.9 with a weight that the individual can lift 20 times; this is a simple way for the patient to select a weight that provides low to moder- In the past, some physicians have been reluctant to recommend ate resistance. The patient should then perform two or three sets strengthening exercises due to a fear that overuse weakness would of 10 repetitions. This guideline will prevent overworking the occur and thus, accelerate disability. This philosophy promotes the muscles with excessively heavy weights. Another general guideline development of disuse weakness and muscle deconditioning which is that if an exercise regimen consistently produces muscle sore- may compound the weakness produced by ALS itself. There has ness or fatigue lasting longer than one half hour after exercise, it is been only a single randomized controlled trial of resistance exercise too strenuous. in ALS.7 The study involved 6 months of training, 3 times per week, following an individualized program for muscles with greater The final form of exercise to be considered is aerobic exercise than grade 3/5 strength on the Medical Research Council (MRC) which helps maintain cardiorespiratory fitness. Drory and col- scale. Those in the training group had higher scores on the ALS leagues reported the beneficial effects of a simple, moderate home functional rating scale (FRS) and SF-36 scores at the end of the exercise program in patients with ALS.13 They randomized 25 training period, suggesting that resistance training may improve ALS patients to receive a moderate daily exercise program consist- function and quality of life. There were no significant adverse ing of gentle aerobic activity such as walking, stationary bicycling, events related to the exercise program. or swimming for 30 minutes or less, or not to perform any physi- cal activity beyond their usual daily requirements. At 3 months, Studies of patients with more slowly progressive motor neuron patients who performed regular exercise showed less deterioration disease, including spinal muscular atrophy, and other neuro- on the ALS FRS and the Ashworth scales. At 6 months, a trend muscular diseases such as muscular dystrophy, hereditary motor toward less deterioration in the treated group was observed. This and sensory neuropathies, and post-polio syndrome suggest that study showed that a regular moderate aerobic exercise program muscles that are only mildly affected by the disease process can be has a short lived positive effect on disability in ALS patients. A strengthened by a moderate resistance strengthening program.22 recent Cochrane review on therapeutic exercise for people with However, a study of high-resistance exercise in a heterogeneous ALS highlights the fact that much more research must be con- group of neuromuscular patients suggested that overuse weak- ducted to determine to what extent strengthening and aerobic ness may develop in muscles exercised eccentrically (lengthening exercise is beneficial in ALS.8 contraction) with high resistance.19 It may be concluded from strengthening studies in these diverse populations of neuromuscu- Given the lack of any apparent contraindication, aerobic exercise lar patients that with moderate resistance training, overuse weak- training is recommended for patients with ALS as long as it can AANEM Course Motor Neuron Disease 33 be performed safely without a risk of falling or injury. In addition fied to suit the individual’s walking environment and needs; for to the physical benefits, this form of exercise often has a beneficial example, they may be fitted with a basket, food tray, or forearm effect on mood, psychological well-being, appetite, and sleep. Pool trough. Walkers with wheels do not need to be lifted, so they are therapy is often an ideal place for patients with ALS to do aerobic usually recommended for patients with ALS. Some walkers come exercise, which can be as simple as walking in the water, with the equipped with brakes. Push down brakes secure a walker when water at mid-chest height. This is best performed in a therapy pool the patient loads his or her weight on the walker and are pre- with a flat, uniform depth floor that is heated to 92 to 95 degrees ferred over squeeze type brakes for patients with hand weakness. Fahrenheit. The warmth of the water will help reduce spasticity and Specialized wheeled walkers have large wheels that can move over facilitate movement. a variety of terrains.

Studies in the transgenic mouse model of ALS have suggested that Orthoses light to moderate aerobic exercise has a neuroprotective effect20,34 but heavy resistance exercise may have a deleterious effect.26 In Orthoses are devices worn on a person’s body designed to addition, there appears to be a gender and exercise interaction (1) improve function by offering support to weakened muscles whereby exercise is more beneficial to female mice. Most recently, and the joints they surround; (2) decrease the stress on compensa- Kaspar and colleagues demonstrated a marked prolongation of tory muscles; (3) minimize local or generalized muscle fatigue; (4) life in the SOD1 transgenic mouse when aerobic exercise and prevent deformity; and/or (5) conserve energy. IGF-1 delivered via gene therapy were administered synergisti- cally. Mice receiving both treatments nearly doubled their mean Many patients with ALS develop neck extensor weakness survival time.18 leading to head drop and neck pain. Several different types of collars that can support the head, protect the weakened muscles, and prevent further deformity are available. For mild to moderate MUSCLE WEAKNESS weakness a soft, foam collar is usually recommended. Soft collars are usually comfortable, well tolerated, and neck movements are Due to the progressive nature of ALS, at some point all patients limited to a certain degree. For moderate to severe weakness, a will require compensatory interventions to manage muscle semi-rigid collar is required, such as the traditional PhiladelphiaTM. weakness. In the early stages of ALS, the task or activity may be Patients find these collars uncomfortable. The HeadmasterTM, adapted in order to achieve function. As the disease progresses, in- ExecutiveTM, and CanadianTM collars have an open air design, creasing environmental adaptations will be necessary. Regardless but do not control as well for lateral instability as the Miami-JTM, of the stage of the disease, the overall goal is to maximize function AspenTM, or MalibuTM collars. In the author’s practice, it has been and promote independence to the highest degree possible using found that the Headmaster collar is well accepted by many patients the least restrictive device or piece of equipment. and is a compromise between providing maximal stability and comfort. For some patients who do not tolerate the Headmaster Mobility Aids collar, the recently described “baseball cap orthosis” provides an acceptable alternative.15 Muscle weakness, spasticity, and resultant balance problems will eventually necessitate the patient’s use of an aid to enhance mobil- An arm sling is an orthosis designed to support the proximal ity and safety. Canes provide the least amount of support and are UE when muscles are weak or if the glenohumeral joint is usually recommended in the early stages of ALS for mild lower subluxed. Slings similar to those used with patients post-stroke extremity (LE) weakness or balance problems. A cane is carried in may decrease pain, prevent soft tissue stretching, and relieve the hand opposite to the most affected leg, requires good upper tension on the neurovascular bundle. A pouch sling or single strap extremity (UE) strength, and can be used on stairs. An adjustable hemisling supports the elbow and wrist; however, these types of aluminum cane easily adapts for various heights and is lightweight. slings position the arm close to the body in adduction, internal An aluminum cane may have a curved handle or an offset handle. rotation, and elbow flexion; with prolonged use, contractures may An offset handle allows the weight to be directed over the cane tip develop. The axilla roll sling (“Bobath” sling) consists of a soft when in contact with the floor, rather than anteriorly, as is the case roll fashioned to fit under the axilla and is secured with a figure with a curved handle. Quad canes provide greater stability than of eight harness. This type of sling holds the humerus slightly straight canes, but all tips must be in contact with the ground for abducted, while supporting the shoulder joint. A humeral cuff stability. The size of the base can vary and these canes are heavier sling consists of an arm cuff on the distal humerus supported by to lift. Canes come in a variety of styles and sizes of hand grips. a figure-eight harness. Patients with hand muscle weakness may be better able to grip an enlarged or molded handle. Splints are hand orthoses that are available commercially or can be custom made. They may be static (no moving parts) or Walkers provide greater support than canes, but are more bulky dynamic (moving parts). Splinting of the wrist or hand is indi- and may be cumbersome in confined spaces. Various types of cated when improving the patient’s hand function or preventing walkers are available (e.g., folding, with or without wheels, with contractures are goals. Splints that may be beneficial for patients brakes, with seating surfaces, etc.) and some walkers can be modi- with ALS include: 34 Rehabilitation of Amyotrophic Lateral Sclerosis AANEM Course

