Neuromuscular Update I

Home , Aceruloplasminemia, Copper toxicity, Enolase deficiency, Hyperreflexia, Hypophosphatemia

Gil I. Wolfe, MD Donald B. Sanders, MD James W. Teener, MD Richard A. Lewis, MD Robert T. Leshner, MD Craig M. McDonald, MD David S. Saperstein, MD Neeraj Kumar, MD James K. Richardson, MD

2008 Neuromuscular Update Course C 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 Neuromuscular Update I

Faculty

Gil I. Wolfe, MD Donald B. Sanders, MD Professor Director Department of Neurology Division of Neurology University of Texas Southwestern Medical School Duke University Medical Center Dallas, Texas Durham, North Carolina Dr. Wolfe is a professor of neurology at the University of Texas (UT) Dr. Sanders received his degree in medicine from Harvard Medical Southwestern Medical School in Dallas, Texas. In September 2004, he was School and trained in neurology at the University of Virginia. He is named to the Dr. Bob and Jean Smith Foundation Distinguished Chair in Professor of Medicine in the Division of Neurology at Duke University Neuromuscular Disease Research. He serves as Co director of the Muscular Medical Center. He founded the Duke EMG Laboratory, where he is the Dystrophy Association Clinics and Director of the Peripheral Neuropathy Co director, and is Director of the Duke Myasthenia Gravis Clinic. He Clinic at UT Southwestern. He is also the Medical Director and acting Vice is the author of many papers on the diagnosis and treatment of neuro- Chair for the department. Dr. Wolfe completed his undergraduate studies muscular diseases, and in 1999 he received the AANEM’s Distinguished at Princeton University and attended medical school at UT Southwestern. Researcher Award. Dr. Sanders is a past-president of the AANEM and has He completed an internal medicine internship and trained as a neurology served on the AANEM’s Workshop, Regional Workshop, and Program resident and neuromuscular/electromyography fellow at the University of Committees, among numerous others. He has also been a board member Pennsylvania Medical Center in Philadelphia. His main research interests of the American Board of Electrodiagnostic Medicine. include idiopathic and immune-mediated peripheral neuropathies and myasthenia gravis. Dr. Wolfe has received the Trephined Cranium Award for excellence in residency teaching on several occasions. He also serves on the medical advisory boards for the Myasthenia Gravis Foundation of America, Charcot-Marie-Tooth Association, and Neuropathy Association, and has been elected Fellow of the American Academy of Neurology and a member in the American Neurological Association. He is certified by the American Board of Psychiatry and Neurology both in neurology and in clinical neurophysiology.

James W. Teener, MD Director Neuromuscular Program Department of Neurology University of Michigan Health System Ann Arbor, Michigan Dr. Teener is Director of the Neuromuscular Program, Co director of the EMG Laboratory, and Associate Professor at the University of Michigan. He completed his residency in neurology and a neuromuscular fellowship at the University of Pennsylvania. His research interests include neuromuscular disorders associated with critical illness and intensive care treatment of severe neuromuscular disease. His clinical interests include the full spectrum of neuromuscular disease. He collaborates widely and provides electrodiagnostic expertise to a wide variety of research projects.

Authors had nothing to disclose.

Course Chair: Gil I. Wolfe, 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. iii

Richard A. Lewis, MD Robert T. Leshner, MD Professor and Associate Chair Professor Department of Neurology Department of Neurology Wayne State University School of Medicine George Washington University School of Medicine and Health Sciences Detroit, Michigan Washington, DC Dr. Lewis is Professor and Associate Chair of Neurology and Dr. Leshner attended Cornell University for his undergraduate and Co director of the Neuromuscular Program at Wayne State University medical studies. Postgraduate work in internal medicine and pediatrics School of Medicine. He is also Director of the Clinical Neurophysiology were performed at the University of Vermont. A fellowship in adult and Laboratory. He trained in neurology at the University of Pennsylvania and child neurology was completed at the University of Colorado. Following remained on the faculty there before taking positions at the University of several years of active duty as a Navy neurologist, Dr. Leshner performed Connecticut and Eastern Virginia Medical School. Dr. Lewis has been a fellowship training in neuromuscular diseases and electrodiagnostic member of the AANEM since 1979 and has been on a number of com- medicine at the Medical College of Georgia under the watchful eye of mittees including the Examination and Education Committees. He has Dr. Thomas Swift. For over 30 years, his main clinical interest has been been a participant in practice parameter committees on conduction block, the diagnosis and treatment of neuromuscular disorders. Dr. Leshner is multifocal motor neuropathy, and peripheral neuropathy. He is Deputy currently a staff neurologist at the Children’s National Medical Center Editor of the Journal of the Neurological Society and on multiple other in Washington, DC. He holds the rank of Professor of Neurology and editorial boards including Muscle & Nerve. He is on the national and in- Pediatrics at the George Washington University School of Medicine and ternational Medical Advisory Boards of the Myasthenia Gravis Association Health Sciences. Dr. Leshner is also the 2008 recipient of the AANEM’s and Guillain-Barre Syndrome/Chronic Inflammatory Demyelinating Distinguished Researcher Award. His research interests involve trans- Polyneuropathy Foundation International. Dr. Lewis’ interests include the lational research in genetic pediatric neuromuscular diseases. He is the clinical and electrophysiologic aspects of the demyelinating neuropathies, proud father of five children and spends most of his free time spoiling his both acquired and inherited. He is probably best known for his paper five (and counting) grandchildren. on multifocal demyelinating neuropathy, a disorder that is now known as “Lewis-Sumner Syndrome.”

Craig M. McDonald, MD Professor Departments of Physical Medicine and Rehabilitation and Pediatrics University of California Davis School of Medicine Davis, California Dr. McDonald is Professor of Physical Medicine and Rehabilitation and Pediatrics and Director of the Neuromuscular Disease Clinics at the University of California (UC) Davis Medical Center. He is Director of the National Institute on Disability and Rehabilitation Research’s Rehabilitation Research and Training Center in Neuromuscular Diseases at UC Davis. His research interests include clinical endpoints in muscular dystrophy, exercise in neuromuscular disease, energy expenditure, quantitative assessment of physical activity, and quality-of-life assessment. iv

David S. Saperstein, MD Neeraj Kumar, MD Private Practice Associate Professor Phoenix Neurological Associates Department of Neurology Phoenix, Arizona Mayo Clinic Dr. Saperstein practices in Phoenix, Arizona at Phoenix Neurological Rochester, Minnesota Associates, is Co director of the Neuropathy Clinic at Banner Good Dr. Kumar received his medical degree from Maulana Azad Medical Samaritan Regional Medical Center, and is a clinical associate professor of College at the University of Delhi, India and subsequently did a residency neurology at the University of Arizona College of Medicine. Dr. Saperstein in internal medicine and neurology in India. He later completed a resi- received a bachelor’s degree in Biology from Boston University. He com- dency in internal medicine at East Tennessee University and a residency in pleted his medical training at the Boston University School of Medicine, neurology at the University of Minnesota. Dr. Kumar is board-certified performed a neurology residency at Wilford Hall USAF Medical Center in neurology, internal medicine, and electrodiagnostic medicine. He has in San Antonio, Texas, and completed a neuromuscular disease/clini- received the Distinguished Teaching Award from the Minnesota Medical cal neurophysiology fellowship at the University of Texas Southwestern Foundations in 1997 and in 2005 was named Teacher of the Year by the Medical Center in Dallas. Dr. Saperstein is board certified by the American Mayo Fellows Association. His current research interests include diseases Board of Psychiatry and Neurology (with added qualifications in clinical of the spinal cord, disorders of copper metabolism, and neurological ill- neurophysiology) and the American Board of Electrodiagnostic Medicine. nesses related to heavy metals. Dr. Saperstein has a particular interest in the diagnosis, classification and management of peripheral neuropathies, with a focus on immune-mediated polyneuropathies and vitamin B12 deficiency neuropathy.

James K. Richardson, MD Associate Professor Department of Physical Medicine and Rehabilitation University of Michigan Ann Arbor, Michigan Dr. Richardson graduated from medical school at the University of Cincinnati. He is currently an Associate Professor within the Department of Physical Medicine and Rehabilitation at the University of Michigan. He is board certified by the American Boards of Internal Medicine, Physical Medicine and Rehabilitation, and Electrodiagnostic Medicine. He has received numerous annual teaching awards for his efforts at the University of Michigan, including six Silver Crutch Awards, and he is the only recipient of Gold and Platinum Crutch teaching awards. In addition he has received a variety of awards for his research, including the 2007 Best Abstract Award at the American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting in Phoenix, Arizona. His primary reserach interest invovles neuropathic gait and he recently received a 5-year RO1 award from the National Institutes of Health to continue this line of research.

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 indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041. v Neuromuscular Update I

Contents

Faculty ii Objectives v Course Committee vi

Oculobulbar Weakness 1 Gil I. Wolfe, MD; Donald B. Sanders, MD

Acute Flaccid Weakness 7 James W. Teener, MD; Richard A. Lewis, MD Spinal Muscular Atrophy 11 Robert T. Leshner, MD; Craig M. McDonald, MD

Myeloneuropathy 21 David S. Saperstein, MD; Neeraj Kumar, MD; James K. Richardson, MD CME Activity and Faculty Evaluation 33

O b j e c t i v e s —The overall objective of this two-part neuromuscular update course is to present participants with clinical cases in neuromuscular diseases. At the end of the entire course, participants will learn how to diagnose, evaluate, and in some instances treat neuromuscular diseases. This course is an excellent review of neuromuscular medicine. Update I covers oculobulbar weakness, acute flaccid weakness, floppy infant, and myeloneuropathy. 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 designates this activity for a maximum of 3.25 AMA PRA Category 1 Credit(s).TM If purchased, the AANEM designates this activity for 2 AMA PRA Category 1 Credit(s).TM This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 09/08 - 09/11. vi Neuromuscular Update I AANEM Course

2007-2008 AANEM NEUROMUSCULAR UPDATE COURSE COMMITTEE Gil I. Wolfe, MD, Chair Dallas, Texas

Jay J. Han, MD Kerry H Levin, MD James W. Tweener, MD Sacramento, California Cleveland, Ohio Ann Arbor, Michigan

Yadollah Harati, MD Dianna Quan, MD Houston, Texas Aurora, Colorado

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

Oculobulbar Weakness

Gil I. Wolfe, MD Professor Department of Neurology University of Texas Southwestern Medical Center Dallas, Texas Donald B. Sanders, MD Director Division of Neurology Duke University Medical Center Durham, North Carolina

CASE DESCRIPTION arm and leg muscles were 4+ with milder weakness of distal upper History limb groups including the intrinsic hand muscles. However, distal lower limbs were normal. No limb fasciculations were seen. Tendon reflexes were normal throughout. Sensation to all modali- A 36-year-old woman presented in August of 1999 with a 10- ties was intact. Coordination and gait testing was normal. month history of nasal dysarthria that worsened toward the end of the day. She later developed horizontal diplopia that would first Prior Studies appear 20 minutes after awakening and fluctuate during the course of the day. Over this 10-month period, she also noticed neck Acetylcholine receptor (AChR) binding antibodies were negative. weakness. The patient would have to strain to keep her head Other pertinent laboratory results included negative antinuclear upright since it would tend to fall forward. There was mild dyspnea, antibodies (ANA) and normal thyroid stimulating hormone dysphagia with nasal regurgitation beginning 7 months prior to (TSH). Chest computed tomography 2 months prior to her clinic her visit, occasional ptosis, and arm weakness that was greater than visit showed no abnormalities. leg weakness. She had some difficulty walking for approximately 5 months. The patient denied sensory symptoms. Current Studies

Past medical history was otherwise unremarkable. There was no AChR binding, modulating, and blocking, as well as striated muscle family history of disorders causing weakness. antibodies, returned negative. Voltage-gated calcium channel (VGCC), anti-Hu, and anti-Ri antibodies were negative. Creatine Before proceeding with the examination, are there any medi- kinase (CK) was normal at 42, and a repeat TSH was normal at cations/supplements that the physician should ask the patient 1.27. A 3 Hz repetitive nerve stimulation (RNS) recording from whether or not they are taking? the abductor digiti minimi (ADM) with a baseline amplitude 13.8 mv showed a 17% decrement at baseline that increased up to 20% Examination 6 minutes after prolonged exercise. Repair of the decrement to 3% was seen immediately following brief exercise. Similar decremental Mental status was normal. On cranial nerve examination, there patterns were seen on 3 Hz RNS of the orbicularis oculi, peaking at was mild right ptosis, but extraocular motility was intact. There 20% 4 minutes after exercise, and of the trapezius, peaking at 15% was clear fatigable eyelid weakness on sustained upgaze. Facial at both 4 and 6 minutes following exercise. weakness was moderate on eye closure and mild in the lower facial musculature. Tongue strength was 4+ without atrophy or fascicula- What should be the physician’s next study or should the physi- tions. Neck flexion and extension were both graded 4-. Proximal cian be satisfied with the work-up of the patient at this point? 2 Oculobulbar Weakness AANEM Course

DIFFERENTIAL DIAGNOSIS impotence, blurred vision, and orthostasis.13 On examination, Myasthenia Gravis there is a limb-girdle pattern of weakness and reduced or absent deep tendon reflexes. A malignancy is present in approximately Myasthenia gravis (MG) is not uncommon as it has a preva- 50% of adult LEMS patients. The tumor is usually a small cell lence as high as 2 to 7 cases per 10,000 population.18Overall, carcinoma of the lung, but other malignancies such as renal cell there is a slight female predominance of 3:2, although males carcinoma and hematologic tumors occur. Malignancy is more predominate in older age groups, and in some clinics, there common in men than in women, and is more likely to occur in are more reports of male MG patients than of female pa- those who are chronic smokers or over age 50. tients. The disease onset can occur at any age, but peaks are observed in the 3rd and 6th decade. MG is characterized by LEMS would seem an unlikely diagnosis in this case. The history weakness and fatigability with typical involvement of the ocular, reveals no autonomic involvement and reflexes were normal on bulbar, truncal, and extremity skeletal muscle. The ocular manifes- examination. With low rate repetitive stimulation, LEMS patients tations are ptosis and diplopia, whereas the bulbar manifestations typically show a decremental response (Figure 1), but immediately are dysarthria, dysphagia, and dyspnea. Proximal limb muscles after exercise, there is prominent facilitation, something not ob- tend to be weaker than distal ones. While classically there is served in this case. Low-amplitude motor responses are typical worsening of symptoms with fatigue, stress, or during later hours of for LEMS, another feature missing from this case. Finally, VGCC the day, temporal symptoms are not always elicited. antibody testing was negative.

In this study, the patient had been previously diagnosed with MG based on presentation and abnormal RNS. Fatigable weakness in the eyelid, bulbar, neck, and limbs is all consistent with the diagnosis. Although a complete panel of AChR antibodies was negative, 15% of generalized MG patients will not harbor these antibodies. As was will see, even equivocal responses to anticholinesterase therapy, intravenous immunoglobulin (IVIg), and thymectomy do not rule out the diagnosis. Single-fiber electromyography (EMG) was not performed on this patient, but from a diagnostic stand- point, the contribution would have been minmal.

Another test to consider is anti-muscle specific tyrosine kinase (MuSK) antibodies. One form of MuSK MG has prominent facio-pharyngeal involvement, and these patients are often more refractory to conventional therapies.11,14 The response to cholinesterase inhibitors is variable in MuSK MG patients; many become worse or have profuse fasciculations with these medications.5 Pyridostigmine and IVIg in particular have not been helpful in treating a majority of these patients.19 The efficacy of thymec- Figure 1 Repetitive stimulation of the ulnar nerve in Lambert-Eaton tomy remains poorly defined in MuSK MG. Studies have shown myasthenic syndrome. At 3 Hz, a 32% decrement is recorded (A). After no or minimal thymic abnormalities in these patients, in contrast brief exercise, the motor amplitude demonstrates a 220% increment over to AChR-Ab positive MG.7,9 On the other hand, the favorable baseline (B). High-rate repetitive stimulation at 50 Hz demonstrates an response to plasma exchange and an ultimately good outcome increment of 195% (C). are typical for MuSK MG. In several series, approximately 75% of MuSK MG patients eventually achieved remission or were in minimal manifestation status.14,19 Table 1 summarizes the immu- Upon confirmation of a diagnosis of LEMS, an extensive search nomodulatory therapies for MG. for an underlying malignancy is imperative. This should begin with radiologic studies and may require bronchoscopy or positron Lambert-Eaton Myasthenic Syndrome emission tomography (PET) scan. Initial treatment should be directed against the malignancy, as this may improve neurologic Lambert-Eaton myasthenic syndrome (LEMS) usually begins grad- manifestations. Clinical experience suggests that immunotherapy ually and is characterized by fatigability and weakness in a limb-gir- without directed treatment of the underlying cancer produces little dle distribution. Unlike MG, patients may note that the weakness clinical benefit. When no malignancy is found, a repeat screen- is worse soon after awakening, but will improve later in the day. ing every 6 to 12 months is advised during at least the first 2 While exercise can transiently improve strength, persistent exertion years of disease, or even longer in patients at risk for malignancy. causes fatigue. Cranial nerve and respiratory involvement is less In general, a trial of pyridostigmine is the first pharmacologic common than in MG. Up to 50% of patients can have mild degrees intervention, although it is often of limited benefit. Drugs that of ptosis, diplopia, dysphagia, and dysarthria. Patients may also enhance the presynaptic release of ACh vesicles are most effective. experience autonomic involvement including dry mouth and eyes, Guanidine hydrochloride is the oldest drug in this group and has 3

Table 1 Immunomodulatory therapies for myasthenia gravis

Agent Initial dose Maintenance dose Onset of Major Adverse Events Lab Monitoring Comments Action Prednisone 15-20 mg qd, 1.5 mg/kg a day, followed 2-4 weeks HTN, diabetes, weight K+, glucose Administer in single increasing by 5 to 10 by slow alternate day taper gain, bone loss, cataracts, every few am dose; watch mg q2-3 days; may (taper by 5-10 mg a month) GI ulcers, psychologic months; for early worsening begin with 60 mg disorders bone density in first week of qd and taper after monitoring administration and benefit established during the tapering phase Azathioprine 50 mg qd Increase by 50 mg 2-10 months Fever, abdominal pain, CBC, LFTs 2-4 10% of patients increments q 2-4 weeks to for initial n/v, anorexia, leukopenia, times in first cannot tolerate target of 2-3 mg/kg responseUp hepatotoxic, skin rash month, then because of flu-like to 24 monthly reaction; major drug months for interaction with peak allopurinol Cyclosporine 100 mg bid Increase slowly as needed 1-3 months Hirsuitism, tremor, CBC, LFTs, Bioequivalence to 3-6 mg/kg on bid gum hyperplasia, HTN, BUN/Cr differs between schedule hepatotoxic, nephrotoxic monthly. Follow preparations; avoid trough drug brand switching levels when possible Mycophenolate 500-1000 mg bid 1000 to 1500 mg po bid 2-12 months Diarrhea, vomiting, CBC weekly Diarrhea may resolve leukopenia for 4 weeks, by switch to tid q2 weeks for dosing 4 weeks, then monthly Cyclophos- 3-5 mg/kg a day; 2-3 mg/kg a day 2-6 months Alopecia, leukopenia, CBC, chemistry Intravenous pulse phamide can be preceded by nausea and vomiting, skin panel, therapy may be less intravenous pulse discoloration, anorexia urinalysis every toxic hemmorh-agic cystitis, 2-4 weeks malignancy Tacrolimus/ 3 mg a day Increase up to 5 mg a day 1-3 months Hypergly cemia, BUN/Cr, Insulin-dependent FK-506 hypertension, headache, glucose, diabetes mellitus hyperkalemia, potassium, developed in 20% of nephrotoxicity, diarrhea, trough levels post-renal transplant nausea and vomiting every few patients. Trough weeks initially, levels<10 ng/ml have then less been effective in MG regularly Rituximab 375 mg/m2 weekly Can follow without further 1-3 months Common: pruritis, nausea, CBC, monitor B lymphocyte counts or every other week infusions or repeat 375 mg/ vomiting, dizziness, hepatic function fall rapidly following for 4 weeks m2 dose every 8-12 weeks headache, Uncommon: closely in infusions. Both serious dermatologic viral hepatitis AchR and MuSK Ab events including Stevens- carriers titers are reported to Johnson syndrome, fall with treatment. aplastic or hemolytic Progressive anemia, leukopenia, multifocal thrombocytopenia, GI leukoencephalopathy obstruction, tumor lysis is rare but of concern syndrome (in lymphoma with this agent patients) IVIg 2 gm/kg over 2-5 0.4-1 gm/kg every 4 weeks; 1-2 weeks Headache, aseptic BUN/Cr Avoid in patients with days can attempt to decrease meningitis, nephrotoxic, recent ischemia frequency over time ischemic events, fluid overload bid = two tiems a day;BUN/Cr = blood urea nitrogen to creatinine ratio; CBC = complete blood count; bid = twice a day; GI = gastrointestinal, HTN = hypertension, IVIg = intravenous immunoglobuli; K+ = potassium; LFTs = liver function tests; MG = myasthenia gravis; qd = every day; tid =three times a day 4 Oculobulbar Weakness AANEM Course proven to be beneficial in some LEMS patients, but side effects Although the patient’s oculobulbar presentation is not atypi- including bone marrow depression, renal failure, gastrointestinal dis- cal for a mitochondrial disorder, family history negated a tress, ataxia, hypotension, paresthesias, confusion, dry skin, and atrial maternal inheritance pattern one would suspect in a mtDNA fibrillation are problematic. Additionally, 3,4-diaminopyridine disorder. The degree of symptom and sign fluctuation and (3,4-DAP) increases the duration of the presynaptic action potential the decremental patterns on RNS would also argue against a by blocking outward potassium efflux. This indirectly pro- mitochondrial myopathy. longs the activation of VGCC and increases calcium entry in nerve terminals, enhancing neurotransmitter release. More Treatment of mitochondrial disorders includes the management of than 85% of patients experience significant clinical improve- cardiac complications and anticonvulsant therapy for patients with ment with 3,4-DAP.13 Most tolerate the drug well, and side seizures.6 Many clinicians recommend a battery of supplements effects such as paresthesias tend to be minor. There is a risk of and antioxidants including vitamins A, C, and E, coenzyme Q10, seizures when daily doses exceed 100 mg. Usually, doses up to 20 L-carnitine, and creatine. Exercise training may also play a role mg 3 times a day are used. Although 3,4-DAP is not approved for in management as it increases peak work, oxidative capacities, and clinical use in the United States, it is available on a compassionate functional performance.15 use basis through a pharmaceutical company located in the United States. There are only a few clinical studies of immunosuppressive Hereditary Inclusion Body Myositis therapy in LEMS. Aggressive immunotherapy is easier to justify in LEMS patients without cancer, as there is concern that such agents An autosomal dominant form of hereditary inclu- may adversely impact immunosurveillance for malignant cells. sion body myositis (h-IBM type 3; OMIM 605637) as- Plasmapheresis, IVIg, corticosteroids, and azathioprine can be effec- sociated with myosin heavy chain IIa (MyHC IIa) gene tive in both neoplastic and non-neoplastic LEMS. In general, the reg- mutations is characterized clinically by mild to severe proximal imens and doses outlined for MG (Table 1) can be applied to LEMS. weakness and external opthalmoplegia.16 Extraocular weakness typically begins with an upgaze paresis and progresses to involve other eye movements. Quadriceps may be severely affected with atrophy Mitochondrial Myopathy and weakness. Congenital joint contractures are present but tend to improve over time. Serum CK levels may be normal in children, Mitochondrial myopathy is a complex group of dis- and are mildly to moderately elevated (up to 10x normal) in adults. orders resulting from mitochondrial dysfunction. Myopathic features are present on EMG. Histopathologic findings Mitochondrial disorders include defects proximal or within on muscle biopsy demonstrate hypotrophic or absent type 2A fibers, the respiratory chain. Molecular defects can either involve non-specific myopathic features including marked variability of mitochondrial deoxyribonucleic acid (mtDNA) or nuclear deoxyri- fiber size and central nuclei, and disorganization of the intermyofi- bonucleic acid (nDNA). Of note, most components of the electron brillar network in type 2A fibers. Rimmed vacuoles are present in transport chain are encoded by nDNA. It is also becoming more severely affected biopsies with neighboring tubulofilamentous clear that some nDNA mutations impair the replication and inclusions of 15 to 20 nm diameter. As with other forms of h-IBM, expression of mitochondrial genes; that is, they produce disease there is no definitive therapy for h-IBM type 3. through disruptive intergenomic communication. The peculiar properties of mitochondrial genetics augment the complexity The absence of early childhood involvement, positive family history of phenotypic expression, as the degree of heteroplasmy of and fixed extraocular motility deficits as well as the presence of decre- mtDNA mutations can differ between tissues. Furthermore, mental patterns on RNS would argue against an h-IBM diagnosis. some tissues are more susceptible to mitochondrial dysfunction than others. Major mitochondrial syndromes are summarized in Oculopharyngeal Muscular Dystrophy Table 2. In general, mitochondrial myopathies are slowly progressive with limb-girdle weakness and exercise intolerance. Oculopharyngeal muscular dystrophy (OPMD) is a late (usually after Short stature, ocular involvement, and hearing loss are common 5th decade) adult-onset disease characterized by ptosis, dysphagia, ex- features. Serum or cerebrospinal fluid lactate levels may be ternal ophthalmoplegia, and mild proximal limb weakness. In North elevated at rest or after exertion. In many mitochon- America, French Canadians in Quebec and Spanish-American fami- drial myopathies, muscle fibers contain increased lies in New Mexico, Colorado, and Arizona are the most commonly numbers of structurally and functionally abnormal affected ethnic groups. On muscle biopsy, rimmed vacuoles are seen mitochondria. These accumulations produce the "ragged-red" on light microscopy and unique nuclear filament inclusions of 8.5 appearance on trichrome-stained sections. Other morphologic nm diameter on electron microscopy. Autosomal dominant and abnormalities include reduced staining on cytochrome-c oxidase recessive forms are recognized, with both inheritance patterns related and succinate dehydrogenase preparations. For definitive to polyadenylate-binding protein nuclear 1 gene defects on 14q11. diagnosis, genetic analysis is available commercially for some GCG trinucleotide repeat lengths greater than 6 are abnormal. of the mtDNA disorders, including Kearns-Sayre syndrome, Molecular testing is commercially available. Polyalanine tract expan- progressive external ophthalmoplegia, myocolonic epilepsy and sions produced by the gene mutation accumulate into undegradable ragged red fibers, and mitochondrial encephalomyopathy with intranuclear inclusions that are believed to sequester other nuclear lactic acidosis and stroke like episodes. proteins and interfere with cellular processes.2 AANEM Course Neuromuscular Update I 5

Table 2 Major mitochondrial syndromes

Syndrome DNA mutation Age of onset/ Distinctive clinical features Laboratory features inheritance PEO mtDNA Single or multiple Childhood/Maternal Ptosis, external ophthalmoplegia, variable limb-girdle Ragged red fibers deletions Point mutations in in tRNA point weakness tRNA. mutations, AD pattern if multiple deletions KSS mtDNA Deletions, duplications < 20 years/ Sporadic Triad of ophthalmoplegia, pigmentary retinopathy and Elevated CSF protein early onset. Others: cardiac conduction defects, ataxia MERRF mtDNA tRNA Lys Childhood to early Seizures, myoclonus, ataxia, hearing loss, optic Lactic acidosis, ragged adulthood/ Maternal atrophy, dementia, neuropathy, lipomas red fibers MELAS mtDNA tRNA Leu Usually < 40 years/ Normal early development, migraine-like headaches, Lactic acidosis, ragged Maternal vomiting episodes (2 of 3 should be present for red fibers diagnosis). Others: stroke, dementia, hearing loss mtDNA mtDNA Various point Childhood to young Variable multisystemic and CNS involvement Variable features on point mutations adulthood/ Maternal muscle biopsy, some mutations with classic mitochondrial pattern mtDNA nDNA Infancy/ Autosomal Generalized hypotonia, cardiomyopathy, renal tubular Ragged red fibers, depletion recessive defects, seizures, hepatic dysfunction cytochome-c oxidase- syndromes deficient fibers Leigh nDNA Complex I and II gene Infancy to early Altered mental status, generalized hypotonia, Lactic acidosis, syndrome mutations childhood/ Various vomiting, ataxia, ptosis, ophthalmoplegia, seizures, cytochome-c oxidase- inheritance patterns cardiomyopathy deficient fibers MNGIE nDNA defect (thymidine Infancy to adulthood/ Neuropathy, leukoencephalopathy, intestinal pseudo- Lactic acidosis, elevated phosphorylase gene) resulting Autosomal recessive obstruction, ptosis, ophthalmoplegia, distal and CSF protein, white matter in multiple mtDNA deletions proximal weakness changes on head MRI, or mtDNA depletion cytochome-c oxidase- deficient fibers

CNS = central nervous system; CSF = cerebrospinal fluid; KSS = Kearns-Sayre syndrome; MELAS = mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes; MERRF = myocolonic epilepsy and ragged red fibers; MNGIE = mitochondrial neurogastrointestinal encephalomyopathy; MRI = magnetic resonance imaging; nDNA = nuclear deoxyribonuclic acid; PEO = progressive external ophthalmoplegia; tRNA Leu = transfer ribonucleic acid leucine; tRNA Lys = transfer ribonucleic acid lysine. This patient did not have fixed ophthalmoplegia or ptosis. Also, during this 2-year period following her initial visit, she received limb weakness progressed more quickly than is expected for OPMD. IVIg, 2 gm/kg induction followed by 0.4 gm/kg month. There There was no supportive family history, and the decrements on RNS was mild improvement with IVIg, but her response to plasma would not be typical for this diagnosis. exchange was considerably greater. In June 2000, she was placed on azathioprine, titrated up to 200 mg a day. Over time, she felt that Diagnostic Study this intervention had the greatest impact on some of her symptoms, especially the diplopia. By January 2003, she had been weaned In January 2004, MuSK antibodies were ordered and returned off of all medications, including corticosteroids, pyridostigmine, positive. By this point, the patient had achieved complete and the azathioprine. She was classified as being in remission at stable remission after several years of struggling with MG-related that point, and remained in complete stable remission on follow- weakness and receiving a variety of interventions. up through 2006, at which point she relocated from North Texas.

Management Case Discussion

Prior to the patient’s initial visit, she had been placed on Although this patient had clinical and electrodiagnostic features pyridostigmine. There was no more than mild improvement typical of MG, in some MuSK MG patients, weakness is limited at doses up to 60 mg 4 to 5 times per day. In June 1999, an to one or more anatomic regions, frequently with marked atrophy, outside neurologist placed her on prednisone, titrating up to 60 especially of facial or oropharyngeal muscles. In the author’s clinic, mg every other day. This also resulted in only mild improvement. MuSK MG patients are more likely than their MuSK-negative In November 1999, she underwent extended transsternal thymec- cohorts to present with respiratory symptoms or neck extension tomy. Benign thymic tissue was found. There was no appreciable weakness. Scoliosis and adynamia of the upper esophagus has improvement over the ensuing months. Prior to the thymectomy, been seen as a manifestation of focal weakness in MuSK MG. she received preoperative plasma exchange (two plasma volume (Sanders DB, Juel VC. MuSK-antibody positive myasthenia gravis: exchanges). She noted marked improvement from this interven- Questions from the clinic. J Neuroimmunol 2008; In Press). Most tion. Following her thymectomy, she underwent several more MuSK MG patients have more than just ocular muscle weakness, plasma exchanges through July 2001. Over a 5-month interval but weakness limited to ocular muscles have been reported.1 6 Oculobulbar Weakness AANEM Course

A markedly greater female predominance has been consistently REFERENCES reported among MuSK MG patients than in MuSK negative MG. There is also a marked racial predominance in the author's clinic, and 1. Caress JB, Hunt CH, Batish SD. Anti-MuSK myasthenia gravis pre- it has been found that a woman with AChR antibody-negative MG senting with purely ocular findings. Arch Neurol 2005;62:1002-1003. is twice as likely to have MuSK MG if she is African-American. The 2. Corbeil-Girard LP, Klein AF, Sasseville AM, Lavoie H, Dicaire MJ, distance north of the equator also appears to be a major determinant Saint-Denis A, et al. PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in ocu- of the proportion of patients with MuSK MG. Within the European lopharyngeal muscular dystrophy nuclear inclusions. Neurobiol Dis and American populations, high proportions (up to 40%) are found 2005;18:551-567. around latitude 40 degrees north, but further north, the proportion 3. Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et 18 falls steeply with lower values in northern Europe. Conversely, al. Clinical correlates with anti-MuSK antibodies in generalized serone- among Pacific countries, the proportion increases from 2% at 15 gative myasthenia gravis. Brain 2003;126:2304-2311. degrees north of the equator to around 35% at 35 to 37 degrees 4. Farrugia ME, Kennett RP, Hilton-Jones D, Newsom-Davis J, Vincent north. This suggests that an environmental factor plays a role in the A. Quantitative EMG of facial muscles in myasthenia patients with etiology of MuSK MG. MuSK antibodies. Clinical Neurophys 2007;118:269-277. 5. Hatanaka Y, Hemmi S, Morgan MB, Scheufele ML, Claussen GC, Wolfe RNS and jitter studies are usually more abnormal in the face than GI, et al. Nonresponsiveness to anticholinesterase agents in patients with the limbs,10 but may give diagnostic findings only if symptomatic MuSK-antibody-positive MG. Neurology 2005;65:1508-1509. 6. Hirano M, DiMauro S. Metabolic myopathies. In: Pourmand R, muscles are tested.14 In this study, the MuSK MG patients jitter was Harati Y, editors. Advances in Neurology: Neuromuscular Disorders. abnormal in the extensor digitorum in only 50%, as compared to Philadelphia: Lippincott Williams & Wilkins; 2002. p. 217-234. 80% of AChR negative, and 91% of AChR-positive patients. 7. Lauriola L, Ranelletti F, Maggiano N, Guerriero M, Punzi C, Marsili F, et al. Thymus changes in anti-MuSK-positive and -negative myasthenia In many MuSK MG patients, EMG studies demonstrate short du- gravis. Neurology 2005;64:536-538. ration, complex, excessively recruited motor unit action potentials 8. Lavrnic D, Losen M, Vujic A, De Baets M, Hajdukovic LJ, Stojanovic (MUAPs), suggesting a myopathy.11 Quantitative measurements V, et al. The features of myasthenia gravis with autoantibodies to in facial muscles have demonstrated reduced MUAP duration and MuSK. J Neurol Neurosurg Psychiatry 2005;76:1099-1102. findings on turns-amplitude analysis similar to a myopathic control 9. Leite MI, Ströbel P, Jones M, Micklem K, Moritz R, Gold R, et al. group, suggesting that the atrophy is not neurogenic but is akin to a Fewer thymic changes in MuSK antibody-positive than in MuSK myopathic process.4 antibody-negative MG. Ann Neurol 2005;57:444-448. 10. Oh SJ, Hatanaka Y, Hemmi S, Young AM, Scheufele ML, Nations SP, et al. Repetitive nerve stimulation of facial muscles in MuSK antibody- MuSK MG patients frequently do not improve with cholinesterase positive myasthenia gravis. Muscle Nerve 2006;33:500-504. inhibitors, which actually worsen weakness in some, and may 11. Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical produce profuse fasciculations. Repetitive discharges after the com- aspects of MuSK antibody positive seronegative MG. Neurology pound motor action potential may be seen in these patients after 2003;60:1978-1980. even low doses of these medications. These findings indicate an 12. Sanders DB. Esophageal adynamia in a patient with muscle specific abnormal sensitivity to ACh and may be a useful indicator of the tyrosine kinase (MuSK) antibody positive myasthenia gravis. Clin adverse effects of these medications. The cause of this sensitivity to Neurophys 2006;117:S122. ACh is unknown, but may be related to an abnormality of acetylcho- 13. Sanders DB. Lambert-Eaton Myasthenic syndrome: diagnosis and linesterase function. treatment. Ann NY Acad Sci 2003;998:500-508. 14. Stickler DE, Massey JM, Sanders DB. MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. Clin Neurophys Almost all MuSK MG patients improve with corticosteroids or 2005;116:2065-2068. plasma exchange, and the latter frequently produces rapid and 15. Taivassalo T, Shoubridge EA, Chen J, Kennaway NG, DiMauro S, dramatic improvement. Most patients also respond to other im- Arnold DL, et al. Aerobic conditioning in patients with mitochon- munomodulatory therapy; the response to other treatments is less drial myopathies: physiological, biochemical, and genetic effects. Ann predictable. Overall, 90% of our MuSK MG patients have improved Neurol 2001;50:133- with selected treatment with 50% having reached a Myasthenia 16. Tajsharghi H, Thornell L-E, Darin N, Martinsson T, Kyllerman M, Gravis Foundation of America Post-Intervention Status of remission Wahlström J, et al. Myosin heavy chain IIa gene mutation E706K or minimal manifestations. As with this patient, two other patients is pathogenic and its expression increases with age. Neurology at the author’s institution are in complete stable remission following 2002;58:780-786. surgical removal of what appeared to be a normal thymus. Thymus 17. Vincent A, Drachman DB. Myasthenia gravis. In: Pourmand R, histology is normal in most MuSK MG patients, arguing against an Harati Y, editors. Advances in Neurology: Neuromuscular Disorders. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 159-188. intrathymic disease pathogenesis. 7,9 However, the high incidence 18. Vincent A, Lang B. The prevalence of MuSK antibody positive my- of improvement, even complete stable remission, that has been seen asthenia gravis worldwide. J Neuroimmunol 2006;178:233. following thymectomy suggests that removal of the thymus may 19. Wolfe GI, Trivedi JR, Oh SJ. Clinical review of muscle-specific ty- 3,8 be of benefit in MuSK MG. Without controlled, prospective rosine kinase-antibody positive myasthenia gravis. J Clin Neuromusc studies, benefit from thymectomy cannot be determined, nor can it Dis 2007;8:217-224. be excluded. 7

Acute Flaccid Weakness

James W. Teener, MD Director Neuromuscular Program Department of Neurology University of Michigan Health System Ann Arbor, Michigan Richard A. Lewis, MD Professor and Associate Chair Department of Neurology Wayne State University School of Medicine Detroit, Michigan

CASE DESCRIPTION DIFFERENTIAL DIAGNOSIS

History The differential diagnosis of acute flaccid paralysis is large and includes a few common “horses” such as Guillain-Barré syndrome In August 2003, a 36-year-old previously healthy woman from (GBS) and a large number of rare causes or “zebras” (Table 1). Michigan developed a “flu-like” illness consisting of diarrhea, vom- Most neuromuscular clinicians will make a diagnosis of acute in- iting, and abdominal pain. Four days later, she suddenly noted flammatory demyelinating polyneuropathy (AIDP) many times in rapidly progressive leg weakness and became unable to walk in less their career, but the clinician must also remain poised to recognize a than 2 hours. A few hours after she noted leg weakness, her left single case of buckthorn intoxication (or other rare cause) which is arm became weak and within 12 hours it was flaccid. She reported unlikely to present more than once in a clinician’s lifetime. It is not no sensory abnormalities. She had mild low back pain. She had appropriate or practical to screen for every rare cause in every case. one episode of bowel incontinence, but believes that was due to Careful attention to the details of the patient history and examina- severe diarrhea. She reported a mild persistent headache. She had tion often provides clues that a “zebra” may be afoot. no known toxic exposures, but did recently return from her family’s yearly July 4th camping trip. No other family members were ill. In In the above case, one of the most striking clinical features is the the emergency room, she was initially fully alert, but 12 hours after extremely rapid progression of weakness. Other important features admission was noted to be confused. include the marked asymmetric arm weakness, lack of sensory complaints, antecedent/concurrent illness, and reflexes which remain Examination present despite prominent weakness. These features should alert the clinician that this may not be a typical case of GBS and lead to On initial examination in the emergency department, the patient a widened search for alternative diagnoses. had a low grade fever of 38.5º C. She was slightly lethargic but fully oriented without neck stiffness. Cranial nerve examination The marked asymmetry and rapid progression should lead the was normal with the exception of mild bifacial weakness includ- examining physician to consider cerebrovascular disease. The com- ing slight weakness of both lip and eyelid closure. The limbs plete loss of reflexes on the left side, lack of facial involvement, and were asymmetrically weak, with Media Research Council (MRC) slight involvement of the right arm are a bit unusual, but do not grade 4 power in most right arm muscles, MRC grade 0 power in alone exclude this possibility. most left arm muscles, and MRC grade 3 power in most muscles of the left leg, while the right was only mildly weak. The sensory The patient’s age is another reason to consider demyelinat- examination was normal. Reflexes were normal in the right arm, ing disease. The progression over hours is a bit unusual, but absent in the left arm, and trace in the legs. She could not stand both inflammatory lesions of the brain and/or spinal cord or walk. Anal sphincter tone was normal. remain possibilities. 8 Acute Flaccid Weakness AANEM Course

Table 1 Differential diagnosis of acute flaccid paralysis The asymmetric weakness in this patient is another feature which may help limit the differential diagnosis. Asymmetric weakness Relatively common causes, or those which are critical to identify is typical with poliomyelitis due to the polio virus itself, or to immediately due to the importance of early treatment other enteroviruses. Infection with other flaviviruses, such as Guillain Barré syndrome West Nile virus, also causes asymmetric weakness. Vasculitic neuropathy Basilar artery occlusion EVALUATION Spinal cord compression Transverse myelitis Additional testing beyond the history and physical examination often allows a precise diagnosis to be made in cases of Myasthenia gravis acute flaccid paralysis. Electrodiagnostic (EDX) testing is Hypophosphatemia the mainstay of the evaluation of acute flaccid paralysis, yet Hypermagnesemia it should be noted that nerve conduction studies (NCSs) and Polio-like infections (West Nile virus, Enteroviruses, Herpesviridae, electromyography (EMG) serve as an extension of the physical CMV, EBV) examination, and rarely provide a precise diagnosis. Further, EDX testing may be relatively insensitive in the acute period. Critical illness neuromyopathy Unless there was distal conduction block or neuromuscular Rare causes of acute flaccid paralysis junction abnormalities, NCSs would not be helpful in the first Botulism day or two. If there was denervation from motor neuron or Lyme disease proximal nerve lesions, conduction studies could not distinguish Wallerian degeneration from conduction block for at least 4 Cytomegalovirus infection in immunocompromised patients days. Because of the severity of symptoms and the acute nature HIV infection of the presentation, early diagnosis will remain dependent on Poliomyelitis other testing. Heavy metal intoxication (arsenic, gold, thallium) Despite these limitations, EDX testing may be very useful after 4 Chemical toxins (organophosphates, vacor) to 5 days to provide accurate localization of the lesion affecting Biologic intoxication (buckthorn, marine toxins, snake bite, tick the MU as well as provide very specific information which mark- paralysis) edly narrows the differential. For example, the identification Periodic paralysis of signs of demyelination brings the diagnosis of AIDP to the Rhabdomyolysis/metabolic myopathy forefront and prominently restricts the differential diagnosis. In Polymyositis addition, EDX testing may confirm the lack of sensory involvement and highlight asymmetry. With this data available, specific Paraneoplastic disorders additional testing can be obtained.

CMV= Cytomegalovirus , EBV= Epstein-Barr virus, HIV= human Magnetic resonance imaging (MRI) of the brain and spinal immunodeficiency virus cord should determine if a central nervous system disorder (e.g., Although extremely rapid progression is not typical of GBS, a number ischemic, hemorrhagic, infectious, or an inflammatory disorder) of other disorders should be considered. Diseases with particularly is present. In addition, a lumbar puncture to evaluate for abnor- rapid progressive weakness include paralytic poliomyelitis or infec- malities in the cerebrospinal fluid (CSF) is indicated. An elevated tion with other neurotropic viruses, various toxins including biologic CSF protein level without pleocytosis (i.e., albuminocytologic dis- agents such as botulism, metabolic disorders such as periodic paraly- sociation) is typical of AIDP, but may be seen in many other dis- sis, and acute myelopathy such as transverse myelitis. A number of orders. The lumbar puncture results may be even more revealing the listed disorders are infectious and would fit well with the patient’s when a CSF pleocytosis is present. Although such a pleocytosis concurrent illness. can occur in GBS, it is atypical and should trigger a search for an alternative diagnosis. Human immunodeficiency virus (HIV), cy- The patient’s lack of sensory complaints and lack of abnormalities on tomegalovirus, and West Nile virus infection are among the most the sensory examination provide powerful localizing information. The common causes of flaccid paralysis in which a CSF pleocytosis differential diagnosis now is reduced to include only disorders confined is present. to the motor unit (MU), that is, the anterior horn cell, motor nerve, neuromuscular junction, and muscle. AIDP typically has sensory Serologic testing should be guided by the remaining disorders involvement, but one subtype of GBS, acute motor axonal neuropa- on the differential diagnosis. Metabolic disturbances such as thy, spares sensory function. Most lesions of the spinal cord would hypophosphatemia, hypermagnesemia, and hypokalemia are cause both sensory and motor dysfunction, making myelitis much easily excluded on most initial hospital chemistry panel screens. less likely. Abnormalities in liver function can occur with many intoxica tions, some infections, and porphyria. The combination of AANEM Course Neuromuscular Update I 9 abnormal liver function studies and pancytope- Prevention. IgM enzyme-linked immunosorbent assay testing nia should trigger an investigation of arsenic intoxication. is available in or through most hospital laboratories in the Confirmation is obtained by measurement of hair or nail United States. arsenic levels or by 24-hour urinary arsenic excretion measurement. Elevation of white blood cell (WBC) count suggests an antecedent or concurrent infection. Measurement DISCUSSION of antibody titers to specific infectious agents may lead to a definite diagnosis. West Nile virus, a member of the family flavivirus, was first isolated in 1937 in Africa. It was first identified in the United States in New York City in 1999, and the number of identified cases Results increased rapidly in the following few years (Figure 1). The virus is transmitted via the Culex pipiens mosquito, with birds being An MRI of the brain and cervical spine performed in the first 24 the primary reservoir of infection. Cases have now been identi- hours was normal. There was an elevated serum WBC count of fied in every state in the continental United States.4 Of infected 15 (103/mm3). Routine chemistry battery was normal. individuals, only about one in 200 develops neurologic disease. Approximately 50% of those develop clinically important weak- Lumbar puncture revealed a CSF protein of 125 mg/dl with ness. A population-based study during a West Nile virus epi- a predominantly lymphocytic pleocytosis (88 WBC, 103/ demic in Colorado identified an overall incidence of West Nile mm3). Rapid immunologic testing for herpes simplex virus associated paralysis of 4.3/100,000.8 In most cases, signs of virus and bacterial meningitis was negative. Serum and systemic viremia, and often meningoencephalitis, accompany the CSF Lyme titers were negative. HIV testing was nega- onset of weakness. However, acute flaccid paralysis can occur in tive. The CSF venereal disease research laboratory results patients without other overt signs of West Nile infection. Such were negative. cases pose a significant diagnostic challenge. At least two distinct