(1) Resting Hand Splint: Patients with hand weakness may For patients with severe spasticity, anti-spasticity features can be be at risk for developing finger flexion contractures. built into the AFO. These features include a full foot plate, build- Resting splints are used to maintain muscle length. ing up the area under the metatarsal heads and the medial longitu- dinal arch, and a peroneal ridge. (2) Anti-Claw Hand Splint: Keeps the metacarpophalan- geal joints in flexion; useful for patients with intrinsic It is important to consider the weight of the orthosis; it may be muscle weakness to prevent “claw hand” deformity and to more fatiguing for the patient to ambulate with a heavy orthosis improve the ability to grasp. than to ambulate without the impairment being corrected. For this reason, knee-ankle-foot orthoses are not generally useful. (3) Volar Cock-up Splint: Supports the wrist in 20 to 30 degrees of extension and is useful for patients who have Wheelchairs and Wheelchair Accessibility wrist extensor and finger extensor weakness which pre- vents them from grasping. At some time point as the disease progresses, the extent of muscle weakness or the energy requirements for ambulation will necessitate (4) Opponens Splint: Designed to support the thumb in an that a patient use a wheelchair for mobility. In the early stage of abducted and opposed position and is useful for patients ALS, a manual wheelchair, preferably lightweight or ultra- light- with prehension difficulties due to abductor pollicis brevis weight, may be used for traveling long distances to conserve energy. and thumb extensor muscle weakness. This wheelchair should be rented on a short-term basis or borrowed from a local Amyotrophic Lateral Sclerosis Association (ALSA) or AFOs are the most common type of orthotic devices used by Muscular Dystrophy Association (MDA) chapter or other source individuals with ALS. Prefabricated AFOs may be purchased “off- because most insurance companies will only reimburse for one the-shelf,” or AFOs may be custom made. For an individual with wheelchair purchase. rapidly progressive ALS who is likely to use the orthosis for a very limited time, a pre-manufactured orthosis may suffice. However, As the disease progresses, a power wheelchair system tailored to the most AFOs are custom made. patient’s current and potential future needs should be purchased. Although power scooters may be suitable for a patient with ad- A solid AFO is usually fabricated from thermoplastic material and equate upper extremity and trunk strength in the earlier stages of is designed to provide maximum immobilization of the ankle-foot ALS, they are of limited use as the disease progresses. Most insur- complex in all three planes of movement. Knee stability can be en- ance companies will not pay for a power wheelchair if the patient hanced by setting the ankle angle in a few degrees of plantar flexion. has already been reimbursed for a scooter because the scooter is Solid AFOs are a good choice for patients who have medial and considered a power mobility device. Thus, the purchase of a scooter lateral instability of the ankle with quadriceps weakness; however, is usually not recommended. the fixed ankle position, combined with quadriceps weakness may make sit to stand transfers, and climbing stairs and inclines The optimum wheelchair to be purchased should be one that has a difficult. high back and adequate head and neck support for weakened trunk muscles, has a reclining or tilt-in-space seat that enables postural A hinged AFO incorporates an ankle joint and may be appropri- changes for resting and pain and pressure relief, and can be modi- ate for the patient with adequate knee extensor strength but mild fied to add a ventilator tray or communication device. Because of ankle dorsiflexion strength loss. A 90 degree plantar flexion stop the complex needs of patients with ALS, potential restrictive factors mechanism can be incorporated into a hinged AFO if the preven- (e.g., accessibility into and within the home, availability of acces- tion of plantar flexion is desired. Transferring from sit to stand is sible transportation, the patient’s financial resources), the expense easier with a hinged AFO than it is with a solid AFO. of a power wheelchair system (up to $30,000), and reimbursement restrictions, the type of wheelchair system to be recommended AFOs with medial and lateral trim lines placed posterior to the should carefully evaluated by the entire rehabilitation team, prefer- midline of the malleolus are known as posterior leaf spring (PLS) ably in a specialized seating clinic. AFOs. PLS braces are more flexible than solid AFOs and allow some plantar flexion to occur during heel strike. Push-off returns For patients who are wheelchair users, ramps are necessary to access the foot to neutral during swing phase, providing dorsiflexion as- the home’s entrance. Ramps need to be sturdily built, with a grade of sistance. These AFOs may be appropriate for patients with mild no more than 1 foot of height for every 12 feet of length (American spasticity and/or a slight footdrop. National Standards Institute, Inc.). Portable ramps and vertical plat- form lifts are commercially available and may be an option. Another alternative for patients with weak quadriceps and a mild foot drop is the floor reaction AFO, a carbon fiber Wheelchair and walker users need a door width of approximately Kevlar brace that wraps around the anterior aspect of the 32 inches to allow clearance for most devices, and about 3 feet of leg. This style of brace is less restrictive than a PLS and pro- space to approach a commode or to turn in a semi-circle. Offset vides the advantage of creating a moment that assists with hinges, which provide an additional 2 inches of clearance and swing knee extension. the door open clear of the door frame can be installed. AANEM Course Motor Neuron Disease 35