NCSs and EMG were performed on day five of admission. All sensory responses in the arms and legs were normal. The motor 300 responses were absent in the left leg and left arm. The right arm 250 and leg had relatively normal responses. The amplitudes did not increase following 15 seconds of exercise (brief exercise test). No 200 decrement was noted on 2 Hz repetitive stimulation of the facial 150 nerve. Needle EMG examination revealed no abnormal sponta- deaths neous activity. It should be noted that the study was performed 100 a few days after onset of weakness and thus, positive waves and fibrillation potentials would not be expected to be present. MU 50 morphology was normal, with no voluntary units in the left arm 0 and leg. 2000 2002 2004 2006 Assessment 10000 In this case, the rapidly progressive asymmetric weakness, the CSF pleocytosis, the viral prodrome, and the development of mild 8000 confusion are features supportive of a polio-like illness producing acute flaccid weakness. Polio virus itself is no longer an important 6000 cause of weakness in the developed world. Vaccine associated poliomyelitis is a persistent but exceedingly rare event, occurring in 4000 Total Cases approximately one case per 2.5 million oral polio vaccine doses. Non-polio enteroviruses and other neurotropic viruses prove to 2000 be more common causes of acute flaccid paralysis.7 Serologic testing for enteroviruses (Coxsackie A and B, echovirus, entero- virus 70 and 71), HIV, Herpesviridae (cytomegalovirus, Epstein- 0 Barr virus, herpes simplex 1 and 2, varicella zoster) and West 2000 2002 2004 2006 Nile virus should be considered in cases such as the one presented. In this patient, both CSF and serum testing revealed the presence of IgM antibodies to West Nile virus. This allows for a Figure 1 West Nile Virus-related deaths and total number of cases per diagnosis of probable West Nile virus infection.2 Confirmation year 2000-2007. Data from Center for Disease Control web page: www. requires sophisticated testing such as the plaque reduction neu- cdc.gov/ncidod/dvbid/westnile/surv&control.htm. tralization test performed by the Centers for Disease Control and 10 Acute Flaccid Weakness AANEM Course weakness syndromes have been reported in patients infected with REFERENCES West Nile virus.1,3,5,6 The most common cause of weakness is 1. Glass JD, Samuels O, Rich MM. Poliomyelitis Due to West Nile likely the primary loss of anterior horn cells with sparing of sensory Virus. N Engl J Med 2002; 347:1280-1281. function. That is the apparent mechanism in the presented case. 2. Gordon SM, Isada CM. West Nile fever: Lessons from the 2002 Less commonly, AIDP has been reported in conjunction with season. Cleve Clin J Med 2003; 70:449-454. West Nile infection. 3. Gorson KC, Ropper AH. Nonpoliovirus Poliomyelitis Simulating Guillain-Barre Syndrome. Arch Neurol 2001; 58:1460-1464. Treatment of flaccid weakness related to West Nile virus infection 4. Johnson RT, Cornblath DR. Poliomyelitis and Flaviviruses. Ann largely consists of supportive care, unless features of typical AIDP Neurol 2003; 53:691-692. are identified. In the latter scenario, treatment with intravenous 5. Leis AA, Stokic DS, Polk JL, Dostrow V, Winkelmann M. A immunoglobulin 400mg/kg/day for 5 days or a course of plasma Poliomyelitis-like Syndrome from West Nile Virus Infection. N Engl exchange is likely as effective as these interventions are in routine J Med 2002; 347:1279-1280. 6. Li J, Loeb JA, Shy ME, Shah AK, Tselis AC, Kupski WJ, Lewis RA. cases of AIDP. No known treatment exists for the acute anterior Asymmetric Flaccid Paralysis: A Neuromuscular Presentation of horn cell loss most typical of flaccid weakness in West Nile virus 9 West Nile Virus Infection. Ann Neurol 2003; 53:704-710. infection. In cases where the degree of denervation is of mild or 7. Marx A, Glass JD, Sutter RW. Differential Diagnosis of Acute moderate severity, considerable recovery is possible. However, if Flaccid Paralysis and Its Role in Poliomyelitis Surveillance. Epidemiol the denervation is severe, the prognosis for recovery of functional Rev 2000; 22:298-316. strength is likely very poor. 8. Sejvar JJ, Bode AV, Marfin AA, Campbell GL, Ewing D, Mazowiecki M, Pavot PV, Schmitt J, Pape J, Biggerstaff BJ, Petersen LR. West Nile Virus-associated Flaccid Paralysis. Emerg Infect Dis2005; 11:1021-1027. 9. Solomon T, Willison H. Infectious causes of acute flaccid paralysis. Curr Opin Infect Dis 2003; 16:375-381. 11

Spinal Muscular Atrophy

Robert T. Leshner MD Professor Department of Neurology and Pediatrics Children’s National Medical Center Washington, DC Craig M. McDonald, MD Professor Department of Physical Medicine & Rehabilitation and Pediatrics University of California Davis Medical Center Sacramento,California

CASE DESCRIPTION ment about all major joints. There is no reflex movement to gentle History noxious stimuli delivered over the sternum and soles of his feet. He responds to this indignity with a weak cry. His arms are held in A 6-month-old male infant is referred for evaluation of severe abduction with flexion at the elbows and pronation of the forearms. hypotonia and failure to achieve motor milestones. The baby His legs are held in extreme abduction with flexion at the knees was the product of a term gestation, born to a Gravida 3, Para 3, and ankles. Head control is essentially absent with the baby held 29-year-old mother. In retrospect, the mother believes that third prone and there is severe head lag when the child is passively pulled trimester fetal movements were not as vigorous as those noted in to a seated position from a supine position. With ventral suspen- her two previous pregnancies. The baby presented vertex and was sion under the axillae, the baby slips through the examiner’s hands. delivered vaginally. Birth weight was 2700 grams. APGAR scores The child is globally areflexic. There is a behavioral response to were 8 at 1 and 5 minutes with points off for color and tone. tickle and pinprick administered over the trunk and limbs, but no However, the child was not noted to be an unduly “floppy baby” active withdrawal from noxious stimuli. Upon gently opening the and the baby fed well. baby’s mouth, fine, nearly constant flickering tongue movements (“fasciculations”) are seen. Initial concerns occurred at 4 months of age when the child failed to achieve milestones that included rolling over and reaching for Screening laboratory studies include a normal complete blood objects. The maternal grandmother noted that the baby’s head count and basic metabolic panel. His creatine kinase (CK) is control was worse than it had been in the newborn period. All elevated at 300 IU (normal < 170 IU). caretakers were concerned that the baby exhibited little spontaneous movement of arms or legs. However, they were encouraged by the baby’s beaming smile and bright eyes “which followed our every DISCUSSION movement as we circled his crib.” Weakness that is associated with either failure to achieve motor There is no family history of parental consanguinity or neuromus- milestones or loss of previously acquired motor function is cular (NM) disease. Physical examination reveals an alert hyper- the symptom most likely to result in urgent NM referral. The vigilant child who makes ready eye contact and smiles socially at the clinician’s first task is localization of the problem to the central examiner. The baby’s respiratory pattern is unusual with retraction or peripheral nervous system; specific syndromes mimicking NM of the chest wall and upward heaving of the abdomen with each diseases must also be excluded. inspiration. There is a generalized decrease in muscle mass but no joint contractures. There is no visceromegaly. The baby lies in bed Weakness due to central nervous system (CNS) disorders is usually with almost no spontaneous limb movement. There is profound characterized by an “elective” distribution with maximal deficits in generalized hypotonia with almost no resistance to passive move- antigravity muscles, and preservation or exaggeration of deep tendon 12 Spinal Muscular Atrophy AANEM Course reflexes. Infants and toddlers often demonstrate hypotonia which is Table 1 Neuromuscular diseases of the infant disproportionate to the degree of weakness. Asymmetric motor deficits and concurrent difficulties with cognitive dysfunction, seizures, (The more common of rare diseases) and other “hard” symptoms of CNS dysfunction point to a central Motor Neuron disorder. Lower motor unit (MU) disorders usually demonstrate Classic autosomal recessive proximal spinal muscular atrophy (SMA) symmetric proximal or distal gradient. Low tone is proportional to Type I and II weakness. Deep tendon reflexes are usually depressed or unobtain- SMA with respiratory distress able (an important exception being post synaptic disorders of the X-linked SMA NM junction). Several disorders that are traditionally classified as NM diseases may present with or be dominated by CNS symptoms. The cognitive impairment seen in children with the infantile form of Peripheral Nerve myotonic dystrophy, Duchenne muscular dystrophy, and mitochon- Genetic neuropathies (Charcot-Marie-Tooth spectrum) drial encephalomyopathies are a few examples. Inflammatory neuropathies (early onset acute or chronic demyelinating polyradiuloneuropathy) Several infant onset NM diseases manifest clinical phenotypes that are so distinct and stereotyped that a diagnosis can be established Neuromuscular Junction on the basis of the history and physical examination. Most of these Myasthenia neonatorum “spot diagnoses” are genetic disorders, and several may be confirmed Congenital myasthenic syndromes by deoxyribonucleic acid (DNA) testing as the sole investigation. Infant botulism When an infant presents with a less specific clinical picture, a systematic consideration of disorders affecting each tier of the lower Myopathies11 MU must be considered (Table 1). It is appreciated that most of the Congenital myotonic dystrophy NM diseases listed have limited specific therapeutic interventions. Congenital muscular dystrophy (merosin negative and merosin positive) 14 Important exceptions include disorders of NM transmission and Early onset facioscapulohumeral muscular dystrophy classic infant onset Pompe disease, which is treated with recombinant Central core disease 8 acid alpha glucosidase enzyme replacement therapy. Myotubular myopathy Multicore/minicore disease Spinal Muscular Atrophy Nemaline myopathy Congenital fiber-type disproportion The clinical data presented above paint a pathognemonic picture of Desmin storage myopathy a child with Type 1 spinal muscular atrophy (SMA). The constella- Metabolic muscle disorders (Pompe disease8; Lipid storage myopathy) tion of paralytic hypotonia, paradoxical abdominal breathing, and Mitochondrial myopathies (including SCO2 mutations and mitochondrial tongue “fasciculations” place SMA on top of the list of differential depletion syndrome ) diagnoses. The trivial elevation of CK is frequently found in children with acute or subacute neurogenic disorders. Syndromic Hypotonia Down syndrome Other lower MU disorders can present a clinical phenotype very Prader Willi syndrome similar to that described above (Table 1). However, the classic clinical picture presented in this case report justifies proceeding with Type 1 SMA presents with clinical symptoms before 6 months DNA studies as the next diagnostic step. It is easy to make an initial of age. These children are never able to achieve independent diagnoses of SMA in children and then later find that the correct di- sitting. agnosis is a congenital muscular dystrophy or congenital myopathy. Type 2 SMA presents with symptoms before 18 months of age. Proximal 5q SMA is part of a family of motor neuronopathies. These children eventually sit unsupported but never achieve SMA is the most common cause of paralytic infantile hypotonia independent ambulation. and is the most common genetic lethal disorder in children under 2 years of age. The disease is inherited as an autosomal recessive Type 3 SMA presents after 18 months of age. Children achieve trait. Gene frequency is estimated at 1:60 to 1:80. The inci- independent ambulation. The clinical phenotype is broader than dence of childhood SMA has been estimated between 1:6000 and that described for younger children with Type 1 and Type 2 SMA, 1:15,000 live births. Symptoms of the disease are attributed to prompting Kugelberg and Welander to describe the phenomenon degeneration of anterior horn cells in the spinal cord and brain- of “juvenile SMA mimicking muscular dystrophy.” stem, culminating in flaccid weakness, respiratory insufficiency, and bulbar deficits. Because the clinical spectrum of proximal Type 4 SMA is known as “adult SMA”. Some of these adult onset SMA is dramatic, the use of an arbitrary classification system patients have SMA reflecting 5q mutations identical to those based on age of onset of symptoms and maximal motor milestones defined in patients with earlier onset SMA. Others have geneti- achieved has been employed. By convention, four SMA phenotypes cally distinct disorders affecting motor neurons (MNs). are defined.10,17 AANEM Course Neuromuscular Update I 13

It must be appreciated that although proximal 5q SMA is far and a role in pre-mRNA editing (splicing) and mRNA metabolism. away the most common form of infantile, genetic MN disease, SMN protein does not act in isolation but as part of a stable multi- other diseases including SMA with respiratory distress (SMARD), protein complex ubiquitously expressed in the cytoplasm and X-linked SMA, and SMA due to mitochondrial dysfunction may nucleus of all eukaryotic cells. In addition to SMN, the complex all present with remarkably similar clinical phenotypes. consists of at least seven other proteins called gemins 2 through.8 This structure plays a key role in the assembly of small ribonucleic proteins (snRNPs) which function as spliceosomes. The SMN TYPE 1 SMA complex in the nucleus co-localizes with Cajal bodies involved in transcription and processing of nuclear RNAs. Cytosolic SMN is Werdnig and Hoffman independently described Type 1 SMA in found in axons and growth cones, as well as the neuromuscular the 1890s. A full century elapsed before the genetic defect was junction. The cytosolic and peripheral actions of the SMN protein localized to chromosome 5q11.2-13 This was followed by the have not been fully elucidated. Researchers debate whether the identification of mutations in the survival motor neuron (SMN) deficiency of SMN produces a primary “central” or peripheral gene. The complexity of gene arrangements in the 5q11-13 dysfunction. Several excellent reviews of this complex subject domain thwarted early efforts to delineate candidate genes. This are available.5, 20 domain is characterized by an inversion duplication with near mirror images of several genes. In 1995, the mystery was solved.12 Two copies of the SMN gene were identified: a telomeric CLINICAL FEATURES SMN1 copy and a centromeric SMN 2 copy. A homozygous deletion, or point mutation, in the SMN1 gene is found in the Classic infantile Type 1 SMA is characterized by early onset of vast majority of patients with SMA. A nearly identical gene, disease symptoms. The disease clearly begins prenatally, but the centromeric SMN2 gene, is present in all patients with the first two trimesters of pregnancy are usually uneventful. proximal 5q SMA. The clinical severity of the phenotype is in part Approximately one-third of mothers report a decrease in fetal determined by the copy number of the SMN2 gene. SMN1 movements in the third trimester of pregnancy. Neonates may and SMN2 genes differ in a single nucleotide substitution. The be totally asymptomatic or may demonstrate obvious symptoms SMN genes are comprised of eight exons. The single nucleotide at birth. Early symptoms include hypotonia, muscle atrophy, change in the SMN 2 gene results in splicing out exon 7 of the generalized weakness, respiratory insufficiency, and bulbar dysfunc- messenger SMN2 ribonucleic acid (RNA). The delta 7 tion interfering with oral feedings.2 messenger RNA (mRNA) results in the translation of a truncated unstable protein. However, approximately 10% of the protein The major manifestations of SMA relate to death or dysfunction translated from the SMN 2 mRNA is full length. Thus, there is a of MNs in the anterior horn of the spinal cord and lower brain- “partial rescue” effect of the SMN2 gene. The number of SMN2 stem. There is no obvious involvement of facial musculature, copies provides a rough correlate as to the clinically predicted nor is there ever involvement of extraocular muscles. This results phenotype. Homozygous or compound mutations of the SMN1 in a bright, responsive facial expression and “precocious” social gene are found in all patients with proximal 5q SMA. A fetal interaction. The evolution of bulbar weakness may make feeding conceptus harboring no SMN2 gene copies is nonviable, precarious with risks of aspiration pneumonia. Quivering tongue culminating in spontaneous pre-implantation miscarriage. Infants movements (tongue fasciculations) are a critical diagnostic feature with only one SMN2 copy number usually have a severe clinical of Type 1 SMA. However, as a caveat to the pediatric neophyte, phenotype with symptoms often noted at birth (e.g., profound quivering tongue movements in a crying baby are notoriously weakness, joint contractures, and clinical and EDX evidence difficult to interpret. Visible and tactile fasciculations of limb of sensory as well as motor neuronopathy). Patients with two muscles are virtually never identified, due in part to overlying copies of the SMN2 gene constitute the majority of infants with adipose tissue present in all but the most emaciated infants. classic SMA type 1 (Werdnig Hoffman disease). Three copies However, quivering movements of outstretched fingers (poly- of the SMN2 gene provide more protection and are usually as- mini-myoclonus) is frequently seen in Type 1 and Type 2 SMA sociated with the Type 2 SMA phenotype. Patients with four or children.2 Profound impairment of head control in both prone more copies of SMN2 usually present a Type 3 SMA (Kugelberg and supine positions is universally encountered and is a very early Welander) phenotype. Current commercially available DNA manifestation of motor compromise. Type 1 SMA infants tend testing includes SMN1 deletions, SMN1 point mutations, and to assume a characteristic posture cruelly termed the “pithed frog SMN2 copy number.16 However, a prediction of the clinical leg position.” The infant’s thighs are flexed at the hip and mark- phenotype cannot be made solely on the basis of a SMN2 copy edly externally rotated; the knees and ankles are flexed. Upper number. extremity posture is characterized by arm abduction, internal rotation of the shoulders, and flexion of the elbows. Although The pathogenesis of SMA is incompletely understood.9,21 Although limb weakness is generalized, it is nearly always more obvious SMN is expressed in all tissues, SMN1 (full length) protein in proximal muscle groups, and leg involvement is more severe deficiency disproportionately affects lower MNs. SMN1 protein is than arms. Unlike children with central hypotonia, noxious localized in both the nucleus and cytoplasm of MNs. 3 The nuclear stimulation does not result in an augmentation of spontaneous or SMN is largely associated with structures called gems which have withdrawal movement. 14 Spinal Muscular Atrophy AANEM Course

The respiratory pattern of children with type 1 SMA is charac- SMA1 due to early involvement of the diaphragm and a gradient teristic and nearly pathognemonic. Due to severe weakness of of distal as opposed to proximal muscle weakness. An X-linked intercostal muscles, the chest wall assumes a flattened and “bell form of SMA has been documented in several, nonrelated fami- shaped” configuration. This is accentuated by relative preservation lies. Recently, mitochondrial diseases producing an SMA picture of diaphragm function. With each inspiration, the anterior thorax have been reported. Two distinct syndromes including defects retracts and the abdomen rises, reflecting diaphragmatic descent. of the synthesis of cytochrome oxidase 2 (SCO2) gene has been delineated.19, 22 These present as atypical SMA1; the findings of Therapeutic interventions in SMA are addressed below. The lactic acidosis and hypertrophic cardiomyopathy are the clues that various aspects of supportive care directly mirror motor deficits separate this disorder from classic SMA. A mitochondrial deple- as described. The single greatest threat to Type 1 SMA children tion syndrome due to thymidine kinase 2 (TK2) may also produce is respiratory insufficiency complicated by atelectasis and aspira- a Type 1 SMA phenotype. tion pneumonia.1 Bulbar dysfunction oftentimes compromises oral intake, culminating in malnutrition. Long-term Type 1 SMA Clinical Trials survivors almost invariably develop orthopedic deformities that include heel cord contractures and scoliosis. A comprehensive The molecular understanding of the pathophysiology of SMA consensus statement regarding the standard of care for SMA is incomplete. The hope is that populations of impaired, but patients was recently published and provides important guidelines potentially viable MNs will respond to appropriate therapeutic for health care providers and caregivers of children with SMA. 23 intervention. Empiric strategies utilizing neuroprotective drugs to facilitate anterior horn cell rescue have included trials of riluzole Laboratory Diagnosis and gabapentin, but the results have been disappointing. Current therapeutic efforts have focused upon increasing SMN2 function. Prior to the development of sensitive molecular DNA testing, the A murine model has been developed with knock out of the SMN1 diagnosis of all types of SMA was based on clinical suspicion sub- gene and introduction of variable copy numbers of the human stantiated by EDX and muscle biopsy findings. In the majority of SMN2 gene. Transgenic mice who harbor multiple copies of the cases, DNA testing has replaced electromyography (EMG) and human SMN2 gene are clinically “nearly normal.” Drugs that muscle biopsy as the definitive diagnostic procedure. Screening increase SMN2 function by upregulation of the gene include tests with CK are normal or are only slightly elevated (<3 times histone deacetylase (HDAC) inhibitors. Trials of HDAC inhibi- the upper limits of normal). EDX studies are rarely performed as tors such as valproic acid, hydroxyurea,4,13, and phenylbuterate are the initial diagnostic investigation in infants manifesting the classic currently underway. The use of antisense oligonucleotides to force clinical Type 1 phenotype, but are very helpful when the clinical di- inclusion of exon 7 in the SMN2 mRNA is under investigation. The agnosis is less certain.6,15 Sensory nerve conduction studies (NCSs) development of high throughput screening techniques facilitates are stated in most text books to be “uniformly normal “and is true preclinical screening of hundreds of thousands of small molecules in most cases of Type 1 SMA. However, very severe cases of Type which may have a salutary effect on either SMN2 upregulation or 1 SMA, usually associated with the molecular genetic correlate of splicing modulation to promote the translation of full length a single SMN2 gene, may demonstrates the EDX phenotype of SMN protein. a profound sensory and motor axonal neuropathy. Motor NCSs usually reveal decreased compound muscle action potential amplitudes, reflecting decreased MU numbers. Motor nerve conduction REHABILITATION AND MANAGEMENT ISSUES IN SMA velocities are either normal or slightly reduced, reflecting a loss of the fastest conducting motor axons. Needle EMG demonstrates The care of patients with SMA is often complex with many medical abnormal insertional activity with fibrillations and positive waves. issues to consider. When possible, a multidisciplinary team There is decreased MU recruitment of rapidly firing MUs (many approach is an effective way to care for SMA patients. A current of which are temporally unstable to delay line analysis). In cases understanding of the clinical management and rehabilitative care of characterized by profound motor deficits and compromised rein- patients with SMA will be reviewed. nervation, MU amplitude and duration are quite variable. True fasciculations are rarely seen in type 1 SMA. Bulbar Dysfunction and Swallowing Problems

Muscle biopsy reveals large group atrophy with whole fascicles of Bulbar dysfunction is more commonly observed in Type 1 SMA, tiny muscle fibers. These alternate with hypertrophic mini-fascicles but can also occur in Type 2 SMA and Type 3 patients especially usually comprised entirely of type 1 muscle fibers. during the later stages of the disease. Such bulbar involvement leads to problems in buccal and pharyngeal propulsion activities during eating, and it can also contribute to impaired airway DIFFERENTIAL DIAGNOSIS protection.6,37,51 The prevalence of self-reported symptoms of swallowing difficulty in 85 Type 2 SMA and III patients was 36.5% The differential diagnosis of SMA includes other autosomal reces- in one study.51 Fluoroscopic swallowing evaluations in four Type sive SMA syndromes such as SMARD, due to mutations of the 1 SMA patients revealed involvement of both the anterior and µ-immunoglobulin binding gene. SMARD differs from the classic posterior phases.37 Impairment of facial musculature in SMA results AANEM Course Neuromuscular Update I 15 in weakened mastication. In addition, SMA patients have been independently.26 Carter and colleagues41 showed significant reduc- found to have abnormal craniofacial growth patterns. The maloc- tions in FVC over time with increasing disease durations in Type clusion of teeth has been attributed to various factors including 2 SMA, but not in Type 3 SMA subjects. In addition, Type 2 weakness of masticatory muscles, tendency for mouth breathing, SMA patients showed relatively more severe declines in maximal and poor head positioning.22,23 Management of malocclusion expiratory pressure (MEP) versus maximal inspiratory pressure in SMA patients may be important for optimal nutrition and (MIP), suggesting relative diaphragmatic sparing.10,11,27,32,33 respiratory function. Progressive restrictive lung disease in Type 3 SMA was shown to be relatively mild and rarely necessitated the institution of ventilatory Body Composition and Nutrition support.3,16,20,49