The bathroom is typically not adequately accessible to individuals overlays, such as alternating air pressure pads, are available to relieve in wheelchairs. If the door frame prohibits clearance of a wheel- pressure and to improve the patient’s comfort when in bed. chair, the patient may transfer to a commode with casters at the door. Equipment that enhances independent or assisted bathing and toileting includes a tub bench or seat, shower/commode chair, MUSCULOSKELETAL PAIN grab bars, and a raised toilet seat. Although the disease process in ALS does not primarily involve Chair glides and stairway lifts can be recommended for those pain pathways, there are a number of secondary painful muscu- individuals with multi level homes. These lifts are measured and loskeletal syndromes that can arise. The best management is to custom made for individual staircases and are very expensive. proactively prevent the development of these syndromes beginning Insurance companies usually do not reimburse for stairway lifts, in the early stages of the disease. but some medical supply companies offer “rent-to-own” options. In addition, local ALSA and MDA chapters may have recycled lifts. The muscle weakness, spasticity, and the progressive loss of mobility encountered in ALS places increased stress on the musculoskeletal Adaptive Devices and Equipment system, contributing to pain generation.5 As ALS advances, patients are at high risk of becoming deconditioned. Deconditioned states A large variety of adaptive devices and equipment is available to are usually associated with a decreased pain tolerance, which may help individuals with muscle weakness perform ADLs, but no one be a factor that negatively impacts quality of life. Pain may exac- type of device is suitable for every patient or for every stage of the erbate fatigue and depression which are also associated with poor disease.23 Medicare does not reimburse for the cost of many of the quality of life in ALS.17,24,31 devices, but a physician’s prescription may allow partial reimburse- ment from third party payers. Patients with ALS are at high risk for developing progressive loss of ROM, particularly in the shoulders. If left untreated, the patient will Weakness of the UEs greatly impacts the patient’s ability to carry develop a frozen shoulder (adhesive capsulitis), which can be very out ADLs. Adaptive devices that prolong independent function painful. It is especially important to maintain shoulder ROM when include utensils with built up handles, universal cuffs to hold uten- the patient can no longer actively raise his arms overhead. Loss of sils, a mobile arm support to assist with self-feeding, button hooks, ROM can result not only in a painful frozen shoulder but has also zipper pulls, a long-handled shoe horn, and modified apparel. A been reported to cause complex regional pain syndrome in ALS.9 consultation with an occupational therapist can help patients select the most useful devices. If a frozen shoulder develops, then more aggressive treatment may be indicated. This would include radiographs to make sure the joint Those individuals with LE weakness may find it difficult to get out cartilage space is intact and to exclude gross anatomic deformities of a chair. Self-powered lifting cushions, such as the Uplift Seat such as a fracture; if there is severe calcification or heterotopic os- AssistTM are relatively inexpensive, portable devices that provide sification, the physician should focus on pain management and not assistance for rising to standing, using hydropneumatics; however, expect significant gains in ROM. An intraarticular corticosteroid the patient must have adequate trunk control and standing balance injection may help reduce inflammation. Topical heat and ice, to use the device safely. Powered seat lift recliner chairs, although given alone or sequentially (contrast therapy) may help reduce pain. much more expensive, are also available for rental or purchase. If local treatment does not control the pain completely, oral pain These chairs enable a person to rise to a standing position or recline medications should be used. by activating an electric control. Because of immobility and neck and trunk muscle weakness leading Transfer boards may be used for transfers once the individual is to poor spinal support, the vast majority of ALS patients will expe- unable to stand. The patient can use the board alone if he or she rience some degree of back and neck pain. Spinal bracing may be has adequate arm strength and good sitting balance, or with the as- used to improve sitting posture and balance. Severe neck flexor and sistance of a caregiver. Other useful devices that assist with mobility extensor weakness can lead to a “floppy head” associated with severe are transfer belts and swivel cushions or seats. Transfer belts ease neck pain and tightness. This condition may be helped by a cervical the burden of the transfer for the caregiver and prevent potential orthosis as described earlier. painful traction on the patient’s upper xtremities. Swivel cushions are lightweight, cushioned seats that swivel in both directions and A number of physical and rehabilitative interventions may be used make getting in and out of a car easier to limit and help treat pain. However, there may be residual pain despite these interventions. Initially, the use of nonsteroidal anti- Individuals who have difficulty transferring, even with the assistance inflammatory drugs (NSAIDs), particularly if there is evidence of of a caregiver, will require a mechanical lift, such as The Easy PivotTM, active inflammatory process like tenosynovitis or arthritis, is helpful. the Hoyer LiftTM, or the Trans-Aid Patient LifterTM. Use of an elec- Regular dosing of acetaminophen (1000 mg every 6 hours) may be tric hospital bed will also facilitate bed mobility and transfers, both used along with an NSAID or alone if NSAIDs are not tolerated. for the patient and the caregiver. A variety of mattresses and mattress Tricyclic antidepressants and antiepileptic drugs can sometimes be 36 Rehabilitation of Amyotrophic Lateral Sclerosis AANEM Course helpful for pain, particularly if there is a neuropathic component, DYSARTHRIA AND COMMUNICATION which can occur in ALS.6 Management of speech and communication changes in ALS Narcotic medicine should be reserved for refractory pain. The medi- requires anticipation of disease progression, early and accurate cations should be given on a regular dosing schedule and titrated to provision of information to the patient, and interventions designed the point of comfort. Oral or sublingual morphine (Roxanol), 10 to to preserve and enhance existing function. While treating current dif- 30 mg every 4 hours, is also effective for comfort care and may help ficulties, the speech pathologist must prepare for further decline.23 relieve “air hunger” in the terminal stages of the disease. Intramuscular delivery route should be avoided due to muscle wasting. Fentanyl or Approximately 24% of patients with ALS present with bulbar signs morphine patches may deliver inconsistent dosing, particularly if and symptoms30 and up to 80% of patients will ultimately develop there is excessive perspiration. The main problems with narcotic bulbar signs regardless of site of onset. Patients develop changes in medication in ALS are respiratory depression and constipation, speech due to upper and/or lower MN dysfunction characterized although they can both be managed during the terminal stages. by progressive weakness and dysfunction in the lips, jaw, tongue, palate, pharynx, and larynx. Altered voice quality, slowed speak- ing rate, and changes in diadochokinetic rates are early and easily SPASTICITY identifiable signs of bulbar changes.3,35 In addition, patients are exquisitely sensitive to even subtle changes in speech function and Spasticity in ALS probably is induced both at the motor cortex will often report symptoms if they are asked about their ability to and at the spinal cord level. Spasticity can adversely affect mobility communicate in various areas of their lives. Patients may report and contribute to pain in ALS but has been poorly studied. The a change in communication effectiveness (i.e., vocal fatigue after Cochrane Neuromuscular Disease Group recently reviewed this giving a presentation) even when their speech is quite normal in the topic and was able to identify only one randomized controlled trial clinical environment, especially during the early part of the day. showing that individualized, moderate intensity walking, swim- ming, or cycling may help to reduce spasticity.2 Remarkably, no Patients experiencing early speech changes in ALS typically use other medical, surgical, or alternative treatment therapy has been compensatory speech strategies to enhance intelligibility. Use of evaluated in a randomized fashion in this patient population. adequate breath support for phrasing and over articulation often allows the patient to continue to participate in all social and com- Despite this lack of data, there are a number of drugs that effec- municative obligations. However, very early in the disease process, tively treat spasticity in ALS. The gamma-aminobutyric acid analog patients complain of fatigue. Many people note that their speech baclofen facilitates MN inhibition at spinal levels and is the agent production is clear in the morning but begins to deteriorate as the of choice. The recommended initial dose is 5 to 10 mg two to day progresses. Therefore, compensatory strategies must them- three times a day, titrating up to doses of 20 mg four times a day. selves be used judiciously and in conjunction with environmental Occasionally higher doses (up to 160 mg per day) are more effec- strategies. For an evening engagement, resting or napping in the tive, but caution is advised. Side effects include weakness, fatigue, afternoon or minimizing speaking early in the day can allow more and sedation. An intrathecal baclofen pump may be beneficial to efficient use of compensatory strategies later in the day. some patients with predominantly upper motor neuron symptoms.27 Tizanidine, an alpha-two agonist similar to clonidine, inhibits ex- Education of family members is a critical step in optimizing com- citatory interneurons and may also be helpful. Dosing range is 4 to munication. If a person close to the patient has hearing loss, refer- 8 mg three to four times a day, with a similar side effect profile to ral to an audiologist can assist in optimizing the communication baclofen. Baclofen and tizanidine can be effectively used together, as environment, as can assuring that partners are speaking face to face long as side effects, particularly increasing weakness and hypoten- in a well lit room without competing noise. sion, are monitored. Benzodiazepines may also be helpful but can cause respiratory depression and somnolence. Slow (30 second sus- For patients with diminished voice volume due to lack of breath support, tained), static muscle stretching may be helpful, particularly in the use of a simple amplification device enhances communication. more symptomatic muscle groups like the gastrocnemius, and may be performed in bed. Positional splinting is also a helpful adjunctive Patients with lower MN dysarthria may benefit from a prosthetic modality but skin must be monitored frequently for pressure areas. palatal lift. A palatal lift is an oral device that will elevate the soft palate to occlude the nasopharyngeal port and allow build up of Another option for focal spasticity that is causing positioning prob- intraoral pressure, which can significantly improve speech quality lems is botulinum toxin injections. These have not been studied in if nasality is one of the primary features of the dysarthria. Studies ALS but are effective in producing local, partial paralysis of a muscle of palatal lifts in ALS patients suggest that patients with nasality, for up to 6 months. Cooling and heating the limb are both short- but comparatively better articulation and slow disease progres- term antispasticity measures that should be performed with physical sion, are the best candidates.14,36 The ability of patients to inhibit therapy supervision to avoid thermal damage to the extremity. the gag response and tolerate the prosthesis is another key aspect to consider in fitting ALS patients with a lift. AANEM Course Motor Neuron Disease 37

Oral motor exercise or strengthening programs beyond light ROM picture or text based, and are accessible in the same ways as described exercise are not recommended for patients with ALS. Even ROM above. These devices can be mounted at the bedside or on wheelchairs. is questionably beneficial, especially since most patients continue to Planning for acquisition of a device should begin aggressively in the “range” their speech and swallowing musculature simply by its daily early stages of bulbar dysfunction because of the high cost of these use. On the other hand, ROM exercise may add to the psychologi- types of AAC devices, usually between $4000 and $6000, and because cal well being of patients who desire to be proactive in maintaining they can take several months to acquire due to the slow insurance current function and preventingfurther deterioration. approval process.

Even in the early stages of bulbar dysfunction in ALS, educa- Patients should be encouraged to seek insurance coverage to pay for tion and planning for augmentative communication is indicated. these devices. Private insurers have different policies, but tend to Alternative Augmentative Communication (AAC) describes any follow Medicare guidelines. AAC devices are currently considered mode of communication other than speech. It includes gesture, Durable Medical Equipment so they are at least partially covered by facial expression, writing, symbol or picture boards, and devices or Medicare. Shortfalls in funding can be made up via a one time $2000 computers that create digitized speech. grant from the MDA , or via local fundraising efforts. Many local chapters of the MDA and ALSA also have device loan programs. Most AAC use by patients with ALS occurs in the middle and late stages of the disease, when intelligibility is significantly impaired, but Late stage patients and their caregivers typically revert to low technol- while patients can still access specialized devices. For patients in the ogy means of communication, such as eye blinking to indicate yes or middle stage of the disease, there are two primary AAC options; low no. The most frequent use of AAC in this stage is for communication technology, which does not require computer technology for opera- of basic needs and clarifying needswith caregivers. tion, or high technology, which utilizes electronic or computerized devices. In all stages of the disease, speech-language pathologists should be aware that some patients with ALS have cognitive deficits affecting Early stage patients typically rely on unaided or low technology word fluency, working memory, and problem solving; these deficits can approaches (such as writing or indicating the first letter of a word) impact the type and complexity of AAC chosen for use by the patient. with increased reliance on high technology during the middle stage (i.e., speech generating device) and a return to low-technology communication methods during the late stage of the disease.12 SUMMARY