Patients with Type 1 and Type 2 SMA are often of small stature Although no specific spirometry parameters for beginning ventila- and have greatly diminished muscle bulk.5,7 Magnetic resonance tory support have been established, it has been found that the insti- imaging of limbs has demonstrated severe muscular atrophy in tution of mechanical ventilation in Type 2 SMA was generally not Type 1 SMA and Type 2.13 In addition, increased subcutaneous required until FVC was about 20% of the predicted value.16,20,31,49 fat is observed in these patients. In comparison, muscles of Type 3 This parameter is not absolute and ventilatory support has been SMA patients showed less atrophy but significant fatty infiltration. initiated at FVC values in the mid-30% range.3 Other useful In these more chronic cases, the use of skin fold measurements may pulmonary function measurements include MIP, MEP, and peak not accurately reflect the percentages of lean and fat mass. cough flow. When these values decline, it can be indicative of poor airway clearance function, increased risk for infection, and Diffuse weakness, bulbar dysfunction, and/or respiratory distress hastened respiratory failure. In most specialty NM disease clinics, may affect feeding in SMA patients. Therapeutic modifications spirometry evaluation is typically performed at least annually for may include use of a premature baby nipple with a large opening, those SMA patients with impaired lung function (and 6 months use of proper head and jaw position along with a semi-reclined or more frequent for those at higher risk). Children older than 5 trunk position, and use of frequent small feedings to minimize years can usually cooperate and follow directions reliably enough fatigue.7,30 The use of larger bolus feeds may distend the stomach to perform spirometry. and encroach upon the diaphragm. Improved nourishment and nutritional status in individuals with SMA has shown to lead to a Over the last decade, advances in noninvasive ventilation feeling of well being and a better quality of life.7 Poor nutritional technology, increased variety of ventilation interface devices, and status, labored feeding, and/or symptoms of dysphagia are indica- miniaturization of ventilators leading to better portability have tions for initiation of supplemental enteral feedings via nasogastric all contributed to improved pulmonary management of patients tube or gastrostomy. Supplemental enteral feedings may be with SMA. Treatment of severe respiratory insufficiency in SMA performed by bolus, gravity drip, or continuously during the night may utilize noninvasive intermittent positive pressure ventilation via a pump. Another common issue facing SMA patients is consti- (NIPPV) via oral and/or nasal interfaces, nasally applied bi-level pation. This is especially problematic for infants. Constipation is positive airway pressure (BiPAP), or positive pressure mechanical thought to be caused by combination of weak abdominal muscles ventilation via a tracheostomy.16,38,49 In any method, the most and immobility. Chronic constipation and impaction can further important factor is to obtain a good seal around the interface. decrease the already impaired lung function, as well as decrease The noninvasive ventilation method is particularly convenient oral intake in these patients. Appropriate dietary management and for nighttime use. In general, nocturnal NIPPV appears to be hydration that is supplemented with laxatives, are effective in the effective for sleep-disordered breathing and nighttime hypoventila- maintenance of optimal bowel care for affected patients. tion encountered in patients with various NM diseases. In most cases, BiPAP mode of ventilation rather than continuous positive Pulmonary Function Testing and Respiratory airway pressure (CPAP) is appropriate for restrictive lung volume Management processes secondary to progressive NM diseases. However, CPAP may have a role, particularly in young infants with Type 1 SMA Restrictive lung disease is the most common and serious complica- who are unable to effectively synchronize with BiPAP. In all cases, tion facing patients with SMA. In general, the severity of restrictive frequent monitoring for adequate mask fit and appropriate ventila- lung disease is proportional to weakness and functional class of tor pressure level settings is necessary. SMA. It is most severe in infants with Type 1 SMA, while it may not affect patients with Type 3 SMA.4,30 Samahu and colleagues26 Continuous invasive ventilatory support via tracheostomy should showed that absolute forced vital capacity (FVC) was significantly be considered when contraindications or patient aversion to related to height index and functional level in 5 to 18 year olds with noninvasive ventilation are present, or when noninvasive ventila- SMA. Ambulatory patients showed normal or near normal values, tion is not feasible due to severe bulbar weakness or dysfunction. while nonsitters showed the lowest values, with absolute FVC less In these cases, discussions following careful consideration of the than 1 to 1.56 liters. A need for ventilatory support through inter- patient/family’s desires, child’s prognosis, and child’s quality of life mittent positive pressure breathing (IPPB) was directly related to can often lead to a satisfactory resolution. For those SMA patients FVC and functional status. Two thirds of those who could only sit requiring full-time ventilatory support, portable ventilators can supported used IPPB compared to only 5% of those who walked 16 Spinal Muscular Atrophy AANEM Course now be easily attached to power wheelchairs, markedly improving goals of surgery. Segmental sublaminar wiring with Harrington quality of life for these patients in the community. rods, or more recently Luque instrumentation, has resulted in an average correction of approximately 50%, with maintenance of the Secretion management and airway clearance are also very impor- correction continuing for years after surgery.17 Anterior surgical tant aspects of respiratory care in SMA patients. Manual cough approaches in SMA patients can result in significant respiratory dif- assist techniques performed by a caregiver, family member, or ficulty postoperatively and diminished pulmonary function over the mechanical insufflator-exsufflators (cough-assist machines) can help long-term. Nocturnal pulse oximetry can provide valuable infor- improve airway clearance and secretion management. In addition, mation about potential post-operative ventilation needs. In those use of these methods in conjunction with noninvasive ventilation patients at risk, pre-operative mask-fitting and initiation of NIPPV pre- and postoperatively have helped significantly to improve the can improve post-operative respiratory recovery.2 Postoperative pulmonary care of patients with SMA that are undergoing surgery. management after scoliosis surgery includes early involvement of Intrapulmonary percussive devices and ventilators are available to physical and occupational therapies, mobilization out of bed when help mobilize secretions and improve pulmonary hygiene. clinically stable, pain control, ventilatory support as needed, and appropriate pulmonary toilet. As in other NM diseases, spinal ar- Sleep disordered breathing and nocturnal alveolar hypoventila- throdesis does not significantly improve the restrictive lung disease tion are manifestations of worsening restrictive lung disease and component of SMA by increasing the FVC. respiratory failure in SMA. Sleep disordered breathing is now recognized as a significant cause of morbidity in SMA.34 Common Decline in some functional activities can occur after spinal signs and symptoms that suggest sleep-disordered breathing include arthrodesis. The most common includes decreased gross motor nightmares, morning headaches, and daytime drowsiness. A skills, transfer ability, self-feeding, hygiene, dressing, independent 8,15,42 polysomnography with continuous CO2 monitoring is helpful in toileting, and ambulation. Spinal fixation may impair both determining sleep-related hypoventilation. However, a nocturnal compensatory lumbar lordosis and lateral trunk sway which are pulse oximetry in the home environment can serve as an acceptable used by ambulatory patients to compensate for proximal weakness. screening tool for sleep-related oxyhemoglobin desaturation and Therefore, surgery is best deferred until ambulatory function loss alveolar hypoventilation when polysomnography is unavailable. is imminent or already lost. Patients and care providers should Other general measures for patients with restrictive lung disease be adequately informed about possible short-term and long-term include yearly influenza and pneumococcal vaccination. A recent functional consequence of spinal arthrodesis. update regarding respiratory care of patients, as well as a consensus statement for standard of care in SMA, are available for more Hip Dislocations and Contractures information and detail.25,48 Nonambulatory SMA patients have a high incidence of coxa valga Spine Deformity of the proximal femur and hip subluxation. Frank hip dislocation associated with pelvic obliquity is commonly noted. Significant pain Scoliosis has been estimated to occur in 78% to nearly 100% of associated with hip subluxation or dislocation is rare.45,52 Operative Type 2 SMA patients.11,14,18 Scoliosis almost always begins in treatment of hip subluxation or dislocation in SMA appears to the first decade of life as a result of severe truncal weakness. The be poor with a high recurrence rate.46,52 Current consensus is curves are collapsing in nature and are either thoracolumbar (62%), nonoperative conservative management. Contractures are problem- thoracic (12%), lumbar (10%), or double curves involving thoracic atic in Type 2 and Type 3 SMA patients who have lost ambulatory with lumbar or thoracic with thoracolumbar (16%).1,14,17,21,25,39,42 function. Reductions in range of motion (ROM) by greater than The average deformity observed over 10 studies was 90 degrees 20º were found among 22% to 50% of Type 2 SMA subjects.11 with a reported range from 20 degrees to 164 degrees.44 Severe Hip, knee, and wrist contractures are the most common. Patients kyphosis may be a common associated deformity18 and virtually all with SMA perceive their elbow flexion contractures to hinder one patients with severe scoliosis have significant pelvic obliquity.17 In or more daily functions and the contractures were reported to be contrast, Type 3 SMA patients who are ambulatory have less sco- associated with greater discomfort.50 Occupational and physical liosis with reported prevalence of 8% to 63%.14,18 Spinal bracing is therapy referral, as well as daily home stretching program with generally used in SMA patients who are unable to walk or to improve caregivers, should continue to prevent formation of significant joint sitting balance. However, bracing has been repeatedly shown to be contractures. Serial casting for contractures can be used, but a clear ineffective in preventing eventual progression of the scoliosis.1,18,35 and practical goal for improved ROM should be kept in mind. In addition, there is concern with bracing that it may compress the rib cage and further impair the pulmonary function by lowering the Osteopenia and Fractures vital capacity.36,40 Osteopenia is a common finding among SMA patients. Fractures Spinal fusion surgery is the only effective treatment for scoliosis in at birth may occur in SMA.9 Falls may also lead to fractures in SMA.1,12,14,17,18,21,35,39,40,42 For children over the age of 10 years SMA after seemingly trivial trauma.19,47 In one series, fractures with curves exceeding 60 degrees, instrumentation with posterior occurred in 15% of Type 2 SMA cases and 12% of Type 3 SMA fusion is the definitive choice.17 Most consider improved cosme- subjects.24 Bone mineral density is significantly reduced in SMA, sis, balance, and comfort in the sitting position to be the primary and the nature of bone mineralization at the epiphysis as compared AANEM Course Neuromuscular Update I 17 to the diaphysis may be different. A recent study of bone density with the care of patients with SMA requires a coordinated multi- in SMA patients by dual energy x-ray absorptiometry (DEXA) scan disciplinary approach. suggests that osteopenia may be secondary to factors other than immobility.28 Currently, there are studies that suggest SMN protein’s possible role in bone remodeling.29,43 Rigid cast CASE STUDY, DISCUSSION, DIAGNOSIS REFERENCES immobilization of fractures should be avoided to prevent a cycle of worsening osteopenia and further fractures. Calcium and vitamin 1. Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E. Long-term D supplementation is reasonable based on DEXA results. survival in Werdnig-Hoffmann disease. Am J Phys Med Rehabil. 2007 May;86(5):339-345. Interventions to Improve Function 2. Brooke, MD: Spinal Muscular Atrophy in “A clinicians view of neuromuscular disease (2nd edition) Williams and Wilkins 1986. Interventions designed to improve functioning of SMA patients 3. 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Burke SW, Jameson VP, Roberts JM, et al: Birth fractures in spinal ventilation in Duchenne muscular dystrophy and spinal muscular muscular atrophy. J Pediat Orthop 1986; 6:34-36. atrophy. Chest 1995; 108(3):779-785. 10. Carter GT, Abresch RT, Fowler WM Jr, et al: Profiles of neuromus- 32. McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Hereditary motor and sensory neuropathy, types I and cular diseases: Becker’s muscular dystrophy. Am J Phys Med Rehabil II. Am J Phys Med Rehabil 1995; 74(suppl):S140-S149. 1995; 74(suppl):S93-S103. 11. Carter GT, Abresch RT, Fowler WM Jr, et al: Profiles of neuromus- 33. McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuro- cular diseases: Spinal muscular atrophy. Am J Phys Med Rehabil muscular diseases: Duchenne muscular dystrophy. Am J Phys Med 1995; 74(suppl):S150-S159. Rehabil 1995; 74(suppl):S70-S92. 12. Daher YH, Lonstein JE, Winter RB, et al: Spinal surgery in spinal 34. Mellies U, Dohna-Schwake C, Stehling F, et al: Sleep disordered muscular atrophy. J Pediat Orthop 1985; 5:391-395. breathing in spinal muscular atrophy. Neuromuscul Disord. 2004 13. Eng GB, Binder H, Koch B: Spinal muscular atrophy: Experience Dec;14(12):797-803. in diagnosis and rehabilitation in management of 60 patients. Arch 35. Merlini L, Granata C, Bonfiglioti S, et al: Scoliosis in spinal muscular Phys Med Rehabil 1984; 65-549-553. atrophy: Natural history and management. Devel Med Child Neurol 14. Evans GA, Drennan JR, Russman BS: Functional classification and 1989; 31:501-508. orthopedic management of spinal muscular atrophy. J Bone Joint 36. Noble-Jamieson C, Heckmatt JZ, Dubowitz V, et al: Effects of Surg 1981; 63-B(4):516-522. posture and spinal bracing on respiratory function in neuromuscular 15. Furumasu J, Swank SM, Brown JC, et al: Functional activities in disease. Arch Dis Child 1986, 61:178-181. spinal muscular atrophy patients after spinal fusion. Spine 1989; 37. Nutman J, Nitzan M, Grunebaum M: Swallowing disturbances in 14:771-775. Werdnig-Hoffmann disease. Harefuah 1981; 101:301-303. AANEM Course Neuromuscular Update I 19

38. Padman R, Lawless S, Von Nessen S: Use of BiPAP by nasal mask 46. Thompson CE, Larsen LJ: Recurrent hip dislocation in intermediate in the treatment of respiratory insufficiency in pediatric patients: spine atrophy. J Pediatr Orthop 1990; 10:638-641. Preliminary investigation. Pediatr Pulmonol 1994; 17:119-123. 47. Vestergaard P, Glerup H, Steffensen BF, et al: Fracture risk in pa- 39. Piasecki JO, Mahinpour S, Levine DB: Long-term follow-up of tients with muscular dystrophy and spinal muscular atrophy.J Rehabil spinal fusion in spinal muscular atrophy population. Clin Orthop Med. 2001;33(4):150-155. 1986; 207:44-54. 48. Wang CH, Finkel RS, Bertini ES, et al; Participants of the International 40. Riddick MF, Winter RB, Lutter LD: Spinal deformities in patients Conference on SMA Standard of Care. Consensus statement with spinal muscle atrophy: A review of 36 patients. Spine 1982: for standard of care in spinal muscular atrophy. J Child Neurol. 7:476-483. 2007;22(8):1027-1049. 41. Samahu FJ, Buncher CR, Russman BS, et al: Pulmonary function in 49. Want TG, Bach JR, Avilla C, et al: Survival of individuals with spinal spinal muscular atrophy. J Child Neurol 1994; 9(3):326-329. muscular atrophy on ventilatory support. Am J Phys Med Rehabil 42. Schwentker EP, Gibson DA: The orthopedic aspects of spinal mus- 1994; 73:207-211. cular atrophy.; J Bone Joint Surg 1976: 58-A:32-38. 50. Willig TN, Bach JR, Rouffet MJ, et al: Correlation of flexion con- 43. Shanmugarajan S, Swoboda KJ, Iannaccone ST, et al: Congenital tractures with upper extremity function and pain for spinal muscular bone fractures in spinal muscular atrophy: functional role for SMN atrophy and congenital myopathy patients. Am J Phys Med Rehabil protein in bone remodeling. J Child Neurol. 2007;22(8):967-973. 1995; 74:33-38. 44. Shapiro F, Specht L: The diagnosis and orthopedic treatment of 51. Willig TN, Paulus J, Lacau Saint Guily J, et al: Swallowing problems childhood spinal muscular atrophy, peripheral neuropathy, Friedreich’s in neuromuscular disorders. Arch Phys Med Rehabil 1994; 75:1175- ataxia, and arthrogryposis. J Bone Joint Surg 1993; 75-A:1699-1714. 1181. 45. Sporer SM, Smith BG. Hip dislocation in patients with spinal muscu- 52. Zenios M, Sampath J, Cole C, et al: Operative treatment for hip lar atrophy. J Pediatr Orthop. 2003 Jan-Feb;23(1):10-14. subluxation in spinal muscular atrophy. J Bone Joint Surg Br. 2005 ;87(11):1541-1544. 20 AANEM Course 21

Myeloneuropathy

Neeraj Kumar, MD Associate Professor Department of Neurology Mayo Clinic Rochester, Minnesota David S. Saperstein, MD Private Practice Phoenix Neurological Associates Phoenix, Arizona James K. Richardson, MD Associate Professor Department of Physical Medicine and Rehabilitation University of Michigan Ann Arbor, Michigan

CASE DESCRIPTION Prior Studies

History Brain magnetic resonance imaging (MRI), including gadolinium-enhanced T1 weighted images, was normal. MRI A 63-year-old woman was evaluated in the multiple sclerosis clinic of the cervical spine revealed an increased signal on the for a 3-month history of intermittent hand numbness and tingling. T2-weighted sequence that involved the posterior parame- The initial clinical impression of a carpal tunnel syndrome was not dian cervical cord and extended from C2 to C6. Also present substantiated on nerve conduction studies (NCSs). One month were moderate spondylotic changes from C3 to C6. MRI of following the hand paresthesias, she noted that neck flexion would the thoracic spine was normal. The initial clinical consideration trigger an electric tingling sensation from her neck down the spine of multiple sclerosis led to a cerebrospinal fluid examination and into both upper and lower extremities. For the same duration, and visual evoked potential studies, both of which were un- she had noted distal lower limb tingling and imbalance that wors- remarkable. Somatosensory evoked potential (SEP) studies ened in the dark. showed a central conduction delay that localized to the cervical segments. Examination Current Studies Mental status and cranial nerves were normal. Strength was normal except for mild weakness of intrinsic hand muscles. Sensory testing Routine biochemical studies were unremarkable. Her hema- revealed mild glove-and-stocking distribution loss of light touch and tology group was normal except for a slight macrocytosis pain sensation with moderate reduction of proprioception, and vi- (mean corpuscular volume 101.2 fl, normal: 81.6-98.3 fl). bration in the toes and fingers. Upper limb coordination, as assessed Serum vitamin B12 was on the lower side of the normal by the finger-nose test, showed worsening with eyes closed (more so range at 211 ng/L (normal: 180-914 ng/L). Serum methyl- on the right side). Deep tendon reflexes were brisk except the ankle malonic acid was elevated at 0.51 µmol/L (normal: 0.08-0.46 jerks which were depressed on the left and absent on the right. The µmol/L) and plasma homocysteine was within normal limits. plantar response was flexor. Romberg test was positive. Her gait was Further investigations done to identify the cause of the low- cautious and worsened significantly when walking tandem. Her only normal vitamin B12 included intrinsic factor antibodies which medication was gabapentin, 900 mg a day, in three divided doses. were positive. 22 Myeloneuropathy AANEM Course

DIFFERENTIAL DIAGNOSIS of hereditary spastic paraparesis, myelopathy or myeloneuropathy is rarely the only manifestation in hereditary disorders. It can be The distal paresthesias in the case presented could have been ex- the presenting manifestation or predominant manifestation during plained by peripheral nerve dysfunction alone. Impaired distal pro- a stage of the disease process. Not infrequently, the MRI in these prioception/ vibration and brisk reflexes suggest localization to the conditions can be normal or show nonspecific findings such as spinal cord with dorsal column and corticospinal tract involvement, cord atrophy. The presence of a signal change involving the dorsal respectively. Worsening of gait in the dark, a positive Romberg, and column or corticospinal tract can help limit the associated differ- the presence of Lhermitte phenomenon, are all manifestations of ential diagnosis. dorsal column involvement. The absence of significant lower limb weakness indicates that her walking difficulty is primarily due to The references provided are restricted to those from the past 5 dorsal column involvement. MRI shows increased signal involving years. Included in the references are review articles and book chap- the dorsal column in the cervical cord. SEP studies show central ters that can direct the interested reader to more detailed bibliog- conduction delay that localizes to the cervical segment. The glove raphies.3,5,6,14,15,21,22,24 and stocking distribution of symptoms and the reduced ankle jerks suggests some peripheral nerve involvement. The patient most likely has a myeloneuropathy and a related differential diagnosis. MYELONEUROPATHIES DUE TO SPECIFIC NUTRIENT DEFICIENCY The differential diagnosis discussed here excludes causes of my- Vitamin B Deficiency and Related Conditions elopathy in which peripheral nerve involvement is not seen. 12 Compressive, inflammatory-infectious, vascular, and traumatic causes of a myelopathy are, therefore, not included. Conditions Neurological signs and symptoms may be the earliest manifesta- such as sarcoidosis, connective tissue disorders, and paraneoplastic tion of vitamin B12 deficiency and not infrequently have a subacute disease can have variable cord and peripheral nerve involvement. onset.14,15,24,25 They may be unaccompanied by hematological These conditions may merit consideration in some situations. The manifestations such as anemia, macrocytosis, neutrophil hyperseg- focus of the differential diagnosis in this case is on metabolic-toxic mentation, or megaloblastic marrow changes. Neurological mani- and hereditary disorders. Many of these conditions have clinical, festations may include a myelopathy with or without an associated electrophysiological, and neuropathological similarities. Dorsal peripheral neuropathy, cognitive impairment, optic neuropathy, column involvement results in impaired position and/or vibration autonomic dysfunction, paresthesias without abnormal signs, and perception and sensory ataxia. Corticospinal tract involvement rarely leukoencephalopathy. Symptom onset may be in the hands; may lead to weakness, spasticity, hyperreflexia, extensor plantar concomitant involvement of the upper and lower limbs may be responses, or sphincteric dysfunction. Variable degrees of periph- seen.25 MRI abnormalities include increased T2-weighted signal in eral nerve and/or optic nerve involvement may be present. While the subcortical white matter and posterior and lateral columns.20 therapy-related improvement may occur in metabolic myelopa- Less common neuroimaging findings include contrast enhance- thies, a common outcome of therapeutic intervention is cessation ment involving the dorsal and lateral columns, decreased dorsal of progression. Electrophysiological studies may show evidence of column signal on T1-weighted images, and cord swelling. central conduction delay, at times with variable peripheral nerve involvement. A term that has been used to describe some of these Though a widely used screening test, serum vitamin B12 measure- myelopathies is central-peripheral distal axonopathy. Use of this ment has technical and interpretive problems and lacks sensitivity 2 term emphasizes the fact that in “dying back disorders” both the and specificity for the diagnosis of vitamin B12 deficiency. Serum central nervous system (CNS) and peripheral nervous system vitamin B12 can be normal in some patients with vitamin B12 de- (PNS) display a distal axonal degeneration. Loss of dorsal root gan- ficiency, and serum methylmalonic acid and total homocysteine glion cells results in axon loss in the peripheral nerves and spinal levels are useful diagnostic studies. One third of individuals with cord. The distal part of the dorsal column in the cervical cord, low-normal vitamin B12 levels may have elevated methylmalonic distal part of the corticospinal tract in the lumbar cord, and distal acid and/or homocysteine levels. Methylmalonic acid is at least peripheral nerves are preferentially involved. as sensitive as homocysteine for the diagnosis of vitamin B12 deficiency but has superior specificity. Folate deficiency can cause Myelopathies that have a metabolic basis are commonly due to an elevation in homocysteine levels. Elevated methylmalonic acid specific nutrient deficiencies (e.g., subacute combined degeneration and homocysteine levels may also be seen in renal insufficiency of the cord due to vitamin B12 deficiency). Some metabolic myel- and rare genetic disorders. opathies have a hereditary basis (e.g., spinal xanthomatosis). Three forms of hereditary myelopathies are recognized: those that have a Despite extensive investigations, the cause of vitamin B12 de- pure or predominantly motor phenotype (e.g., hereditary spastic ficiency often remains unknown. Vitamin B12 deficiency com- paraplegia [HSP]), those with a predominantly ataxic phenotype monly results from reduced gastrointestinal absorption. The

(e.g., Friedreich ataxia [FA]), and those with a white matter or incidence of vitamin B12 deficiency increases with age and is due leukodystrophy phenotype (e.g., adrenomyeloneuropathy [AMN]). to accompanying hypochlorhydria. This is because an acidic envi-

The identification of new genes and loci has blurred the distinction ronment in the stomach is needed for vitamin B12 to be released between these three categories. With the exception of some forms from food. Pernicious anemia, a prior history of gastric surgery AANEM Course Neuromuscular Update I 23

(bariatric surgery, surgery for peptic ulcer disease), and other Because of copper’s ubiquitous distribution and low daily require- causes of malabsorption (ileal disease, pancreatic insufficiency, ment, acquired dietary copper deficiency is rare. Copper deficiency bacterial overgrowth) are additional etiologies of vitamin B12 may result from malabsorption, excess zinc ingestion, and inade- deficiency. Pernicious anemia is associated with positive intrinsic quate supplementation during enteral or total parenteral nutrition. factor antibodies. Other laboratory findings of limited specificity Not infrequently, the cause for copper deficiency is not known. Of in pernicious anemia include an elevated serum gastrin, decreased the known causes of acquired copper deficiency, the most common pepsinogen I, and gastric parietal cell antibodies. Despite the is a prior history of gastric surgery. As stated earlier, a prior history fact that methionine synthase requires folate as a cosubstrate, for of gastric surgery is also a risk factor for B12 deficiency. In a recent reasons that are not understood, neurological complications due series of post-bariatric surgery related neurological complications, to folate deficiency are rare and controversial. Folate deficiency myelopathy due to copper and/or vitamin B12 deficiency was noted often coexists with other nutrient deficiencies. The megaloblastic as the most commonly seen neurological complication.10 A low anemia due to folate deficiency is indistinguishable from that serum copper does not imply copper deficiency. Wilson disease, seen in vitamin B12 deficiency. Nitrous oxide (“laughing gas”) a disease of copper toxicity, is also associated with a low serum is a commonly used inhalational anesthetic agent that has been copper. In Wilson disease, urinary copper excretion, free serum abused due to its euphoriant properties. It is a potent oxidizing copper, and copper content in the liver and brain is elevated. A agent that produces irreversible oxidation of the cobalt core of low serum copper can also be seen in some carriers of the Wilson cobalamin and renders methylcobalamin inactive. Earlier reports disease gene. Aceruloplasminemia, a disorder of iron metabolism, of nitrous oxide toxicity were among dentists, medical or nursing is also associated with a low serum copper despite there being no staff working in poorly ventilated surgeries, and in patients with disturbance in copper metabolism. a borderline vitamin B12 status after prolonged nitrous oxide anesthesia. More recently, the practice has been seen among uni- Copper and vitamin B12 deficiency can coexist. Both may be associ- versity students. Neurological manifestations may be seen despite ated with hematologic manifestations with or without neurologic a normal vitamin B12 level. Signs and symptoms appear relatively derangement. Continued progression of symptoms in patients with rapidly with nitrous oxide toxicity but may be delayed by a few a subacute combined degeneration due to vitamin B12 deficiency weeks after acute exposure. Increased prevalence of vitamin B12 despite adequate vitamin B12 replacement should prompt a search deficiency has been recognized in human immunodeficiency for underlying copper deficiency. virus (HIV) infected patients with neurological symptoms. The histopathology of acquired immune deficiency syndrome (AIDS) Vitamin E Deficiency associated myelopathy resembles that of subacute combined degeneration seen in vitamin B12 deficiency. The pathogenesis in Neurologic manifestations of vitamin E deficiency include a many cases of AIDS-associated myelopathy may not be related to progressive spinocerebellar syndrome with peripheral neuropathy direct HIV infection of the spinal cord.4 and dorsal column dysfunction. Clinical features include gait difficulty, hypo- or areflexia, pyramidal signs, impaired position and In the case presented, the clinical presentation and neuroimaging vibration perception, dysarthria, ophthalmoplegia, and pigmen- are consistent with the subacute combined degeneration that is tary retinopathy.14,15,24 The clinical presentation may be similar seen with vitamin B12 deficiency. Her low-normal vitamin B12 to that of subacute combined degeneration or Friedreich ataxia. levels suggest that the neurologic manifestations could be due to MRI may show high-signal lesions on T2-weighted images in the vitamin B12 deficiency. The elevated methylmalonic acid levels posterior columns. confirmed metabolically significant vitamin B12 deficiency. The underlying cause of vitamin B12 deficiency in her case is pernicious In patients with neurological manifestations due to vitamin E anemia. deficiency, the serum vitamin E levels are frequently undetect- able. Serum vitamin E levels are dependent on the concentra- Copper Deficiency tions of serum lipids. Hyperlipidemia or hypolipidemia can independently increase or decrease serum vitamin E, respec- The most common manifestation of acquired copper deficiency tively, without reflecting similar alterations in tissue levels of the is a myelopathy or myeloneuropathy that resembles the subacute vitamin. Serum vitamin E concentrations may be artifactually 13,16 combined degeneration seen with vitamin B12 deficiency. Also in the normal range in patients with vitamin E deficiency due described is asymmetric motor weakness and atrophy with sensory to cholestatic liver disease, a condition in which lipid levels are signs or symptoms and electrodiagnostic (EDX) evidence of diffuse often elevated. denervation.26 Hematological manifestations of acquired copper deficiency (anemia, neutropenia, and a left shift in granulocytic Vitamin E deficiency in adults may be due to gastrointestinal, and erythroid maturation) are not always present. Spinal cord MRI pancreatic, or hepatic disease. In addition to these causes, par- in patients with copper deficiency myelopathy may show increased ticularly in children, vitamin E deficiency may be seen due to signal on T2-weighted images in the paramedian cord, most com- genetic defects in α-tocopherol transfer protein (ataxia with monly cervical. Copper deficiency-associated myelopathy has been vitamin E deficiency), apolipoprotein B (homozygous hypo- described in various animal species. Often seen in ruminants, it has betalipoproteinemia), microsomal triglyceride transfer protein been referred to as “swayback” or enzootic ataxia. (abetalipoproteinemia or Bassen-Kornzweig disease), or due 24 Myeloneuropathy AANEM Course to defective chylomicron synthesis and secretion (chylomicron methyl-n-butyl ketone are hexacarbons that were commonly used retention disease).14,15 in industrial solvents and household glues. More recently, the most common source of n-hexane exposure has been intentional inhalation of household glues for intoxication (“glue-sniffer’s TROPICAL MYELONEUROPATHIES neuropathy”). These hexacarbon solvents are metabolized to 2, 5-hexanedione which is largely responsible for their neurotox- The term tropical myeloneuropathies has been used to describe icity. Methyl ethyl ketone may be present in solvent mixtures a number of conditions seen in several developing countries.21,22 containing n-hexane or methyl n-butyl ketone and can poten- Often the precise cause is unknown but has been considered to tiate the neurotoxicity of these agents. Repeated exposures to be nutritional or toxic. Two major categories recognized in the these hexacarbons causes a progressive, symmetric, ascending, past were patients with prominent sensory ataxia (tropical ataxic sensorimotor, distal axonopathy that may have a Guillain-Barré neuropathy [TAN]), and those with prominent spastic paraparesis syndrome-like presentation.23 Despite cessation of exposure, (tropical spastic paraparesis [TSP]). The term TAN was originally continued progression may occur for weeks (“coasting”) prior to used to describe an ataxic neuropathy with optic atrophy seen arrest and significant subsequent improvement. With improving in Nigeria which was related to chronic cassava consumption peripheral neuropathy, evidence of central dysfunction such as and related cyanide exposure.15,22 Human T-cell lymphotrophic spasticity may become evident. Workers exposed to monomeric virus, type I (HTLV-I) myelitis had been called TSP in many acrylamide in grouting and those who handle monomeric acryl- equatorial regions and HTLV-I-associated myelopathy in Japan. amide in the production of polyacrylamide flocculents are at HTLV-II is also recognized to cause a chronic myelopathy that risk of acrylamide neurotoxicity. Acrylamide intoxication results resembles TSP. In addition to TSP, other neurologic manifestations from dermal absorption or inhalation. Acute neurotoxicity due of HTLV-1 infection include a myopathy, peripheral neuropathy, to acrylamide poisoning is characterized by an encephalopathy cognitive impairment, and an amyotrophic lateral sclerosis-like and gait ataxia that may be followed by a delayed neuropathy.7 (ALS) syndrome.1 Subacute-myelo-optico-neuropathy (SMON) is A progressive, distally prominent, symmetric, dying back, large- a myeloneuropathy with optic nerve involvement that affected in- fiber, axonal, sensorimotor neuropathy is the hallmark of chronic dividuals in Japan, and elsewhere, to a lesser degree between 1955 toxicity. The neurotoxicity is mediated by cerebellar Purkinje and 1970.12 Epidemiological studies have suggested that SMON cell injury and by degeneration of distal axons in the PNS was the result of toxicity from the antiparasitic drug clioquinol. and CNS. SMON was characterized by subacute onset of lower limb paresthesias and spastic paraparesis with optic atrophy. Tendon hyperreflexia and extensor plantar responses were seen though at times the ankle HEREDITY MYELOPATHIES OR MYELONEUROPATHIES jerk was absent. The precise mechanism of action of clioquinol has WITH A PURE OR PREDOMINANTLY MOTOR PHENOTYPE been unclear. Clioquinol is a copper chelator. Identification of a myelopathy resulting from acquired copper deficiency has led to The HSPs are a diverse group of heterogenous neurologic disor- speculation that clioquinol-induced neurotoxicity could have been ders in which the predominant symptom is insidiously progres- a consequence of copper deficiency.17 From 1991 to 1994, an epi- sive walking difficulty due to bilateral, fairly symmetric, lower demic in Cuba affected more than 50,000 persons and caused optic limb spasticity.3,5 Additional manifestations may include urinary neuropathy, sensorineural deafness, dorsolateral myelopathy, dysau- urgency and mild impairment of distal lower limb vibration tonomia, bulbar dysfunction, and axonal sensory neuropathy.21,22 perception. In uncomplicated or pure HSP, the spastic weakness Identified risk factors included irregular diet, weight loss, smoking, is confined to the lower limbs. Brisk reflexes may be seen in the use of alcohol, and excessive sugar consumption. upper limbs, but upper limb strength and dexterity, speech, and swallowing remain unaffected. In complicated or complex HSP, TOXIC MYELONEUROPATHIES additional neurologic or systemic findings may be present. These include mental retardation, dementia, ataxia, peripheral neuropa- The signs and symptoms of acute organophosphate toxicity are thy, amyotrophy, seizures, deafness, dysarthria, ichthyosis, optic due to acetylcholinesterase inhibition and resulting muscarinic atrophy, retinitis pigmentosa, and cataracts. Symptom onset may and nicotinic dysfunction. In some patients, after resolution of occur at any age. Distal muscle weakness and wasting can be seen the cholinergic crisis, an intermediate syndrome develops. This in some HSPs (e.g., SPG17 and SPG20). is likely a neuromuscular junction defect characterized by weakness of neck flexors, proximal limb, and respiratory muscles. The age of symptom onset, rate of progression, clinical features, and Organophosphate induced delayed neurotoxicity occurs 1 to 3 degree of disability vary between different genetic subtypes and also weeks after acute exposure and after a more uncertain duration within the same family. This is most likely due to the existence of of chronic exposure to certain organophosphate compounds.14 genetic modifiers. Autosomal dominant, autosomal recessive, and It may occur in the absence of the cholinergic or intermediate X-linked modes of inheritance are described. Autosomal dominant phase. The symptoms include distal paresthesias, progressive leg is the main mode of inheritance and this subgroup is predominantly weakness and wasting, and cramping muscle pain. There may associated with the pure forms. Family history may be absent due to be evidence of upper limb involvement and pyramidal tract incomplete ascertainment, de novo mutations, late symptom onset, dysfunction. Sensory loss is mild when present. N-hexane and asymptomatic carriers, and phenotypic variability with mild manifes- AANEM Course Neuromuscular Update I 25 tations. Almost 40 loci and 15 HSP genes have been discovered. HSP neuropathy can be associated with pyramidal-pattern lower limb loci are designated spastic paraplegia followed by a number that in- weakness, dorsal column dysfunction, gaze-evoked nystagmus, dicates the order of their discovery. Genetic testing is available for visual dysfunction, and absent ankle jerks.9 MRI may show in- some HSPs. Genetic testing typically examines coding sequences creased T2-signal involving the pontine tegmentum, inferior olives, and intron-exon splice junctions. Sequence abnormalities in gene anterior horns, and dorsal columns. promoter and other regulatory elements are not assessed. Large deletions may not be detected by standard techniques. Additionally, the MYELONEUROPATHIES WITH A LEUKODYSTROPHY yield of identifying mutations in patients without a family history is PHENOTYPE relatively low. The term leukodystrophies is used to describe an ever expanding While genetic confirmation is desirable, the diagnosis of HSP group of rare neurologic disorders with defined clinical, patholog- is often clinically made after excluding other causes. The rela- ical, imaging, and genetic characteristics.18 The dysmyelinating tively non-progressive gait pattern of some early-onset forms of inherited leukodystrophies that enter in the differential diagnosis HSP may resemble cerebral palsy. Extension of spasticity and of myeloneuropathies include adrenoleukodystrophy, metachro- incoordination to the upper limb is seen in primary lateral matic leukodystrophy, globoid cell leukodystrophy, or Krabbe sclerosis and ALS, helping to distinguish these forms of motor disease. The onset of neurologic manifestations in leukodystro- neuron disease. phies is generally preceded by a period of normal development. The initial manifestation may be bilaterally symmetrical spasticity with weakness and ataxia. In some childhood-onset leukodystro- HEREDITY MYELONEUROPATHIES WITH A CEREBELLAR phies, a demyelinating peripheral neuropathy may be present PHENOTYPE (e.g., metachromatic leukodystrophy, globoid cell leukodystrophy). Leukodystrophies may also be associated with cognitive and The initial evaluation of an ataxic patient should include an behavioral disturbances (e.g., adrenoleukodystrophy, adult-onset assessment for acquired causes. This screening should be considered metachromatic and globoid cell leukodystrophy) and optic nerve even if a hereditary cause is suspect. Most hereditary ataxias include involvement. Pattern recognition on MRI is a key diagnostic aid. CNS involvement beyond the cerebellum, most notably, the brain- Definitive diagnosis often requires genetic studies or pathologic stem and spinal cord.6 The early stages are often associated with a confirmation. Additional testing employed in the work up of spastic-ataxic gait. Additional features such as dementia, behavioral leukodystrophies include enzyme analysis on leukocytes or fibro- changes, retinopathy, pyramidal or extra pyramidal features, auto- blasts, urine for metabolic studies, skin biopsy, nerve conduction, nomic dysfunction, and peripheral nerve involvement may be seen and evoked potential studies. Despite extensive investigations, as the disease progresses. many leukodystrophies often remain undiagnosed. In context of a discussion of the differential diagnosis of myeloneuropathies, FA is the most common recessively inherited ataxia. Identification some conditions merit further explanation. of the underlying genetic defect has revealed existence of milder forms including those with later onset (beyond 25 years). These Adrenomyeloneuropathy patients lack prominent extra-CNS involvement. Reflexes may be present, and spasticity, rather than ataxia, may be the predominant AMN is an X-linked disorder characterized by impaired oxidation manifestation. Mild cerebellar atrophy (a feature not associated of very long chain fatty acids (VLCFAs). The following pheno- with typical FA) may be seen. Hence, genetic testing for FA should types are recognized: childhood cerebral, adolescent cerebral, be considered in adult-onset ataxias. However, the presence of adult-onset cerebral, AMN, Addison only, and asymptomatic prominent cerebellar atrophy in adult-onset ataxia merits con- or presymptomatic.19 Over 25% of patients with adrenoleu- sideration of the spinocerebellar ataxias (autosomal dominant), kodystrophy have the AMN form. AMN generally presents in the multisystem atrophy type C, or, as an exclusionary diagnosis, second to fourth decade as a slowly progressive spastic paraparesis idiopathic late onset cerebellar ataxia. The differential diagnosis with dorsal column and sphincteric dysfunction. Eventually, includes conditions like ataxia with vitamin E deficiency, abeta- many patients with AMN may develop cerebral involvement and/ lipoproteinemia, Refsum disease, cerebrotendinous xanthomato- or adrenal dysfunction. Fifty percent of heterozygote women sis (including its spinal variant), mitochondrial recessive ataxia develop an AMN-like syndrome and 20% of carriers have normal syndrome, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, plasma concentration of VLCFAs. Mutation analysis may be ataxia with oculomotor apraxia type 1 and 2, and others. Many of required for diagnosis. these disorders are rare, have a geographical predilection, and early age of onset. Later-onset presentations of ataxia-telangiectasia, and Pelizaeus-Merzbacher disease. ataxia with oculomotor apraxia are being increasingly recognized. Mitochondrial disorders that are included in the differential diag- Pelizaeus-Merzbacher disease is an X-linked disorder caused by a nosis of ataxic syndromes include myoclonic epilepsy with ragged defect in the proteolipid protein. The clinical spectrum includes red fibers, mitochondrial encephalopathy with lactic acidosis and a mild form presenting as spastic paraplegia (SPG2) with or stroke, neuropathy-ataxia-retinitis pigmentosa, coenzyme Q10 de- without nystagmus and ataxia.8 Female heterozygotes may also ficiency ataxia, and Kearns-Sayre syndrome. Leber hereditary optic have clinical manifestations. 26 Myeloneuropathy AANEM Course

Adult polyglucosan Body Disease NCSs are important for confirming the presence of neuropathy, as myelopathy alone can produce sensory impairments that mimic Adult polyglucosan body disease is a progressive neurologic polyneuropathy. In addition, determining if the neuropathy is pri- disorder characterized by upper and lower motor neuron in- marily axonal or demyelinating is important for guiding further volvement. The pathological hallmark is the presence of peri- workup. In most cases of myeloneuropathy, the neuropathy is odic acid-Schiff positive cytoplasmic spheroids composed of axonal. Findings of demyelination would warrant evaluation for branching polysaccharides (polyglucosan bodies) in the brain, a leukodystrophy. NCS findings in adrenomyeloneuropathy are spinal cord, peripheral nerves, and other organs. The clinical typically axonal, but demyelinating findings may be seen in other features include weakness, spasticity, incontinence, dementia, leukodystrophies such as metachromatic leukodystrophy and and peripheral neuropathy.11 A myelopathic presentation is rec- Krabbe disease. ognized. MRI findings include cerebral, cerebellar, and spinal cord atrophy with extensive, confluent, nonenhancing areas of Just as NCSs can help confirm the presence of neuropathy in a increased T2-signal involving the periventricular and subcortical patient with myeloneuropathy, SEPs can be useful in confirming white matter. a spinal cord lesion in polyneuropathy patients with large fiber sensory deficits and uncertain clinical findings of myelopathy. Cerebrotendinous Xanthomatosis In patients with myeloneuropathy, laboratory evaluation for

Cerebrotendinous xanthomatosis is an autosomal recessive lipid vitamin B12 deficiency is important and usually of very high storage disorder characterized by impaired hepatic conversion of yield. As previously outlined, testing for abnormalities of copper cholesterol to cholic and chenodeoxycholic acids due to deficiency and zinc are important additions to the laboratory assessment of of the hepatic mitochondrial enzyme sterol-27-hydroxylase. This myeloneuropathy. Testing for these deficiencies will be described leads to elevated plasma cholestanol. Cholesterol and cholestanol in more detail below. Vitamin E deficiency typically produces a accumulate in affected tissues leading to cataracts, tendon spinocerebellar ataxia picture, but the presentation of vitamin xanthomas, and neurological abnormalities. Cerebrotendinous E deficiency may resemble a myeloneuropathy. Testing serum xanthomatosis presents with chronic diarrhea and cataracts vitamin E levels is easily done and is without pitfalls, but will be in children. Neurological symptoms develop after the second of low-yield in most cases. decade and include pyramidal or extrapyramidal manifestations, cerebellar signs, cognitive decline, epilepsy, and neuropathy.14 Blood count findings of anemia (especially macrocytic) supports

Spinal xanthomatosis presents as a slowly progressive spinal cord vitamin B12 deficiency. Anemia, leukopenia, or pancytopenia may syndrome without cognitive decline, cerebellar dysfunction, or be seen in copper deficiency. However, a significant number of tendon xanthomas. MRI may show cerebral, cerebellar, brain- patients with vitamin B12 or copper deficiency will have normal stem, and callosal atrophy with focal and diffuse hyperintense blood counts and indices. lesions in the cerebral and cerebellar white matter on T2-weighted images. The spinal form may also show an increased signal on Additional, potentially useful blood tests include the angiotensin T2-weighted images in the lateral and dorsal column of the converting enzyme level for sarcoid and erythrocyte sedimenta- spinal cord. tion rate , antinuclear antibodies, and other serologies for collagen vascular disorders. If the clinical setting warrants, HIV serology should also be obtained. Serology for HTLV-I and HTLV-II may EVALUATION also be helpful in patients with a history of blood transfusion, intravenous drug use, or for those with a history of travel to the To help the clinician sort through the diagnostic considerations Caribbean or southeast Asia. outlined above, important tests such as spinal MRI, NCSs, electromyography (EMG), SEPs, and certain laboratory tests are In young patients or those with suggestive brain MRI scans or needed. family histories, laboratory evaluation for leukodystrophies could be undertaken. This would include assays for very long chain fatty Spinal MRI is important in excluding a structural cause for acids and arylsulfatase. myeloneuropathy. In most cases with clinical findings of both myelopathy and polyneuropathy, the cause will be metabolic, Nerve biopsy is not routinely indicated in the evaluation of a but an MRI is important, especially in older patients, where patient with myeloneuropathy. However, it may be helpful in a compressive myelopathy might coexist with a coincidental the diagnosis of a suspected leukodystrophy or inflammatory cryptogenic polyneuropathy (polyneuropathy occurs in greater process. In a patient with prominent motor findings and urinary than 3% of older adults.)1 In cases of nonstructural myeloneu- problems, with or without cognitive deficits, nerve biopsy may be ropathy, MRI may be entirely normal. When present, abnormali- performed to look for evidence of polyglucosan body disease. ties typically consist of relatively nonspecific T2 signal changes. When spinal MRI shows white matter signal changes, brain The most likely causes for a myeloneuropathy syndrome are

MRI may be helpful by providing indications suggestive of vitamin B12 or copper deficiency. The diagnosis of these condi- a leukodystrophy. tions will be discussed in more detail. AANEM Course Neuromuscular Update I 27

Vitamin B12 Deficiency to 90% of pernicious anemia patients, but have also been seen in healthy older adults.3 Elevations of fasting serum gastrin are ap- 23 The standard vitamin B12 assay is not always sufficiently sensi- proximately 70% sensitive and specific for pernicious anemia. tive. A significant proportion of vitamin B12 deficient patients The combination of elevated gastrin and anti-parietal cell anti- 22 may have serum vitamin B12 levels that are within the normal bodies is highly suggestive of pernicious anemia. range.30 Measurement of the serum metabolites methylmalonic acid (MMA) and homocysteine (Hcy) can significantly improve Conditions other than pernicious anemia can produce vitamin 19,30 diagnosis. Among persons with serum vitamin B12 levels B12 deficiency. These include dietary avoidance (vegetarians), within the normal range, MMA and Hcy testing will reveal gastrectomy, gastric bypass surgery, ileal disease, pancreatic vitamin B12 deficiency in 5% to 10% of those having a serum insufficiency, bacterial overgrowth and medications (such as 2 vitamin B12 level less than 300 pg/ml, and in 0.1% to 1% of histamine-2 blockers, proton-pump inhibitors and metformin. 19 those with a serum vitamin B12 level greater than 300 pg/ml. No apparent cause of deficiency is identified in a significant 18,25 Among patients with polyneuropathy, serum metabolite testing number of patients with vitamin B12 deficiency. In the will demonstrate vitamin B12 deficiency in a significant number absence of symptomatic gastrointestinal disease, it is probably 24,29 of cases in which serum vitamin B12 levels are normal. It not necessary to seek a diagnosis of pernicious anemia in a patient is unknown whether this also is the case for myeloneuropathy with vitamin B12 deficiency because this information will not patients, as comparable studies have not been performed in alter management.31 this population.