Even in the latest stage, when some patients have chosen perma- Rehabilitation is a critical component of care for the patient with nent mechanical ventilation, most patients continue to retain some ALS. It helps patients maintain mobility, communication, nutri- ability to communicate. Some patients utilize eye gaze or blinking tion, and independence as long as possible, despite disease progres- and infrared technology to operate AAC devices. However, the sion, and also helps to prevent the development of pain associated longer a patient is ventilated, the more likely he is to become locked with immobility. Thus, rehabilitation has the ability to significantly in, or unable to access any reliable muscle movement for commu- improve the quality of life for the patient with ALS. In the early nication purposes.16 Techniques are currently being developed that stages of ALS, an exercise program may be a useful prehabilitation will allow these patients to utilize electroencephalograpghy EEG strategy to delay the onset of disability. Once significant muscle signal to operate an AAC device, but these systems are available weakness is present, assistive mobility devices, wheelchairs, orthoses, only as part of clinical trials with extremely limited access. adaptive equipment to assist with ADL, and home modifications serve to minimize disability and help patients maintain their in- Use of high technology AAC requires subspecialized speech- dependence. Musculoskeletal pain, which is secondary to muscle language pathology intervention. There is a surfeit of devices on weakness, and spasticity may further limit function in patients the market and a specialized vocabulary; choosing a system that with ALS. Both pain and spasticity respond to a combination of is appropriate for a particular individual can be challenging. Prior physical rehabilitation techniques and pharmacologic management. exposure to and comfort with use of computers tends to influences Appropriate speech therapy interventions allow the patient to main- patients’ choices. tain communication and maximize nutritional status. The overall goal of rehabilitation is to optimize function and quality of life. One popular AAC device is the LightWRITERTM. This is a simple device that many people with basic typing skills are comfortable using. For those with impaired hand function, the device can be set ACKNOWLEDGEMENTS to scan the alphabet, and the patient can select via use of a switch. Switches are usually buttons or wands that are touch or pressure The following individuals have contributed their ideas to this manu- sensitive. They can be positioned so that any preserved muscular script through ongoing clinical and writing collaboration with me over action can activate them. the years: Gregory T. Carter, MD; Vanina DalBello-Haas, PT, PhD; Suzanne Danforth, SLP. Some of the information in this manuscript Higher level AAC technologies include use of laptop, palm, was gleaned from a chapter written in collaboration with this group of or desktop computers. These utilize programs which can either be colleagues. Thank you for your support. 38 Rehabilitation of Amyotrophic Lateral Sclerosis AANEM Course

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Treatment for Amyotrophic Lateral Sclerosis - Evidence-based Management

Robert G. Miller, MD California Pacific Medical Center San Francisco, California

It is a privilege to give the Richard K. Olney Lecture honoring a great neurologist, clinical investigator, teacher, and seasoned veteran of the battle with amyotrophic lateral sclerosis (ALS). Dr. Olney began his career as a researcher in clinical neurophysiology and neuromuscular disease. He was an extremely popular teacher and widely respected for his investigative work which gradually shifted to a strong focus on ALS. His many contributions were novel, and always relevant to clinical practice. He has openly and courageously shared his struggle with ALS, so that others would become more aware of the disease. Dr. Olney is a role model for all of us, rising to heroic proportions as he has faced this disease with grace and dignity.

INTRODUCTION fatigue, depression, and anxiety, pain, constipation, and ter- minal symptoms. The treatment options for each of these are Although amyotrophic lateral sclerosis (ALS) is incurable, it is not discussed below. untreatable. There have been significant advances in symptomatic treatment options for patients with ALS making this a treatable Muscle Cramps: Muscle cramps, the abrupt onset of forceful and disease.6 Taking the time to remove misconceptions about the painful involuntary muscle contraction of a limb muscle group, disease, educating the patient about prognosis, explaining the are very common in ALS. Proper diet, adequate hydration, and expected course of ALS, and describing various available thera- avoiding over-exertion of weakened muscles can all help the pies may be the greatest gift an ALS clinician can give a patient. patient avoid this symptom. Quinine sulfate, which was previously Locking arms with a patient to stare this disease straight in the face suggested for treating muscle cramps, has been withdrawn by the imparts courage and hope for the patient and, surprisingly, it can Food and Drug Administration due to safety concerns. There are be extremely rewarding to the clinician. no other consistently helpful medications recommended at this time. (Table 1). Alternative therapies aimed at slowing the disease process are widely utilized by patients, in fact 85% of patients are utilizing alternative Muscle fasciculations: Muscle fasciculations are present in virtu- therapies at an average cost of $350.00 per month.3 Unfortunately, ally all ALS patients and are frequently resistant to pharmacother- there is currently no evidence for efficacy of any of these regimens. apy. It is important to reassure patients that muscle fasciculations However, the physician’s role is to steer the patients away from are of no pathophysiological significance and do not require drug harmful or exploitative therapies (i.e., stem cell transplants in treatment. China), and toward those treatments which may be helpful in bat- tling ALS. Even though this exploration process can be difficult, Spasticity: Spasticity requires treatment in a minority of patients it is incredibly important to instill and preserve a sense of hope in with ALS. Pharmacotherapy is warranted when limb stiffness the patient. results in pain, impaired mobility, or difficulty in patient care. Treatment usually begins with baclofen or tizanidine.