A number of MRI findings may be seen in vitamin B12 myeloneu- It has been recommended that MMA and Hcy be measured ropathy, but the MRI is often completely normal. Common in patients with serum vitamin B12 levels less than 300 pg/ MRI abnormalities include an increased T2-weighted signal in ml.7 However, other authors suggest raising this cutoff to the subcortical white matter and posterior and lateral columns. 350 pg/ml.18,25 It remains uncertain whether there is a suf- Less common findings include contrast enhancement involving ficiently high serum vitamin B12 level above which would the dorsal and lateral columns, decreased dorsal column signal on deem testing MMA and Hcy unnecessary. The author proposes T1-weighted images, and swelling of the cord.26 measuring serum metabolites in all myeloneuropathy patients. If either is elevated and no alternative cause for myeloneu- NCSs play an important role in identifying polyneuropathy. ropathy is identified, empiric vitamin B12 replacement therapy A common misperception is that the neuropathy in vitamin is reasonable. B12 deficiency is demyelinating. This results from the fact that demyelination is seen pathologically in the spinal cord as well

Unfortunately, there are further difficulties in the laboratory di- as from early EDX studies of vitamin B12 deficiency neu- agnosis of vitamin B12 deficiency. Although elevated serum levels ropathy. In early series, only motor conduction velocities were 4,20 of MMA or Hcy are rather specific for vitamin B12 deficiency, measured. However, in most studies employing modern there are some caveats. Hypovolemia, renal insufficiency, and NCS techniques, the neuropathy of vitamin B12 deficiency certain genetic disorders can produce elevations of either MMA has been found to be axonal. 5,6,13,21,29,33 This is corroborated or Hcy.2 Hypothyroidism, increased age, and deficiency of folate by findings on sural nerve biopsy. 14,21 There are no NCS or or pyridoxine are potential causes of elevated Hcy.2 Genetic causes EMG findings which, when detected in an individual patient, of MMA elevations are quite rare and vitamin B12 is the only would suggest vitamin B12 deficiency as opposed to other causes deficiency which increases MMA. of neuropathy. 29

A decreased serum vitamin B12 level and an elevated MMA and/ SEPs will demonstrate spinal lesions in a significant percentage or Hcy confirms the diagnosis of a vitamin B12 deficiency. In the of vitamin B12 deficiency patients with neurologic symptoms. 5,6,10,13,15,33,35 appropriate clinical setting, a normal vitamin B12 level with an el- In some cases, SEPs may be the only test to reveal 12,28 evated MMA is very specific for vitamin B12 deficiency. If the Hcy abnormalities. but not the MMA is elevated, empiric vitamin B12 replacement therapy can be initiated with a repeat Hcy level obtained after Copper Deficiency several weeks. If an elevated MMA or Hcy level is secondary to vitamin B12 deficiency, it will return to normal after 1 to 2 weeks Copper deficiency is a much less common cause for myeloneuropa- 31 of replacement therapy. Alternatively, in the case of a normal thy than vitamin B12. Fortunately, the diagnostic evaluation is more serum vitamin B12 and elevated serum metabolite, confirmatory straightforward: a normal serum copper level excludes deficiency. testing could be pursued. The Schilling test has traditionally been Serum zinc should also be performed as increased zinc (usually the next test used in patients who are found to have low serum taken in the form of nutritional supplements) can cause impaired vitamin B12. However, most hospitals have stopped performing gastrointestinal absorption of copper. this test due to problems with accuracy, cost, and radiation exposure.32 Anti-intrinsic factor antibodies are extremely specific for Spinal MRI in patients may be normal or show increased T2 signal. pernicious anemia, but these antibodies are present in only about In some cases, brain MRI may show white matter changes resem- 50% of patients.3 Anti-parietal cell antibodies can be found in up bling demyelination.27 28 Myeloneuropathy AANEM Course

NCSs and EMG in patients with copper deficiency myeloneu- An important consideration, however, is the duration of symp- ropathy typically show an axonal sensorimotor polyneuropathy, toms before treatment. Patients with longstanding symptoms are although a purely motor neuropathy has also been described.8 less likely to show a good therapeutic response.9,11,34 Myelopathy may respond quickly to therapy, but the response of neuropathy to treatment may be slow and incomplete.29 Even if immediate TREATMENT improvement is not observed, replacement therapy in vitamin 29 B12 deficient patients may prevent progression. One other Most myeloneuropathy syndromes have no specific treatment, consideration regarding treatment is that in approximately 2% of although vitamin B12 and copper deficiencies are exceptions. patients, sensory symptoms may initially worsen during the first month of treatment before improvement is seen.9 The reason for

Vitamin B12 Deficiency this is not known.

There is no known ideal approach to vitamin B12 replacement. A Copper Deficiency common regimen is 100 to 1000 mcg intramuscularly (IM) for 5 to 7 days, followed by monthly 100 to 1000 mcg IM injections.7 No specific studies have been conducted to determine the best An alternate approach is to begin with 1000 mcg IM per week approach to copper replacement therapy. Therefore, there is no for one month, followed by 1000 mcg IM per month thereafter. clear consensus with respect to the ideal form, dose, route, or

Some patients with vitamin B12 deficiency can likely be effectively duration of therapy. For patients with copper deficiency induced treated with oral vitamin B12. Individuals with pernicious anemia by excess zinc intake, cessation of zinc supplementation is usually are capable of absorbing small amounts of orally administered the only intervention necessary. As is also the case for vitamin B12 3 vitamin B12. The daily requirement for vitamin B12 is 1 to 2 mcg, deficiency, even when copper deficiency is caused by malabsorp- and approximately 1% of orally administered vitamin B12 can be tion, oral replacement therapy is usually sufficient. As stated above, absorbed by patients with pernicious anemia.3,17 Therefore, an there is no clearly established regimen. The author uses the strategy oral vitamin B12 dose of 1000 mcg per day should be sufficient. employed by Kumar and colleagues at the Mayo Clinic, who have Several series report successful oral treatment of vitamin B12 defi- had the most experience with copper deficiency myeloneuropathy: ciency.31 In a randomized trial that compared treatment with 2000 6 mg/d of elemental copper orally for a week, 4 mg/d for another 16 mg oral vitamin B12 per day to 1000 mg intramuscular vitamin week, and 2 mg/d thereafter. Repeat serum copper levels should 31 B12 per month , both groups showed similar improvements be obtained periodically to assess the adequacy of replacement. If in hematologic indices, serum MMA and Hcy, and neurologic adequate replacement cannot be obtained with oral therapy, then symptoms. However, only 8 out of 33 subjects had neurologic cupric sulfate can be given intravenously at a dose of 2 mg per day symptoms and the methods used for assessing improvement are for 5 days. Repeat courses are given as needed. not described. Although the authors of this study could not demonstrate a superior clinical outcome in either group, the patients Neurological improvement following copper replacement varies. A treated with oral vitamin B12 had significantly higher serum number of myeloneuropathy patients do not show significant resolu- 16 vitamin B12 and lower MMA levels at the study’s conclusion tion, but further progression can be prevented. In contrast, hemato- (4 months).17 logical abnormalities typically respond quickly and fully to therapy.

The author uses an oral replacement strategy in most cases, in- structing patients to take 1000 mcg per day. The most common GENERAL CONSIDERATIONS FOR REHABILITATION condition being treated this way is vitamin B12 deficiency polyneuropathy. In patients with severe neurological deficits or who Some general comments about the patient’s biomechanical status are experiencing a subacute onset, a traditional parenteral re- can be made based on the history and physical examination pre- placement strategy is used. Admittedly, there are no clear data that sented. A patient’s diminished ability to maintain balance in the guide this. dark is consistent with impairment in somatosensory function, with excess reliance on vision, and is the historical equivalent of the posi-

Approximately 1 month after beginning oral vitamin B12 replace- tive Romberg test on examination. An analogous historical feature ment therapy, the author obtains repeat serum vitamin B12, MMA with regard to the upper extremities (UE) is the inability to button and Hcy levels. If these do not show normalization, patients are effectively without view of the clothing fasteners. For example, pa- usually switched to parenteral therapy. Among patients initially tients with diminished UE somatosensory function often relate that placed on parenteral therapy, a switch to oral treatment could be they cannot fasten the top two buttons in a shirt without a mirror, tried. As long as MMA and Hcy remain normal, one can assume this may be thought of as a UE Romberg test in that it represents adequate replacement. a task that cannot be performed without visual input. The report of diminished proprioception at the toes makes it likely that ankle It is not clear whether the rate or degree of symptomatic improve- proprioceptive thresholds are increased (worse) at the ankle, if high 15 ment can be used as a guide to assess the adequacy of vitamin B12 technology quantification of these thresholds were to be obtained. replacement. The dogma has been that the neurological deficits of This is of functional relevance because increased proprioceptive 9 vitamin B12 deficiency respond rapidly to replacement therapy. thresholds at the ankle are inversely related to stability in unipedal AANEM Course Neuromuscular Update I 29 stance14 and likely contribute to increased gait variability,12 which Physical Training is a marker for falls.6 Although strength was found to be normal clinically in the patient presented, older persons with neuropathy In 20 older subjects with neuropathy who were randomized to due to diabetes with clinically normal ankle strength have a de- a 3-week balance and ankle strengthening program or a 3-week creased rate of strength (torque) development at the ankle. This sham exercise program, intervention subjects showed significant impairment in rate of strength development strongly relates to uni- improvements in unipedal balance time, functional reach, and pedal stance time.5 A rapid rate of torque generation in the lower tandem stance.11 The trial was small and single blind so firm extremities (LE) is intuitively important, given that there are only conclusions cannot be drawn; however, the exercises were well tol- about 500 ms available with which to arrest a fall. It is likely that erated, and thus, are reasonable to consider for this type of patient. the patient presented would have, on high technology evaluation, a In addition, strengthening of the hip abductor/adductor groups decreased rate of torque generation. and trunk musculature is intuitively appealing as a technique that may minimize excessive lateral trunk shift during gait. The author has seen clinical improvement in the gait of patients with CLINICAL MANAGEMENT OF NEUROPATHIC GAIT neuropathy who have followed such programs. Finally, in a second- 13 Patient and Family Education ary analysis of gait data previously obtained, active ankle frontal plane range of motion (ROM) (i.e., ankle inversion/eversion) was a significant predictor of step-width variability and range during Because of its insidious onset, and the fact that patients often appear neuropathic gait on a smooth surface, independent of neuropathy to walk reasonably well under ideal conditions, it is common for severity.2 Therefore, although cause and effect were not confirmed both physicians and patients to underestimate the impact of neu- by this work, the data suggest that increasing ankle eversion and ropathy. It is important for the physician to explain to the patient inversion ROM may allow improved frontal plane control during and family that the patient has lost a special sense that is likely of neuropathic gait. Finally, strengthening of the UEs so that 25% to greater importance than vision in the maintenance of balance.4 30% of the patient’s body weight can be supported on a cane may They should also be informed that the rapid generation of strength be beneficial for reasons described below. A reasonable physical in the LEs, necessary to prevent a fall is lost. They should be also therapy program would include: strengthening of the ankles and be told that it takes considerable concentration for a person with hips with emphasis on muscles that control motion in the frontal neuropathy to walk3 and so distractions should be avoided while plane (ankle invertors/evertors and hip ab/adductors), maximizing the patient is ambulating. If the patient is walking on a firm, flat, frontal plane ankle ROM, progressively more challenging balance and familiar surface with good lighting and no distractions, then and gait exercises and UE strengthening so as to support 25% to the patient is probably safe. In all other circumstances, the patient 30% of body weight with one limb. should employ UE touch of a wall, cane, other person, or use ankle orthoses that provide lateral support.13 External Devices

Environmental Modification The ability of canes to improve balance has been confirmed in two separate protocols involving patients with neuropathy. In the first Reliable and convenient support surfaces for UE touch (which case, a cane was found to markedly improve the ability of older markedly increases robustness to perturbations), should be made neuropathic subjects to maintain unipedal balance for 3 seconds available in the patient’s home, especially near stairs or other ir- when challenged with an inverting or everting perturbation.1 Two regular surfaces. These need not be obvious fixtures such as grab findings were of clear clinical significance: (1) subjects performed bars, but can be pieces of furniture such as desk tops and sofa arms. equally well whether the perturbation was toward or away from Specific advice given by a visiting physical and/or occupational the cane; and (2) up to 25% to 30% of a patient’s body weight therapist can be of value to the patient. was placed on the cane during this simulated emergent recovery of balance. In a separate study, 43 older neuropathic subjects Optimize Vision underwent gait analysis on an irregular surface in low light conditions with and without three interventions; a cane, ankle orthoses, With the progression of the patient’s somatosensory dysfunction, and touch of a vertical surface.13 The interventions were chosen vision becomes the chief source of afferent information for main- to improve frontal plane control, given the injury potential of taining postural stability. Therefore, the patient should be evalu- lateral falls. Step width variability and step time variability were ated by an ophthalmologist to assure optimal vision. The patient chosen as outcomes, given work supporting the former as a marker should not use bifocals, even those with transitional lenses, as they of dynamic frontal plane control,8 and the association between have been found to be an independent predictor of falls.7 This the latter and falls.6 Each of the three interventions significantly effect, identified in an unselected group of older persons living in decreased step width and step time variability, as compared to the the community, is likely even more important in the neuropathy baseline condition, and did so after the subject was given just 5 patient described in this case. The patient should be advised to minutes of practice with each intervention. It seems likely that use “walking” glasses, which correct distance vision only, and have the interventions made the subjects more robust to perturbations a separate pair of glasses to be used for reading. during single stance which, in turn, allowed for a more controlled placement of the swing limb. 30 Myeloneuropathy AANEM Course

Accentuating Plantar Surface Sensation 11. Klein CJ, Boes CJ, Chapin JE, Lynch CD, Campeau NG, Dyck PJ. Adult polyglucosan body disease: case description of an expanding genetic and Older persons with decreased plantar sensation demonstrated clinical syndrome. Muscle Nerve 2004;29:323-328. more rapid responses to frontal plane perturbations when standing 12. Konagaya M, Matsumoto A, Takase S, et al. Clinical analysis of long- on small (1 mm) ball bearings.9 In addition, a similar group of standing subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 patients showed diminished standing sway when insoles provided years after its ban. J Neurol Sci 2004;218:85-90. 13. Kumar N. Copper deficiency myelopathy: Human Swayback. Mayo Clin vibratory noise to the plantar surface of the feet.10 The effect of Proc 2006;81:1371-1384. these interventions on the gait of patients with neuropathy under 14. Kumar N. Metabolic Myelopathy and Myeloneuropathy. In: Noseworthy standard and challenging conditions is not yet known. JN, ed. Neurological Therapeutics. Principles and Practice, 2nd ed. Abingdon: Informa Healthcare, 2006: 1766-1781. 15. Kumar N. Nutritional neuropathies. Neurology Clinics 2007;25 (1):209-255. UPPER EXTREMITY FUNCTION 16. Kumar N, Gross JB, Jr., Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology If the patient describes difficulty with the performance of self care 2004;63:33-39. and typical domestic activities due to UE weakness, clumsiness, or 17. Kumar N, Knopman DS. SMON, clioquinol, and copper. Postgrad Med loss of dexterity, then a referral to an occupational therapist is desir- J 2005;81:227. able. In addition to recommending specific exercises to maximize 18. Lyon G, Fattal-Valevski A, Kolodny EH. Leukodystrophies: clinical and genetic aspects. Top Magn Reson Imaging 2006;17:219-242. residual neuromuscular function, adaptive equipment to simplify 19. Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystro- specific tasks can be recommended and prescribed. phy. Nature Clinical Practice Neurology 2007;3:140-151. 20. Pittock SJ, Payne TA, Harper CM. Reversible myelopathy in a 34-year- MINIMIZING LOSS OF FUNCTION IN THE EVENT old man with vitamin B12 deficiency. Mayo Clin Proc 2002;77:291-294. OF A FALL 21. Roman GC. Nutritional disorders of the nervous system. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in Despite everyone’s best efforts, the patient is still at increased risk for health and disease, 10th ed. Baltimore: Lippincott Williams and Wilkins, falling due to her age and gender. Evaluating and then optimizing 2006: 1362-1380. bone density is the best way to minimize the risk of fracture and the 22. Roman GC. Tropical Myeloneuropathies. 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Evoked responses in from a challenging unipedal balance test. Arch Phys Med Rehabil vitamin B12 deficiency. Ann Neurol 1981; 9:407-409. 1996;77(5):446-452. 16. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin 2. Carter SE, Thies SB, DeMott T, Ashton-Miller JA, Richardson JK. Proc. 2006;81:1371-1384. The relationship between frontal plane ankle range of motion and step 17. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. width variability in older persons with peripheral neuropathy. American Effective treatment of cobalamin deficiency with oral cobalamin. Blood Academy of Physical Medicine and Rehabilitation. Honolulu, Hawaii, 1998; 92:1191-1198. November 9 – 12, 2006. (abs.) 18. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. 3. Courtemanche R, Teasdale N, Boucher P, Fleury M, Lajoi Y, Bard C. Prevalence of cobalamin deficiency in the Framingham elderly popula- Gait problems in diabetic neourpathic patients. Arch Phys Med Rehabil tion. Am J Clin Nutr 1994; 60:2-11. 1996;77:849-55. 19. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobala- 4. Fitzpatrick R, McCloskey DI. Proprioceptive, visual and vestibular min deficiency: II. Relative sensitivities of serum cobalamin, methylma- thresholds for the perception of sway during standing in humans. J lonic acid, and total homocysteine concentrations. Am J Hematol 1990; Physiol 1994;478(Pt 1):173-86. 34:99-107. 5. Gutierrez MS, Helber MB, Dealva D, Ashton-Miller, Richardson JK. 20. Mayer RF. Peripheral nerve function in vitamin B12 deficiency. Arch Mild diabetic neuropathy affects ankle motor function. Clin Biomech Neurol 1965; 13:355-362. 2001;16(6):522-528. 21. McCombe PA, McLeod JG. The peripheral neuropathy of vitamin B12 6. Hausdorff JM, Rios DA, Edelberg HK. Gait variability and fall risk in deficiency. J Neurol Sci 1984; 66:117-126. community-living older adults: a 1-year prospective study. Arch Phys 22. Metz J, Bell AH, Flicker L, Bottiglieri T, Ibrahim J, Seal E et al. The Med Rehabil 2001;82(8):1050-56. significance of subnormal serum vitamin B12 concentration in older 7. Lord SR, Dayhew J, Howland A. Multifocal glasses impair edge-contrast people: a case control study. J Am Geriatr Soc 1996; 44:1355-1361. sensitivity and depth perception and increase the risk of falls in older 23. Miller A, Slingerland DW, Cardarelli J, Burrows BA. Further studies on people. J Am Geriatr Soc 2002;50(11):1760-66. the use of serum gastrin levels in assessing the significance of low serum 8. MacKinnon CD, Winter DA. Control of whole body balance in the B12 levels. Am J Hematol 1989; 31:194-198. frontal plane during human walking. J Biomech 1993;26(6):633-44. 24. Nardin RA, Amick AN, Raynor EM. Vitamin B12 and methylmalonic 9. Maki BE, McIlroy WE. Postural control in the older adult. Clin Geriatr acid levels in patients presenting with polyneuropathy. Muscle Nerve. Med, Studenski S, Ed. 199;12(4):635-58. 2007;36:532-535. 10. Priplata AA, Niemi JB, Harry JD, Lipsitz LA, Collins JJ. Vibrating insoles 25. Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J, Kaye K and balance control in elderly people. Lancet 2003;362(9390):2003-04. et al. High prevalence of cobalamin deficiency in elderly outpatients. J 11. Richardson JK, Sandman D, Vela S: A focused exercise regimen im- Am Geriatr Soc 1992; 40:1197-1204. proves clinical measures of balance in patients with peripheral neuropa- 26. Pittock SJ, Payne TA, Harper CM. Reversible myelopathy in a 34-year- thy. Arch Phys Med Rehabil 2001;82(2):205-9. old man with vitamin B12 deficiency. Mayo Clin Proc 2002;77:291-294. 12. Richardson JK, Thies SB, Ashton-Miller JA. An exploration of step 27. Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS. CNS time variability on smooth and irregular surfaces in older persons with demyelination associated with copper deficiency and hyperzincemia. neuropathy. Clinical Biomechanics 2008;23(3):349-56. Neurology 2002;59:1453-1456. 13. Richardson JK, Thies S, DeMott T, Ashton-Miller JA. Interventions 28. Saperstein DS, Jackson CE, Nations SP, Wolfe GI, Barohn RJ. improve gait regularity in patients with peripheral neuropathy while Uncommon neurologic manifestations of pernicious anemia with coba- walking on an irregular surface under low light. J Am Geriatr Soc lamin deficiency. Neurology 2001; 56(Suppl 3):A417. 2004;52(4):510-15. 29. Saperstein DS, Wolfe GI, Gronseth GS, Nations SP, Herbelin LL, Bryan 14. Son J, Ashto n-Miller JA, Richardson JK. Unipedal balance, neuropathy, WW, Barohn RJ. Challenges in the identification of cobalamin-deficiency and frontal plane ankle proprioceptive thresholds. American Association polyneuropathy. Arch Neurol. 2003;60:1296-1301. of Neuromuscular and Electrodiagnostic Medicine. Phoenix, Arizona, 30. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum October 17 – 21, 2007. (abs.) methylmalonic acid and total homocysteine determinations for diagnos- 15. Van den Bosch C, Gilsing MG, Lee SG, Richardson JK, Ashton-Miller ing cobalamin and folate deficiencies. Am J Med 1994; 96:239-246. JA. Peripheral neuropathy effect on ankle inversion and eversion detec- 31. Stabler SP. Screening the older population for cobalamin (vitamin B12) tion thresholds. Arch Phys Med Rehabil 1995;76:850-856. deficiency. J Am Geriatr Soc 1995; 43:1290-1297. A detailed summary of 32 AANEM Course Neuromuscular Update II

P. James B. Dyck, MD Jennifer A.Tracy, MD Ted M. Burns, MD Maureen R. Nelson, MD Dianna Quan, MD Vinay Chaudhry, MD Yadollah Harati, MD Jay J. Han, MD Justin Y. Kwan, MD Kerry H. Levin, MD Anthony A. Amato, MD

2008 COURSE F AANEM 55th Annual Meeting Providence, Rhode Island

Faculty

P. James. B. Dyck, MD Ted M. Burns, MD Associate Professor Associate Professor Department of Neurology Department of Neurology Mayo Clinic University of Virginia Rochester, Minnesota Charlottesville, Virginia Dr. Dyck received his medical degree from the University of Minnesota Dr. Burns is an associate professor of neurology at the University of School of Medicine, performed an internship at Virginia Mason Hospital Virginia (UVA) in Charlottesville. He graduated from Kansas University in Seattle, Washington, and a residency at Barnes Hospital and Washington Medical School and completed his neurology residency at the UVA. University in Saint Louis, Missouri. He then performed fellowships at the He later completed 1-year fellowships in electromyography/neuromus- Mayo Clinic in Rochester, Minnesota in peripheral nerve and electromyo- cular diseases at UVA and peripheral nerve diseases at the Mayo Clinic graphy. He is currently an associate professor of neurology at the Mayo in Rochester, Minnesota. He is board-certified in neurology, clinical Clinic. Dr. Dyck is a member of several professional societies, including neurophysiology, and electromyography. Dr. Burns is Director of the the AANEM, the American Academy of Neurology, the Peripheral Nerve EMG laboratory at UVA, Director of the UVA neurology residency Society, and the American Neurological Association. His current research program, and Director of the UVA clinical neurophysiology fellowship interests include pathological studies of peripheral nerve disorders and program. He is the editor of the weekly podcast for Neurology. He is clinical trials in peripheral neuropathies. also the editor of the AANEM’s Nerve and Muscle Junction podcasts. He is a member of the AANEM’s Continuing Medical Education committee and also a member of the American Board of Psychiatry and Neurology’s Jennifer A. Tracy, MD (ABPN) Neurology Clinical Neurophysiology committee, and the ABPN Fellow Neurology Recertification and Maintenance of Certification committee. Neurology Department Mayo Clinic Maureen R. Nelson, MD Rochester, Minnesota Director Dr. Tracy is a neuromuscular (muscle) fellow in the neurology department at Mayo Clinic, Rochester, Minnesota. She received her undergraduate Pediatric Rehabilitative Services training at Harvard and Radcliffe Colleges and received her medical degree Carolinas Rehabilitation and Levine Children’s Hospital from the University of Connecticut. She performed her preliminary in- Charlotte, North Carolina ternal medicine and neurology residencies at Mayo Clinic Rochester and Dr. Nelson attended the University of Illinois and then the University of a clinical neurophysiology (EMG) fellowship at Massachusetts General Illinois College of Medicine. She performed her internship and residency Hospital then returned to the Mayo Clinic for a neuromuscular (periph- in physical medicine and rehabilitation at The University of Texas Health eral Nerve) fellowship. Her main research interests are in pathological pat- Science Center at San Antonio, then a pediatric rehabilitation fellow- terns differentiating hereditary from acquired demyelinating neuropathies, ship at the Alfred I. duPont Institute in Wilmington, Delaware. Her and autoimmune and paraneoplastic neuropathies. current position is Director, Pediatric Rehabilitative Services at Carolinas Rehabilitation and levine children’s Hospital in Charlotte, NC. She is an adjunct associate professor, in the Department of Physical Medicine and Rehabilitation, University of North Carolina Chapel Hill.