Treating Symptoms Pseudobulbar affect: Excessive laughter or crying are common occurrences and are often disturbing for patients with pseudobul- The most common symptoms of ALS are muscle cramps, bar involvement. The combination of quinidine (60 mg/day) and muscle fasciculations, spasticity, pseudobulbar affect, urinary dextromethorphan (60 mg/day) appears to be effective but it is still urgency or frequency, sialorrhea, laryngospasm, insomnia, considered to be an investigational treatment.6 40 Treatment for ALS - Evidence-based Management AANEM Course

ties. Glycopyrrolate or amitriptyline are usually the medications of TABLE 1 Commonly used medications for symptomatic choice. Botulinium toxin injection is an option which is helpful for amyotrophoc lateral Sclerosis treatment the refractory patient. The use of focal irradiation has rarely been employed in sialorrhea treatment. For thick phlegm, guaifenesin is generally used. Symptoms Medication Muscle cramps and spasms diltiazem Laryngospasm: Laryngospasm, a sudden closure of the vocal cords, is common in patients with ALS and often precipitates gabapentin a panic reaction which aggravates the attack. Triggering factors Spasticity (stiffness of limbs) lioresal include smoke, alcohol, spicy foods, sinus drainage, and gastric tizanidine reflux. Attacks resolve spontaneously in less than 1 minute. benzodiazepines Providing reassurance for ALS patients that the attack will resolve quickly is helpful. H1 and H2 blockers may be helpful in manag- Excessive crying or laughter quinidine and dextromethorphan ing laryngospasm. tricyclic antidepressants selective serotonin reuptake Insomnia/Fatigue: As many ALS patients become depressed, inhibitors insomnia, early morning wakening, and fatigue are very common valproate symptoms. Antidepressants may help restore a nourishing sleep and reduce fatigue. lithium

Urinary urgency or frequency Oxybutynin Depression and Anxiety: Depression and anxiety affect 25% to 50% of ALS patients. Effective therapy for depression is often Excessive saliva tricyclic antidepressants extremely gratifying for the patient and physician. Selective sero- glycopyrrolate scopolamine tonin reuptake inhibitors are often used. botulinium toxin injection Thick phlegm or post nasal drip guaifenesin Pain: More than 50% of patients experience pain with increased immobility. When nonsteroidal anti-inflammatory drugs becomes nebulizer treatments ineffective, opioids should be utilized. Laryngospasm (throat closing sen- benzodiazopines sation) Constipation: Constipation is common in ALS patients. Insomnia tricyclic antidepressants zolpidem Hydration and adherence to a dietary program are important in the management of constipation. temazepam Depression/anxiety selective serotonin reuptake Terminal Symptoms: Most patients develop dyspnea, agitation, inhibitors anxiety, and air hunger in the final phase of ALS. Liberal use of venlafaxjne buproprion opioids, and benzodiazepines are considered to be the standard mirtazepine of care.

Pain nonsteroidal anti-inflammatory drugs, aspirin SLOWING DISEASE PROGRESSION narcotics ( morphine, oxycontin) Excess glutamate appears to cause excitotoxic damage to Nausea prochloperazine MNs in ALS. Riluzole inhibits the presymptomatic release Constipation stool softeners of glutamate. Four placebo controlled clinical trials have 14 laxatives shown a modest beneficial impact in ALS. In the meta- analysis of these trials, there was an increase in survival, but fiber the average was only 2 to 3 months. More recent reports of enemas patients on long-term riluzole suggest that survival may be extended further (4 to 20 months), although these were not controlled trials. Urinary urgency or frequency: When there is upper motor neuron involvement, urinary urgency and frequency is common. Riluzole is a safe and well tolerated pharmacological option that The use of oxybutynin is usually the first pharmacological inter- has few side effects, occasional patients experience of nausea and vention used to control this symptom. fatigue. More than threefold elevation of serum transaminases are rare. Due to the high cost and a perception held by many Sialorrhea: Excessive salivation and drooling are common and neuromuscular physicians that it offers little value, riluzole is used bothersome in patients with bulbar and pseudobulbar abnormali- by only 50% to 60% of patients. AANEM Course Motor Neuron Disease 41

Evidence-based Treatment The classification scheme, which is used to grade the strength of evidence, is contained in Table 2. The strength of recom- Most of the symptomatic treatment recommendations are based on mendations is described in Table 3. Because there was no class the author’s personal experience and anecdotal suggestions. Many I evidence to guide management in ALS, none of the recom- treatment strategies in medicine are based upon lessons learned in mendations could be classified as standards. However, class II training, personal opinion, or “curbside consults” with colleagues evidence was available and many of the recommendations were or experts. As a result, there is substantial variation in treatment classified as guidelines while some with lower strength evidence practices between different physicians and between tertiary care were classified as options. The guidelines focus upon five areas: centers. Evidence-based medicine provides a firm basis for deci- informing patients about the diagnosis and prognosis, treating sion making in managing patients with ALS. In the evidence-based sialorrhea and pseudobulbar affect, nutrition and percutaneous medicine process, all pertinent studies are analyzed, the evidence endoscopic gastrostomy (PEG), respiratory insufficiency, and examined, and the recommendations are formulated to guide clini- palliative care. cal decision making. The resulting systematic review is based on a statistical analysis of all available studies and differs substantially TABLE 3 Classification of recommendations from narrative reviews, which are not evidence-based.