Authors had nothing to disclose.

Course Chair: Gil I. Wolfe, 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. AANEM Course Neuromuscular Update II iii

Dianna Quan, MD Yadollah Harati, MD Associate Professor Professor Department of Neurology Department of Neurology and Neuromuscular Diseases University of Colorado Denver School of Medicine Baylor College of Medicine Aurora, Colorado Houston, Texas Dr. Quan received her undergraduate degree from the University of Dr. Harati is a Professor of Neurology and Director of the Neuromuscular Chicago and her medical degree from Columbia University College of Diseases Section at Baylor College of Medicine, Director of the Muscle Physicians and Surgeons. She completed her neurology residency and and Nerve Pathology Laboratory, Neuropathy, and ALS Clinic. He is the fellowship training in neuromuscular disorders and electrodiagnosis at the Chair-elect of the Neuromuscular Section of the American Academy of Hospital of the University of Pennsylvania. She is currently an associate Neurology (AAN) and past-chair of AAN’s Committee on Neuromuscular professor of neurology at the University of Colorado Denver School of Pathology. He is a member of Editorial Board of Journal of Clinical Medicine located in Aurora, Colorado, where she is Program Director Neuromuscular Disorders and past member of Journal of ALS and Other of the Neuromuscular Medicine Fellowship and Director of the EMG Motor Neuron Diseases. Dr. Harati has published over 100 articles and laboratory. She has been an active member of the AAN and AANEM and book chapters. He is the co-editor of two books: Neuroimmunology for serves as a medical editor for the online e-Medicine Textbook of Neurology Clinicians (1998), Advances in Neuromuscular Diseases (2002) and editor and a frequent ad hoc reviewer for Muscle & Nerve, among other journals. of a monograph on Peripheral Neuropathies (2007). Dr. Harati is active Her interests include peripheral neuropathy, amyotrophic lateral sclerosis, in teaching and research in the affiliated hospitals of Baylor College of and postherpetic neuralgia. Medicine.

Vinay Chaudhry, MD Professor Jay J. Han, MD Department of Neurology John Hopkins University School of Medicine Assistant Professor Baltimore, Maryland Department of Physical Medicine and Rehabilitation Dr. Chaudhry is presently a professor of neurology, the Vice-Chair of University of California Davis Clinical Affairs, and the Director of the Neurology Outpatient Center at Sacramento, California the John Hopkins University School of Medicine in Baltimore. He is a Dr. Han is Assistant Professor at the Department of Physical Medicine Codirector of the John Hopkins EMG laboratory. He is also working and Rehabilitation at the University of California Davis. He is toward earning his Masters of Business Administration degree. Dr. also the Director of the Neuromuscular Medicine Fellowship and Chaudhry is involved in several medical organizations and was recently ap- Co Director of the MDA Neuromuscular Diseases Clinic at UC Davis. pointed to the Board of Directors of the American Academy of Neurology He completed his undergraduate studies from the Stanford University (AAN). He has been an active member of AAN and AANEM, among with honors, and attended UCSF School of Medicine. He completed his others. He is on the editorial board of Neurologist and Muscle & Nerve and internship and PMR residency at the University of Washington, and sub- has been a reviewer for numerous other medical journals. sequently completed a focused clinical and research fellowship (NIH K12) in neuromuscular disorders. Dr. Han has clinical focus in neuromuscular diseases affecting both adult and pediatric populations, specifically the various muscular dystrophies, as well as electrodiagnosis. His research interests focus on the development of functional outcome measures in patients with neuromuscular disorders and research using electrodiagnosis/ electromyography (EMGs) in the animal models of various neuromuscular diseases. iv Neuromuscular Update II

Justin Y. Kwan, MD Anthony A. Amato, MD Research Fellow Professor of Neurology, Harvard Medical School EMG Section Department of Neurology National Institutes of Health Brigham Women’s Hospital Bethesda, Maryland Boston, Massachusetts Dr. Kwan received his medical degree from the State University of New Dr. Amato is the Vice-Chairman of the Department of Neurology and the York at Buffalo, New York. He completed is Neurology residency and Director of the Neuromuscular Division and Clinical Neurophysiology neuomuscular fellowship at Baylor College of Medicine. He is currently a Laboratory at Brigham and Women’s Hospital in Boston. He is also research fellow in the EMG Section of the National Institutes of Health in Professor of Neurology at Harvard Medical School. Dr. Amato is Bethesda, Maryland. His clinical interests include peripheral neuropathy, co-author on the second edition of Electrodiagnostic Medicine with myopathy and muscular dystrophies, myasthenia gravis, amyotrophic Drs. Dumitru and Zwarts and on the recently published, Neuromuscular lateral sclerosis, autonomic nervous system disorders, and nerve and Disorders, with Dr. Jim Russell. He has been involved in clinical research muscle pathology. trials involving patients with amyotrophic lateral sclerosis, peripheral neuropathies, neuromuscular junction disorders, and myopathies. Kerry H. Levin, MD Chairman Department of Neurology Cleveland Clinic Professor of Medicine (Neurology) Cleveland Clinic Learner College of Medicine Cleveland, Ohio Dr. Levin received his bachelor’s degree and his medical degree from Johns Hopkins University in Baltimore, Maryland. He then performed a residency in internal medicine at the University of Chicago Hospitals, where he later became the chief resident in neurology. He is currently Chairman of the Department of Neurology and Head of the Neuromuscular Disease Center at Cleveland Clinic. Dr. Levin is also a professor of medicine at the Cleveland Clinic College of Medicine of Case Western Reserve University. His current research interests include myasthenia gravis, polyneuropathy, and radiculopathy.

Contents

Faculty ii

Objectives iii

Course Committee vi

Brachial Plexopathy 1 P. James B. Dyck, MD; Jennifer A. Tracy, MD; Ted M. Burns, MD; Maureen R. Nelson, MD

Small-Fiber Neuropathy 11 Vinay Chaudhry, MD; Dianna Quan, MD; Jay J. Han, MD

Metabolic Myopathy 19 Yadollah Harati, MD; Justin Y. Kwan, MD; Jay J. Han, MD

Progressive Asymmetric Weakness 25 Kerry H. Levin, MD; Anthony A. Amato, MD; Jay J. Han, MD

CME Activity and Faculty Evaluation 33

O b j e c t i v e s — The overall objective of this two-part neuromuscular update course is to present participants with clinical cases in neuromuscular diseases. At the end of the entire course, participants will learn how to diagnose, evaluate, and in some instances treat neuromuscular diseases. This course is an excellent review of neuromuscular medicine. Update II covers brachial plexopathy, painful small- fiber neuropathy, metabolic myopathy, and asymmetric motor weakness. 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 designates this activity for a maximum of 3.25 AMA PRA Category 1 Credit(s).TM If purchased, the AANEM designates this activity for 2 AMA PRA Category 1 Credit(s).TM This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 09/08 - 09/11. vi Neuromuscular Update II

2007-2008 AANEM NEUROMUSCULAR UPDATE COURSE COMMITTEE Gil I. Wolfe, MD, Chair Dallas, Texas

Jay J. Han, MD Kerry H. Levin, MD James W. Tweener, MD Sacramento, California Cleveland, Ohio Ann Arbor, Michigan

Yadollah Harati, MD Dianna Quan, MD Houston, Texas Aurora, Colorado

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

Brachial Plexopathy

P. James B. Dyck, MD Ted M. Burns, MD Associate Professor Associate Professor Department of Neurology Department of Neurology Mayo Clinic University of Virginia Rochester, Minnesota Charlottesville, Virginia

Jennifer A. Tracy, MD Maureen R. Nelson, MD Director Fellow Pediatric Rehabilitative Services Neurology Department Carolinas Rehabilitation and Levine Children’s Hospital Mayo Clinic Charlotte, North Carolina Rochester, Minnesota

CASE DESCRIPTION PATIENT EXAMINATION AND EVALUATION

A 63-year-old man awoke one morning feeling well, moved his On examination, the patient’s mentation and cranial nerve func- neck and felt a “snap” in the back of his neck. He walked down tion were normal. He had severe weakness, both proximal and the stairs and by the time he reached the bottom, severe pain was distal, and absent reflexes, in bilateral upper extremities (UEs), with shooting from his shoulders down both arms into his fingers. The dense loss of pinprick sensation over a right superficial radial nerve man had associated severe weakness of both hands and arms. He distribution. Normal strength, sensation, and deep tendon reflexes drove himself to a local emergency department, holding his hands were noted in the lower extremities (LEs). His plantar responses on the bottom of the steering wheel because he was unable to raise were flexor. He did not have high arches or hammertoes. There them higher; he was sent home with morphine after being told were no cerebellar signs, and his gait and station were normal. he had a “pinched nerve”. The symptoms did not resolve. He complained of sharp, stabbing pains shooting down his arms from An evaluation included elevated fasting glucose at 304 mg/dL the shoulders, “like an electric fence”, as well as severe prickling, and hemoglobin A1c at 13.5%. He had normal or negative com- paresthesias, and cramps. The patient began his evaluation at plete blood count (CBC), creatinine, sedimentation rate, serum the Mayo Clinic 2 days after his symptoms began. During the protein electrophoresis and immunofixation, angiotensin-convert- 3 weeks after symptom onset, he lost 17 pounds. After 3 weeks, ing enzyme (ACE), antineutrophil cytoplasmic antibodies (ANCA), the pain was somewhat improved, especially on the left, though rheumatoid factor, antinuclear antibody (ANA), extractable nuclear it still kept him awake at night, but his weakness and paresthesias antigens (ENA), syphilis and human immunodeficiency virus. were unchanged. Cerebrospinal fluid (CSF) analysis revealed elevated protein at 80 mg/dL and glucose of 108 mg/dL, with only one nucleated cell, no The patient’s medical history was remarkable for Type 2 diabetes unique oligoclonal bands, a normal immunoglobulin G index, neg- mellitus, coronary artery disease, hypertension, and hypercholester- ative microbiology studies (including Lyme disease), and cytology. olemia. His medications included aspirin, atorvastatin, lisinopril, venlafaxine, famotidine, and metformin. He was on disability from Nerve conduction studies (NCSs) revealed low amplitude median a prior back injury which left him with three herniated disks in sensory antidromic responses on the right (10 mV) and left (12 his lumbosacral spine. His 57-year-old brother also had diabetes mV). Right radial sensory response was absent. Ulnar motor mellitus and painful feet; there was no other history of neuropathic amplitudes were low (5.0 mV on right and 5.3 mV on left). Right symptoms in his family. ulnar sensory response was low amplitude (4 mV). Right peroneal 2 Brachial Plexopathy AANEM Course motor response was normal amplitude (4 mV) with normal distal complete recovery of function in most patients, though it may take latency (6.3 ms) and mildly slow conduction velocity (37 m/s). months to years before a good functional outcome is achieved. Right sural response was normal amplitude for age (2 mV) with These cases are usually isolated, but have been known to recur in a mildly prolonged distal latency (4.7 ms). Needle examination some cases. of the right upper limb revealed fibrillation potentials in the first dorsal interosseus (FDI), deltoid, biceps, infraspinatus, pronator A large study of the natural history of patients with brachial plexus teres, and triceps, with no activation in the deltoid and infraspi- neuropathy was carried out by Tsairis, Dyck, and Mulder, which natus, and reduced recruitment in the FDI and biceps. On the characterized the clinical presentation as well as outcome of these left side, there were fibrillation potentials in the flexor pollicis patients.18 A total of 99 patients were reviewed in the study, only longus (FPL) and pronator teres, with no activation of the FPL and 1 of whom had a family history of brachial plexus neuropathy. A reduced recruitment in the pronator teres; examination of the left slight majority (54/99) had no history of illness, immunization, or biceps and deltoid was normal. Examination of cervical paraspinal toxin exposure in the month prior to symptom onset. If a preced- muscles was normal. There were mildly long duration motor units ing illness was reported, it was usually a respiratory infection, or (MUs) in the right anterior tibialis and medial gastrocnemius, what was described as a “flu-like illness”. Of interest however, eight with normal examination of the vastus lateralis. The findings were patients did report a marked increase in strenuous activity shortly consistent with a subacute neurogenic process of the right and left before the onset of their brachial plexopathy. For the vast majority brachial plexus in a patchy distribution, with more severe involve- of patients (95/99), severe pain, usually of sudden onset, was the ment of the right upper trunk and the left lower trunk/median first symptom, and lasted from a few hours to a few weeks. Most of nerve distribution. A mild sensorimotor peripheral neuropathy was the patients developed maximal weakness within 2 to 3 weeks after also found. A diagnostic procedure was performed. the onset of pain. The overall prognosis was good, but as noted, recovery was slow. After 1 year, 60% of the patients with primarily upper brachial plexus lesions reported they had returned to normal, DIFFERENTIAL DIAGNOSIS whereas none of the patients with primarily lower plexus lesions reported a return to normal at 1 year. However, of the 84 patients The differential diagnosis for patients presenting with brachial with followup data, 67 had returned to normal by the time of their plexopathy is broad and should be considered thoroughly in the last examination. evaluation of each patient. In certain clinical settings, alternative disorders such as cervical root disease and primary shoulder Van Alfen and colleagues recently reported on 246 patients with pathology must be considered. Clues to the accurate diagnosis of either idiopathic or hereditary NA and reviewed their clinical brachial plexopathy may include time course, presence of associ- information; data was collected prospectively on some patients, ated diseases (e.g., diabetes mellitus, cancer), presence of trauma, retrospectively in others.19 A mean age of onset of 41.3 years was presence of significant pain, and whether the disorder is unilateral found. Involvement beyond the brachial plexus was less common or bilateral. in the idiopathic group (17.3%, most commonly in the lumbosacral plexus or the phrenic nerve). Nearly all of the patients Neuralgic Amyotrophy suffered severe pain that was exacerbated by movement or contact to the affected area, typically resulting in sleep disturbances. The A common cause of brachial plexopathy is an inflammatory- mean time until onset of weakness was 13.6 days in men, and 8 immune mechanism with Parsonage-Turner syndrome, also known days in women. Recurrent episodes occurred less frequently in the as neuralgic amyotrophy (NA). This is perhaps the most well- idiopathic group; however, 26.1% suffered at least one recurrence, recognized cause. Beghi and colleagues surveyed medical records with a median time interval of nearly 6 years to recurrence. CSF of patients in Rochester, Minnesota, and found an overall incidence analysis was performed in few patients, and in those, a minority rate of 1.64 cases per 100,000 population.1 MacDonald and (n=4, 12.5%) had abnormalities believed to be related to their colleagues found an incidence rate of 3 cases per 100,000 popula- syndrome (elevated protein in two). NCS and electromyography tion in a group of London practices.11 Inflammatory-immune (EMG) were abnormal in 96.3% of patients. Overall, outcomes in brachial plexopathy can present with severe pain, typically involv- these patients were not as favorable as other studies have suggested. ing a shoulder girdle. This may occur in the context of a recent Of the patients with idiopathic brachial plexopathy who had 3 or infection, immunizations, or even surgical procedures, which are more years of followup, 46.2% suffered from ongoing chronic pain; believed to trigger a more widespread immune attack on nerves; 69.4% had ongoing mild paresis, but only 2.8% were left with however, frequently such a history cannot be elicited. Following severe paresis. The authors reviewed outcomes of patients who a period of intense pain (often requiring the use of narcotics), a had been treated with corticosteroids versus untreated patients and patient will typically develop weakness, which may be quite severe, acknowledge the difficulty of interpreting such data since treatment along with areas of numbness. The pain will usually subside as involved different doses and durations. Overall, weakness was weakness is developing. Weakness and sensory loss are often found to improve faster in treated patients (28.3%) versus (6.3%) patchy in inflammatory-immune plexus lesions, and may be a untreated patients. This result was statistically significant. NCSs clue to diagnosis. Some respiratory symptoms can also occur in and EMG tend to show patchy involvement of the brachial plexus, the context of hemidiaphragm paralysis (which can be seen on and abnormalities that often extend proximally to the root level, a routine chest x-ray). The overall prognosis is good, with near- manifesting with fibrillations and/or long duration MUs in cervi- AANEM Course Neuromuscular Update II 3 cal paraspinal muscles. Findings on magnetic resonance imaging leagues, of their 60 patients (15%), 9 who presented with diabetic (MRI) of the brachial plexus vary. It is not unusual to have these lumbosacral radiculoplexus neuropathy also had UE involvement; studies reported as normal, and findings, when they occur, can 5 had unilateral UE involvement, and 4 had bilateral asymmetric be subtle. Higher-resolution (e.g., 3 Tesla) MRI can be helpful in involvement.8 In most of these patients, arm deficits resolved after distinguishing these features. A retrospective study of radiologic a matter of months. At this time, the best treatment for diabetic findings in 26 patients with the diagnosis of Parsonage-Turner cervical radiculoplexus neuropathy remains unclear. syndrome by clinical and/or electrophysiologic groups and an abnormal MRI found that the most common abnormalities identi- Necrotizing Vasculitis fied were changes of edema and/or atrophy in the supraspinatus or infraspinatus muscles, consistent with denervation changes.14 Another inflammatory cause of brachial plexopathy is necrotizing vasculitis. This can either be systemic or nonsystemic necrotiz- A study of brachial plexus biopsy of four patients with progressive ing vasculitis. The nonsystemic necrotizing vasculitis is probably worsening brachial plexopathy revealed significant mononuclear caused by a similar mechanism of microvasculitis as diabetic or perivascular inflammation in both the epineurium and endoneu- nondiabetic cervical or lumbosacral radiculoplexus neuropathies rium, without evidence of necrotizing vasculitis from nerves in the (discussed above). In contrast, systemic vasculitis usually involves brachial plexus; these pathological findings are strongly supportive large epineurial vessels with fibrinoid necrosis. Patients with micro- of the presumption of an inflammatory-immune pathogenesis vasculitis are more likely to present with a syndrome that involves of Parsonage-Turner syndrome.15 In 2001, Dyck and colleagues the upper part of the plexus, whereas large vessel vasculitis more reviewed 12 nerve biopsies of distal arm nerves (usually superficial often presents as discrete mononeuropathies. Typically, patients radial) and 8 nerve biopsies taken directly from the brachial plexus will have prominent pain as well as weakness and numbness. They in patients with brachial plexopathy.4 Fiber loss (multifocal in may have elevated sedimentation rates or other markers of sys- half of the cases) and changes were found, suggestive of immune temic illness such as an elevated rheumatoid factor, positive ANAs, mechanisms and microvasculitis.4 The authors concluded that positive ANCAs, and positive ENAs, among others. In systemic inflammation and neuropathic change can involve the plexus and vasculitis, patients may also have other organ system involvement the more distal peripheral nerves (PNs) in these attacks. Immune such as pulmonary, gastrointestinal, kidney, sinus, and others. In modulating agents such as methylprednisolone are often used in general, a tissue biopsy will be needed to make a diagnosis of ne- an attempt to speed recovery or limit functional deficit, but no crotizing vasculitis. Upper limb nerves that can be biopsied include large controlled study has been performed and the efficacy of these the superficial radial nerve, the antebrachial cutaneous nerves, agents is uncertain. and others.