In 1999, the American Academy of Neurology (AAN) sponsored an evidence-based review of management strategies for patients A= Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least with ALS15 to improve the standard of care of ALS patients. A two consistent Class I studies.) multi-disciplinary task force identified 5350 abstracts and 750 relevant articles that met predetermined inclusion criteria. The B= Probably effective, ineffective, or harmful for the given condition in following principles of managing patients with ALS were agreed the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.) upon: (1) Respect for patient autonomy; (2) The importance of informing patients in their cultural and psychosocial context; (3) C= Possibly effective, ineffective, or harmful for the given condition in Attention to appropriate timing for decision making, which may the specified population. (Level C rating requires at least one Class II change over time; and (4) The importance of providing the full study or two consistent Class III studies.) continuum of care from diagnosis through the terminal phase. U= Data inadequate or conflicting; given current knowledge, treatment is unproven. TABLE 2 Classification of evidence for therapeutic intervention Informing the patient: Information should be shared personally with patients and families in quiet surroundings by the attending Class I Randomized, controlled clinical trial with masked or objective outcome assessment, in a representa- physician. The cultural background of each patient should be tive population. Relevant baseline characteristics carefully considered. There are several points to share with the are presented and substantially equivalent among patient that will offer them reassurance and much needed hope. treatment groups or there is appropriate statisti- First, more than 20% of patients survive longer than 5 years, cal adjustment for differences. The following and more than 10% of patients survive more than 10 years. It is are required: a) concealed allocation; b) primary also important for them to known that symptomatic treatments outcome(s) clearly defined; c) exclusion/inclusion are available and can provide substantial help. Riluzole slows criteria clearly defined; and d) adequate accounting the disease process, and the momentum of research in this area for drop-outs (with at least 80% of enrolled subjects is accelerating. completing the study) and cross overs with numbers sufficiently low to have minimal potential for bias Nutrition: Patients with symptomatic dysphagia should be Class II Prospective matched group cohort study in a informed about PEG. Evidence suggests that patients with representative population with masked outcome PEG have prolonged survival. Indications for PEG include assessment that meets b-d above OR a randomized progressive weight loss and choking while eating. Evidence in- control LED trial in a representative population that dicates that the risk of PEG placement increases with declining lacks one criteria a-d respiratory function.15 Class III All other controlled trials (including well-defined natural history controls or patients serving as own Recommendations: PEG is indicated for patients with controls) in a representative population, where out- symptomatic dysphagia and should be placed soon after come is independently assessed, or independently derived by objective outcome measurement.* symptom onset (Guideline). For optimal safety and efficacy, PEG should be placed when vital capacity is more than 50% of Class IV Studies not meeting Class I, II or III criteria including predicted (Guideline). consensus, expert opinion or a case report.

* Objective outcome measurement: an outcome measure that is unlikely Respiratory Management: Most patients with ALS die from to be affected by an observer’s (patient, treating physician, investigator) respiratory insufficiency. When vital capacity falls to 50%, re- expectation or bias (e.g., blood tests, administrative outcome data). spiratory symptoms are often present and planning decisions 42 Treatment for ALS - Evidence-based Management AANEM Course should be made. Evidence indicates that noninvasive positive Referral to hospice in the terminal phase of ALS should be dis- pressure ventilation (NPPV) is an effective treatment for hy- cussed (Option). In addition, it is important to address advance poventilation, can prolong survival, and may improve the pa- directives well in advance of the terminal phase and reevaluate these tient’s quality of life.3 Invasive (tracheostomy) ventilation may directives with the patient at least every 6 months (Option). more effectively prolong survival, but carries a greater financial and care burden. When initiating mechanical ventilation, it is critical to determine the circumstances under which a patient UPDATING THE AAN PRACTICE PARAMETER wishes to withdraw from mechanical ventilation, as communica- tion will eventually be compromised in all patients with ALS. Recently, the AAN reviewed the ALS practice parameter. The Finally, evidence indicates that adequate treatment with opioids, authors analyzed studies from 1998 to 2007 that related to prior oxygen, and anxiolytics should be provided when withdrawing topics as well as new areas such as cognitive and behavioral impair- mechanical ventilation. ment, multidisciplinary clinics, and communication for patients with ALS. Seven Class I studies, 9 Class II studies, 48 Class III Recommendations: NPPV should be offered as an effective studies, and 25 Class IV studies in ALS were identified. The revised therapy for hypoventilation, and as a method to prolong survival report was submitted for publication. in patients with ALS (Guideline). When long-term survival is the goal, invasive ventilation should be offered and the patient TABLE 5 What to include in most end of life discussions and family should by fully informed of the burdens and benefits (Guideline). In accordance with the principle of patient au- tonomy, physicians should respect the right of the patient with General: Goals of Treatment ALS to refuse or withdraw any treatment, including mechanical Relative emphasis on life prolongation ventilation (Guideline). When withdrawing ventilation, adequate Relative emphasis on quality of life opiates and anxiolytics should be used to relieve dyspnea and anxiety (Guideline). Routine Indications Advance directives Living will TABLE 4 Triggers for end-of-life discussions Healthcare proxy Do not (attempt) resuscitation (DNR) orders Urgent Indications Imminent death Other life-sustaining therapies, such as: Talk about wanting to die Mechanical ventilation Inquiries about hospice or palliative care Feeding tube Recently hospitalized for severe progressive illness Antibiotics Severe suffering and poor prognosis Hemodialysis Palliative Care Management of pain and other symptoms Routine Indications Discussing prognosis Relief of psychological, social, spiritual and existential suffering Discussing treatment with low probability of success Creating opportunity to address unfinished business Discussing hopes and fears New recommendations include that the use of riluzole should be Physician would not be surprised if the patient died within 6 to considered to slow the disease progression (Level A).14 The use of 12 months noninvasive ventilation (NIV) should be considered in treating re- spiratory insufficiency in ALS to lengthen survival (Level B),2 and Palliative Care: All management efforts should be directed toward to improve quality of life (Level C). PEG should be considered to improving comfort and quality of life for patients with ALS. Tables stabilize weight in patients with ALS and to prolong survival (Level 4 and 5 offer suggestions to determining the appropriate time to B).16 Botulinum toxin B should be considered to treat refractory discuss end of life care and other relevant topics.17,18 sialorrhea (Level B).10 Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care Recommendations: When non-narcotic analgesics fail to manage delivery, prolong survival (Level B),7, 11, 20,21 and to enhance quality pain, opioids should be administered liberally in accordance of life (Level C). All other management strategies appear to lack with the World Health Organization guidelines (Option). For strong evidence. dyspnea in the terminal phase, opioids are used alone or with supplemental oxygen to treat dyspnea at rest in patients with The task force concluded that there are many treatments available ALS, despite the risk of respiratory depression with higher for patients with ALS that can alleviate suffering. NIV, PEG, and doses (Option). multidisciplinary clinics are the most significant and offer the best AANEM Course Motor Neuron Disease 43 evidence. Symptomatic therapies and palliative care are recognized picture of the effectiveness of different therapies and allows further as extremely important in patient management, but have been the modifications that can improve the standard of care. Additionally, subject of very little systematic investigation in ALS. More high- a comprehensive picture of ALS patients has emerged from the quality, controlled studies are needed to guide management and ALS CARE database. to assess outcomes in patients with ALS, including those with cognitive impairment.9,12,19 The ALS CARE database was established by an advisory board of leaders in the ALS community. All practicing neuromuscular phy- sicians in North America were encouraged to participate by report- IMPLEMENTING GUIDELINES AND EVALUATING ing data pertaining to the diagnosis, prognosis, and treatment of OUTCOMES IN ALS patients with ALS. Patients and caregivers provided demographics, rated their quality of life, and supplied other disease-specific mea- Publication of evidence-based guidelines is often not enough to sures. Data was collected at the time of patient enrollment and at change physician behavior. Some physicians are not aware of the follow-up intervals of 3 to 6 months. A study coordinating center guidelines; others may not agree with some of the guidelines. Third at the University of Massachusetts Medical School in Worcester, party payor policies and limited fiscal resources may limit imple- Massachusetts, collated and analyzed data and assured confidential- mentation. Finally, studies to determine whether guidelines have ity. Physicians received a confidential patient management analysis improved the quality of patient care are needed to continue the that compared their patterns to those of all participating physicians quality improvement process. (Table 6).7

A large, multicenter, long-term database was established to Since 1996, the ALS CARE database has enrolled over 5600 pa- monitor the recommended treatment of ALS symptoms and tients. Thirty-one enrollment sites accounted for 90% of the data the consequential patient responses. The ALS CARE database collected. Statistically, among the patients enrolled in the database, was initiated with the goal of creating more uniform treatment 93% are Caucasian, and 61% are male. The average age is 58 ± standards. By tracking outcomes, the database provides a clearer 13.2 years, and 6% developed the familial form of ALS.

Table 6 Changes in management of patients with amyotrophic lateral sclerosis (ALS) over the 8 years since inception of ALS CARE

Parameter 1997 2004 P value PARAMETERS THAT INCREASED Patients enrolled in ALS CARE within 6 mo of diagnosis, % 31 61 NA Patients taking riluzole, % 45 (1998) 56 <0.001 Patients taking sialorrhea medication, % 12 (1999) 17 <0.0001 Patients receiving treatment for pseudobulbar affect, % 28 42 <0.0001 Patients receiving treatment for depression, % 23 42 <0.0001 Patients receiving treatment for sleep disturbance, % 17 29 <0.0001 Patients receiving PEG when FVC was <50% of predicted, % 3 16 <0.0001 Patients receiving NIPPV when FVC was <40% of predicted, % 5 9 <0.0001 Use of nutritional supplements, % of patients 9 19 <0.0001 Use of physical therapy, % of patients 31 43 <0.0001 Use of occupational therapy, % of patients 19 31 <0.0001 PARAMETERS THAT DECREASED Patients taking gabapentin, % 13 4 <0.0001 Patients enrolled in a clinical trial at the time of enrollment in the ALS CARE database, % 34 8 <0.0001 PARAMETERS THAT REMAINED UNCHANGED Mean delay between first symptom and diagnosis, mo 13 14 NS Patients with depression, % 39 45 NS Patients who died at home, % 49 42 NS

FVC = forced vital capacity; NIPPV = noninvasive positive pressure ventilation; PEG = percutaneous endoscopic gastrostomy 44 Treatment for ALS - Evidence-based Management AANEM Course

Among the drug therapies, 52% of patients in the ALS CARE those with frontotemporal dementia and some patients with bulbar database were receiving riluzole at the time of enrollment. Other dysfunction and marked sialorrhea, are unable to adapt to its use. medications that were used included gabapentin (8%), creatine (39%), high-dose vitamins or antioxidants (48%), nontraditional The ALS CARE database has definite limitations. There is neither medications (15%), and other unspecified medications (42%). At independent monitoring nor pathologic confirmation of diagnoses the time of enrollment, 89% of patients were satisfied with their to assure accurate registration. The largest percentage of enroll- medical care, which often included nonpharmacologic interven- ment came from relatively few centers. Data collection based on tions such as physical therapy (47%), occupational therapy (39%), voluntary surveys is inherently biased. Therefore, it is not certain speech therapy (35%), home nursing care (30.6%), social worker whether results are generalizable to the entire ALS population. visits (30.6%), dietary advice (30%), or psychological/psychiatric There is no control group involved and the results are descriptive counseling (29%). rather than experimental. Due to great expense and a lack of con- tinued funding, the maintenance of the database and enrollment is One of the most informative aspects of the ALS CARE database ending. Less expensive approaches using the web based ALS con- is the ability to detect changes in the care provided by physicians. nection may prove to be more cost effective. The 1999 publication of the AAN recommendations for treatment of ALS left treatment decisions up to the physician.4 Nevertheless, these recommendations may have had a significant impact on CONCLUSION patient care, as shown by increased adherence to guidelines over an 8-year period since the inception of the ALS CARE database (Table Although ALS is not yet curable, there have been significant ad- 2). For example, symptomatic pharmacotherapy for ALS symp- vances in symptomatic treatment options for patients. The 1999 toms such as constipation, cramps, depression, disturbed sleep, AAN Practice Parameter provided guideline to physicians and the spasticity, and sialorrhea were underutilized prior to the adoption new guideline will further assist physicians treating patients with of the AAN guidelines. A comparative study was performed to this disease. The ALS CARE database has provided powerful, evaluate whether clinical practice changed in subsequent years.4 longitudinal determinations of treatment potential regarding the The AAN recommendations for the management of sialorrhea disease course of ALS. In addition, the development of a new included the use of anticholinergic drugs. Prior to this publication, web based to monitor patient outcomes (www.alsconnection.org) 54% of patients were offered medications to treat sialorrhea. The will provide further opportunity to examine the care received by treatment rate increased to 75% following the publication of the patients, especially those who cannot attend specialized ALS clinics, AAN guidelines (p = 0.0085). and will provide more information about treatments available for this disease. One of the most common symptoms reported by patients in the ALS CARE database is depression. It was reported in 41% of those enrolled. 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