Diabetic Cervical Radiculoplexus Neuropathy PN Sarcoidosis

Another important entity to consider is diabetic cervical radicu- Rarely, PN sarcoidosis (PNS) may present with prominent UE in- loplexus neuropathy. Patients with diabetes mellitus have long volvement. PNS is usually a sensory predominant syndrome, and is been known to be at risk for “diabetic amyotrophy”, or by the often a monophasic illness. Neurosarcoidosis will typically present name preferred for its anatomical specificity: diabetic lumbosacral subacutely. Clues to the presence of possible sarcoidosis would radiculoplexus neuropathy. A study of the clinical, electrophysi- include a history of sarcoidosis, elevated ACE levels, and elevated ologic, and pathologic features of 33 patients with diabetic lum- calcium levels. Burns and colleagues studied the clinical, electro- bosacral radiculoplexus neuropathy was performed by one of the physiological, and pathologic features of PNS in 57 patients.2 The authors.5 This disease process begins with severe pain, generally in most common neuropathic pattern is a polyradiculoneuropathy; the thigh, followed by both weakness and sensory loss. It is typi- almost half of the patients in this series had asymmetric involve- cally associated with Type 2 rather than Type 1 diabetes mellitus, ment. While overall it is much more common to have LE pre- and the glycemic control usually is good. Weight loss is common. dominance, 8/57 (14%) of their patients had UE greater than LE Though the initial presentation is often segmental and unilateral, involvement. To make this diagnosis, a nerve biopsy or other tissue it ultimately involves the entire LE and in most patients in this will generally be needed. Consequently, in an upper limb and series (32 of 33), it became bilateral (median time to bilaterality sensory predominant syndrome, sarcoidosis should be considered. 3 months). Pathologic study of nerve in these patients showed findings diagnostic or highly suggestive of microvasculitis in half Multifocal Inflammatory Demyelination of the cases, with an abnormal degree of inflammation found in all cases. Of interest, while this study focused on an LE problem, Another inflammatory cause of a brachial plexopathy is multifocal one-third (n=11) of the patients were also found to have UE ab- inflammatory demyelination. The Lewis-Sumner syndrome, or normalities, 8 were found to have UE mononeuropathies, and 3 multifocal chronic inflammatory demyelinating polyneuropathy , had bilateral but asymmetric cervical radiculoplexus neuropathies.5 is a long-described entity that presents as an asymmetric neuropa- The coexistence of these UE findings is suggestive of a common thy. However, even more focal involvement of the brachial plexus underlying mechanism and may also represent microvasculitis, from inflammatory demyelination can occur and has recently but coexisting compression neuropathies could be responsible for become more recognizable.17 The NCSs may not show typical some of these cases of UE involvement. In a series by Katz and col- demyelinating changes since the lesions may be more proximal than 4 Brachial Plexopathy AANEM Course the sites where the nerve is studied, and focal conduction blocks Perineuriomas do not need to be resected, but a diagnosis cannot and slowing may not be demonstrated. In such cases, proximal be definitively made without a nerve biopsy. They differ from focal stimulation can be very useful. As opposed to typical chronic hypertrophic neuropathy (such as CIDP) in that they have pseudo inflammatory demyelinating polyneuropathy (CIDP), which can onion-bulbs instead of true onion-bulbs. These pseudo onion- usually be diagnosed without the need of nerve biopsy, focal CIDP bulbs are made out of perineurial cells (which react to ENA) and may require biopsy for a firm diagnosis. Through the use of tar- not out of Schwann cells (as in true onion-bulbs). Neurofibromas geted fascicular biopsies taken at the sites of lesions on MRI (focal and schwannomas can also cause brachial plexopathy. In the case of increased T2 signal, enlargement, or enhancement of a segment of neurofibromas, one would expect other cutaneous manifestations nerve), many such cases have been diagnosed over the last several of neurofibromatosis, such as café au lait spots, and axillary freck- years. Nerve biopsy may show epineurial and endoneurial inflam- ling. Malignant nerve sheath tumors can occur sporadically or in mation with demyelination and/or onion-bulbs. Often, these cases association with neurofibromatosis. Granulocytic sarcoma, a focal are predominantly motor and involve little pain.3 Correct diagnosis form of acute myelogenous leukemia, has been reported to present is very important in these cases as they are potentially treatable, and as a brachial plexopathy.12 Clues to the presence of a malignant PN pathologic diagnosis, in particular, is helpful in ruling out other eti- sheath tumor rather than a benign process include significant pain, ologies such as malignancies. Patients who have failed a treatment and rapid progression of symptoms. The prognosis for this tumor trial with an immunosuppressive drug or have a history or lesion is poor and often requires amputation of the affected limb. that is worrisome for malignancy are frequently biopsied. Other Considerations Tumors Other infiltrative conditions that cause brachial plexopathies include Tumors can also cause brachial plexopathies. Clues to a mass lesion lymphoma and amyloidosis. Lymphoma can directly involve PNs. that is responsible for the plexopathy include a history of cancer, In only about half of the cases at Mayo Clinic, Rochester was the and the presence of Horner’s syndrome on the same side of the lymphoma recognized before it was found in PN. Features that plexus lesion, which can suggest the extension of tumor into the should cause a physician to consider that lymphoma is the cause of area of the sympathetic chain. At times, a palpable lump may be the brachial plexopathy include severe pain, weight loss, constitu- observed in the supra- or infraclavicular area, which can sometimes tional symptoms (including night sweats and fever), and associated induce shooting neuropathic pain when palpated. One of the more cranial neuropathies or other radiculopathies. CSF involvement common groups of tumors that can cause brachial plexopathies are with lymphoma cells is common, but repeated lumbar punctures metastatic tumors. These include breast, lung, and lymphoma. The may be necessary to obtain a positive cytology. A review of 23 authors have personally seen many cases of breast cancer present patients with lymphomatous involvement by PN found that the with brachial plexopathy, often years after the original tumor. One most common clinical presentation was brachial plexopathy (n=7), important differentiation is brachial plexopathy caused by infiltra- followed by polyradiculoneuropathy.16 Another condition that can tive tumor versus one caused by radiation injury. Radiation injury cause a brachial plexopathy is focal amyloid deposition. This focal causing a brachial plexopathy is also quite common, frequently in amyloid deposition (often called amyloidoma) can certainly involve the context of treatment for breast cancer. When the plexopathy roots, plexus, or individual nerves, and while rare, should be con- is from tumors, it is often more painful. Plexopathies due to ra- sidered; this often presents insidiously over years, but can produce diation injury frequently will show myokymia on EMG, but the focal neuropathies. presence of myokymia does not exclude metastatic tumor. Harper and colleagues studied patients with neoplastic brachial plexopathy Paraneoplastic syndromes can present as brachial plexopathies; in and radiation plexopathy and found that 63% of patients with these syndromes, patients develop pain, weakness, and numbness in radiation plexopathy had myokymia on EMG, while only 2 of 55 association with a malignancy but not due to direct tumor infiltra- patients with neoplastic plexopathy demonstrated myokymia on tion. They are likely the result of an immune mechanism. Similar EMG, both with only brief myokymia in a single muscle.7 Overall, immune-mediated brachial plexopathies can occur after surgery. the most common muscles in which myokymia was found were the pronator teres and the abductor pollicis longus. Radiation plexopa- Vascular causes of brachial plexopathies also occur. Vascular mal- thy will often present many years after the initial radiation.7 formations can occur in nerve, but are rare.

Another type of tumor that causes focal neuropathy, including Other important causes of brachial plexopathy are trauma, stretch, brachial plexopathy, is perineurioma. Perineurioma is a benign compression, or surgical injury. There are many causes of trauma tumor or malformation of perineurial cells that produces pseudo to the brachial plexus, with motor vehicle accidents a common onion-bulb-like formations. They occur half the time in children inciting event. In these, it is important to try to separate avulsion and the other half in adults. They are very slowly progressive injury from true brachial plexus injury. It is also important to neuropathies. Although they tend to be motor predominant, separate those cases in which a nerve is transected (cases that may most of them do have mild sensory involvement. Pain, especially require nerve surgery) from those cases where the nerve is damaged severe pain, is atypical. MRI shows gradual enlargement of nerve but not transected (unlikely to require surgery). Stretch injury fascicles (fusiform) without focal nerve tumors, and CSF analy- to the brachial plexus can occur with either an upward thrust of sis is generally normal.6,13 There is avid contrast enhancement. the arm over the head, or by a stretch of the neck away from the AANEM Course Neuromuscular Update II 5 shoulder; these can cause injury to an infant during delivery (Erb’s be inflammatory-immune, and thus, potentially responsive to im- or Klumpke’s palsy). The prognosis is usually good in the non- munomodulatory therapy such as corticosteroids (as is suggested transected nerve injuries, and physical therapy is helpful in their by improvement in pain with corticosteroid treatment of two recovery. Although damage to the brachial plexus can occur by patients in this study). stretch or compression in normal nerve, it occurs more readily in entities in which the nerve is more susceptible to injury, such as hereditary neuropathy with liability to pressure palsies (HNPP). STANDARD EVALUATION In this condition, the brachial plexus can be compressed by back- pack straps over the shoulders, the improper use of crutches, and In the evaluation of patients with brachial plexopathy, a wide improper positioning during surgery. A more controversial cause variety of conditions must be considered. Aggressive workup is of compressive injury is thoracic outlet syndrome; the putative required to determine the etiology of this potentially disabling con- etiology is compression of some part of the brachial plexus by dition. These studies generally include an MRI of the cervical spine a rib or fibrous band, leading to what is usually a lower plexus as well as the brachial plexus. The brachial plexus MRI is particu- syndrome, which can be exacerbated by position. Various surgical larly useful if a high resolution (3 Tesla) magnet and gadolinium are procedures are considered, including rib or band resection as well used. NCSs and EMG are essential for localization. NCSs of the as scalenectomy. superficial radial and the lateral and medial antebrachial cutaneous nerves, with comparison to the opposite side, can be particularly Hereditary cause of brachial plexopathy should also be considered. helpful. An extensive needle EMG examination may be required As previously mentioned, HNPP can lead to the development of a because the disease process is often patchy. A thermoregulatory brachial plexopathy as well as mononeuropathies at common sites sweat test may show patchy sweat loss. Quantitative sensory testing of compression. It is typical to have a superimposed mild periph- can show the different classes of fibers involved, such as large my- eral neuropathy with this condition. This is often asymptomatic elinated fibers with vibration, small myelinated fibers with cooling, and is only found by electrophysiologic testing. Useful features in and unmyelinated fibers with heat-pain thresholds. A broad range this diagnosis include a positive family history, and the presence of of blood work should be considered, such as sedimentation rate, more than one compressive neuropathy or plexopathy, particularly CBC, rheumatological markers (e.g., rheumatoid factor, ANA, in a different part of the body. Multiple mononeuropathies caused ENA, ANCA), ACE (looking for sarcoidosis), paraneoplastic an- by vasculitis are much more likely to be associated with significant tibody panel (looking for cancers), fasting blood sugar (looking pain. Other hereditary considerations include neurofibromatosis for diabetes mellitus), hemoglobin A1C (looking for glucose dys- (as described previously), and hereditary brachial plexus neuropa- regulation over the course of previous months), immunofixation thy. Attacks of brachial plexopathy can occur at any age, even in (looking for monoclonal proteins such as could be seen in focal childhood. Patients with this entity will generally have multiple amyloid, lymphoma, or monoclonal gammopathy of undetermined attacks of brachial plexopathy which are usually very painful. Like significance - associated neuropathies), and spinal fluid evaluation Parsonage-Turner syndrome, improvement in pain often coincides (looking for abnormal protein, cell count, cytology). Occasionally, with development of weakness in the affected limb. Cranial nerve a bone-marrow biopsy (looking for a hematological malignancy involvement can occur, as can lumbosacral plexus involvement, or amyloid) is helpful. More specific evaluations should then be either simultaneous with or independent from, attacks of brachial performed, depending on the evaluation results. Ultimately, to plexopathy. There is generally good resolution between episodes. conclusively evaluate brachial plexopathies, a nerve biopsy may be Family history and history of multiple attacks is helpful in making required in some cases. With this approach, the underlying cause this diagnosis. However, it may not be possible to distinguish of brachial plexopathies can often be determined and the appropri- cases of hereditary brachial plexus neuropathy from typical ate treatment initiated. Parsonage-Turner syndrome. Several dysmorphic features, such as hypotelorism, have been reported in these families, but the clinical significance of this is uncertain. Some families with this disorder CLINICAL AND ELECTRODIAGNOSTIC EVALUATION have been found to have an abnormality at chromosome 17p25, 10,21 while other families have not.20 There is clearly some genetic The most important diagnostic tool for the evaluation of a pos- heterogeneity. CSF analysis may show elevated protein, but gen- sible brachial plexopathy is a thorough and accurate history. The erally not a pleocytosis. NCSs and EMG are important, but it history must be accompanied by a solid understanding of the risk must be remembered that the findings are often patchy. MRI of factors for development of brachial plexopathy. The most common the brachial plexus may be useful, but a negative study does not etiologies of brachial plexopathy include trauma, surgery (e.g., rule out this entity. A study by Klein and colleagues of four pa- related to arm positioning, injury with interscalene or axillary re- tients with hereditary brachial plexus neuropathy with UE nerve gional anesthetic block), birth injury, inherited genetic mutations biopsy showed significant abnormalities in two of the four nerves (e.g., hereditary neuralgic amyotrophy), a primary autoimmune studies.9 The findings consisted of increased rate of axonal degen- process (e.g., Parsonage-Turner, or NA), previous radiotherapy, eration, and inflammatory infiltrates which involved and caused and neoplastic invasion.2,9,11 Systemic vasculitis and PNS are destruction of blood vessel walls (microvasculitis); necrotizing other uncommon etiologies. Diabetes mellitus is a risk factor for vasculitis was not observed. These findings suggest that despite an immune-mediated brachial plexopathy (i.e., diabetic cervical the hereditary basis of the disease, the pathologic process may still radiculoplexus neuropathy secondary to microvasculitis).1,5 Thus, if 6 Brachial Plexopathy AANEM Course a prior or concomitant history of any of these risk factors (e.g., pre- only when symptoms are relatively mild and before the examina- vious surgery, trauma, family history, diabetes, etc.) is present, the tion and EDX testing identifies plexopathy. The most important clinician should strongly consider that etiology, yet still consider mimic of brachial plexopathy is probably cervical radiculopathy or other plausible causes. It is also helpful to appreciate that recent polyradiculopathy. These nerve root lesions also typically present infection, vaccination, and parturition are triggers for the immune- with both weakness and pain.8 The pathomechanism of nerve root mediated plexopathies (e.g., hereditary NA and NA).6,7,10,13,14,15,16 injury can be structural (e.g., neural foraminal stenosis or disk There are often other clues in regards to etiology that are found in herniation), infectious (e.g., Lyme neuroborreliosis), or neoplastic the symptomatology of the plexopathy. For example, the abrupt, (e.g., carcinomatous meningitis). In this case, infectious cervical spontaneous onset of shoulder UE symptoms favors an immune- polyradiculopathy is perhaps the most likely alternative etiology mediated (e.g., microvasculitic) mechanism as seen with hereditary (other than plexopathy); EDX testing will prove helpful in exclud- NA, NA, and diabetic cervical radiculoplexus neuropathy (CRPN), ing this possibility. whereas a more gradual or insidious onset of symptoms would point towards neoplastic invasion or radiotherapy. Localization

Other details about the course of symptoms and degree of pain The history, neurologic examination, and EDX testing are very are also important considerations. Immune-mediated plexopathies helpful in confirming and localizing a brachial plexopathy, but (e.g., NA) usually begin with severe pain, last days to weeks, and localization requires that the examiner have a reasonably good un- are followed by the development of weakness a few days to a few derstanding of the neuroanatomy of the plexus.2,3,12 The brachial weeks later.10,14 Radiotherapy (e.g., for breast cancer) usually pres- plexus is derived from the anterior primary rami of the C5 - T1 ents with much less pain than what is experienced by patients with roots. After exiting the intervertebral foramen, the roots divide plexopathy due to malignancy or to immune-mediated mechanism. into ventral primary rami, which contribute to the plexus, and Radiation-induced plexopathy usually presents more gradually posterior primary rami, which innervate the paraspinal muscles of and can occur months to decades after radiotherapy. Recurrent, the neck. Several individual nerves (e.g., phrenic, long thoracic) painful brachial plexopathy is most typical of hereditary NA.15,16 branch directly off the roots prior to formation of the trunks. The The identification of accompanying symptoms is also important. roots otherwise converge to form three trunks—upper, middle, For example, weight loss is a common accompaniment of diabetic and lower—in the supraclavicular fossa at the lateral border of CRPN, as well as plexopathies secondary to neoplasm or a more the anterior and medial scalene muscles. The plexus transitions systemic process such as vasculitis. from trunks to cords via divisions (anterior and posterior) just beneath the clavicle. Lesions involving roots or trunks occur in In the patient previously described in the case presentation, the the supraclavicular portion of the plexus, whereas lesions involving temporal evolution was of an abrupt onset neuropathic process that the cords and terminal nerves occur in the infraclavicular portion. only gradually and incompletely resolved. The neuropathic process Supraclavicular plexopathies are more common than infraclavicular involved both UEs. The pain was so severe that the patient required lesions. The lateral, medial, and posterior cords—named accord- narcotics. The patient had not experienced antecedent trauma, ing to their anatomic relationship to the axillary artery—form surgery, or radiotherapy. There was no family history of brachial below the clavicle in the proximal axilla and terminate in one or plexopathy. These factors suggested that an immune-mediated more nerves. plexopathy was very likely. Furthermore, the clinical setting was remarkable for diabetes mellitus and significant weight loss; dia- The neurologic examination should focus on identifying any betes mellitus is believed to be a risk factor for immune-mediated motor, sensory, and reflex impairment referable to the different brachial plexopathy, and many of these patients experience contem- components of the plexus. A diminished or absent biceps reflex poraneous weight loss. Thus, the most likely etiology for brachial would be expected for a brachial plexopathy involving the upper plexopathy in this patient is diabetic CRPN. Additional evaluation, trunk, for example. Weakness involving the hand and wrist would including examination and electrodiagnostic (EDX) testing, can be point towards lower trunk/medial cord involvement. In addition to helpful in supporting this probable diagnosis. localizing a lesion to particular trunks and cords, the examination can sometimes help determine whether lesions are preganglionic (e.g., root avulsion) or postganglionic (e.g., upper trunk plexopa- CONSIDERING OTHER POSSIBLE ETIOLOGIES thy). Weakness of the rhomboid muscles (from C4 and C5 roots) and the serratus anterior muscle (from C5, C6, and C7 roots) In addition to considering etiologies for brachial plexopathy, the would suggest involvement as proximal to the cervical root. As clinician needs to consider early in the work-up whether the process discussed later, needle EMG examination of these muscles and cer- may simply be mimicking plexopathy and rather be caused by an vical paraspinal muscles will also be helpful in determining where alternative etiology. The presence of neuropathic pain can reason- the lesions are along the length of the nerve. In this case, both ably exclude from consideration pure motor processes that can proximal and distal UE weakness was identified, and UE reflexes affect the UEs, such as motor neuronopathies (e.g., amyotrophic were absent, suggesting bilateral pan-plexopathy. lateral sclerosis), disorders of neuromuscular junction transmission (e.g., myasthenia gravis), and myopathies. Shoulder injuries can EDX testing helps confirm the diagnosis and localization of a sus- sometimes superficially mimic brachial plexopathy, but usually pected plexopathy.2,3,8,12 Rarely, non-neuropathic processes (e.g., AANEM Course Neuromuscular Update II 7 rotator cuff tendinitis) can mimic brachial plexopathy, in which ment of motor unit action potentials of weak muscles can continue case EDX testing and the neurologic examination will be normal. to help with localization. Abnormalities on Needle EMG can map More commonly, EDX testing serves to confirm localization of a out the location of the plexus lesions. The presence of fibrillation neuropathic process to the plexus. A watershed for the localization potentials in paraspinal muscles would point to radiculopathy; of plexopathies is the dorsal root ganglia (DRG), with lesions in- however, the absence of fibrillation potentials in the paraspinals volving segments proximal to the DRG (e.g., root) are classified as does not exclude radiculopathy because needle EMG of paraspinal preganglionic lesions whereas those distal to the DRG (e.g., trunk) muscles will be normal in about half of patients with radiculopa- are labeled as postganglionic lesions.2,3,8,12 Assessment of sensory thy.8 Needle EMG abnormalities found in the rhomboid muscle nerve action potentials (SNAPs) is very helpful with this localiza- (dorsal scapular nerve, C4 and C5 roots), and of the serratus ante- tion because the preservation of SNAPs favors a preganglionic rior muscle (long thoracic nerve, C5, C6, and C7 roots) would also lesion (e.g., radiculopathy), while the dimunition or loss of SNAPs suggest a proximal cervical root lesion. Needle examination can also favors a postganglionic lesion (e.g., plexopathy). For a unilateral sometimes assist in determining etiology. For example, plexopathies plexopathy, the SNAP abnormality should be on the side of the secondary to radiotherapy are sometimes associated with myokymic lesion, and for asymmetric plexopathies, the SNAP abnormali- discharges on needle study, whereas plexopathies due to another ties should theoretically be more severe on the more affected side. cause (e.g., neoplasm) are much less likely to reveal myokymic Side-to-side differences in SNAP amplitude of greater than 50% discharges.4 In this case, the Needle EMG abnormalities pointed are typically considered significant, but repeat testing at the same to bilateral pan-plexopathies, with more severe involvement of the sitting to confirm that this finding is not simply technical is advis- right upper trunk and left lower trunk/median nerve. able, particularly given the significance of such a finding for localization. Differentiating preganglionic (e.g., radiculopathy) from The history and examination strongly pointed toward diabetic postganglionic plexopathy is a particularly important request when CRPN as the etiology of the patient’s UE pain and weakness. EDX trying to differentiate a structural (e.g., spinal stenosis), infectious testing confirmed the localization and importantly excluded cervi- (e.g., Lyme disease), or carcinomatous cervical polyradiculopathy cal polyradiculopathies (because the SNAPs were low or absent, from a plexopathy. Determining whether a traumatic plexus injury and the paraspinal muscles were normal on EMG), providing EDX is preganglionic or postganglionic is also important for surgical evidence against the patient’s manifestations being caused by cervi- management. For instance, preganglionic lesions (e.g., root avul- cal polyradiculopathies (e.g., Lyme neuroborreliosis). sions) are generally not amenable to direct plexus repair with nerve grafting, and hence would more likely be surgically treated with a The additional studies performed on the patient (e.g. CSF analysis nerve transfer (e.g., spinal accessory nerve to suprascapular nerve analysis, blood work) did not reveal another potential etiology. in order to allow shoulder abduction, ulnar nerve fascicle to flexor Neuroimaging of the brachial plexus and cervical nerve roots is carpi ulnaris to the musculocutaneous nerve in order to allow elbow frequently performed to search for compressive or infiltrative eti- flexion). On the other hand, postganglionic lesions (e.g., upper ologies (e.g., malignancy). Rarely, sensory nerve biopsy might be trunk plexopathy) may be directly repaired at the plexus with nerve indicated. Microvasculitis is frequently found in nerve biopsies in grafting or internal neurolysis. Sensory NCSs for brachial plexopa- patients with diabetic CRPN, neuralgic amyotrophy, and heredi- thy should include assessment of median, ulnar, radial sensory and tary neuralgic amyotrophy.1,13 lateral antebrachial cutaneous nerves. In this case, the low or absent median (bilateral), and ulnar and radial sensory responses, in the context of a sural sensory response that was normal for age, suggests REHABILITATION TREATMENT ISSUES that the clinically suspected brachial plexopathies are postganglionic (or at least not purely preganglionic). The etiology of brachial plexus palsy may frequently be unknown, and the scientific literature proving efficacy of treatments may be Motor NCSs should be performed, particularly to look for low minimal, but solace can be taken in the knowledge that brachial compound muscle action potential amplitudes over muscles plexitis has historically been described in a somewhat less than a innervated by affected nerves. Median and ulnar motor NCSs straightforward manner. The support for this statement begins should always be performed; radial and musculocutaneous motor with the unprecedented number of different names by which this NCSs can sometimes be performed, but rarely provide critical diagnosis is known---at least 10 different names have been used. information that can’t be obtained through the needle examina- Also, an article in 1924 described the cause as mostly musculosk- tion. In this case, the ulnar motor amplitude was low, whereas the eletal, occurring more in women, declining "probably because the peroneal motor amplitude was normal, consistent with the clinical knitting craze is dying out", with the wearing of furs as an impor- impression of brachial plexopathy. tant cause, leading to "undue warmth" which was then relieved by throwing off the fur, then getting a "severe local chill" of the Needle EMG helps localize the lesion, both longitudinally (i.e., supraspinatus, worsened if it was raining, with the final cure being where along the length of the nerve or root), and specifically to massage.2 Additionally, in 1909, a treatment for brachial plexus components of the plexus (e.g., upper trunk). Needle EMG should neuralgia was described with good results that called for injecting ideally be performed at least 2 to 3 weeks after onset to maximize 70% to 80% alcohol into the nerves. This treatment to motor the data that can be collected from the study, but it still can be nerves, at least for spasticity, continues today. The other medica- helpful to perform a study earlier than that because reduced recruit- 8 Brachial Plexopathy AANEM Course tions described as trialed in the same article include osmic acid and Hopefully, treatment of the primary etiology, pain, and sleep chloroform injections, as well as large doses of strychnine tonic.6 deprivation will help resolve the issue of weight loss. If poor appetite becomes an issue, there are medications to assist with appetite The treatment of a patient with a brachial plexus injury begins with stimulation. exersice. The treating physician should prescribe that a patient be seen for occupational therapy (OT) or physical therapy. The Because of the expected recovery from the weakness and pain, in patient should begin an exercise program to work on range of most cases, it will be necessary for the patient to have a temporary motion exercises, both during in-office therapy and at home on job adjustment or reassignment until the patient can return to pre- a daily basis. An exercise program for these patients is designed vious work responsibilities.3 to keep the joints in a functional position, avoiding or treating contractures, while awaiting nerve recovery. For affected muscles that had active movement, the therapists instruct the patient in CASE PRESENTATION AND DIFFERENTIAL DIAGNOSIS strengthening exercises to be gently performed as part of a daily REFERENCES exercise program. 1. Beghi E, Kurland LT, Mulder DW, Nicolosi A. Brachial plexus The OT, or an orthotist, should provide bracing (orthoses) for any neuropathy in the population of Rochester, Minnesota, 1970-1981. functionally significant joint deficits. The purpose of the orthosis Annals of Neurology 1985; 18: 320-323. is for protection and proper positioning of the joints, and/or to 2. Burns TM, Dyck PJ, Aksamit AJ. The natural history and long-term increase active function. In this case, the patient may benefit from outcome of 57 limb sarcoidosis neuropathy cases. Journal of the a shoulder support on one or both sides for positioning, prevention Neurological Sciences 2006; 244: 77-87. of dislocation, and pain minimization. This has not been proven 3. Dyck PJB, Dyck PJ. Chronic inflammatory demyelinating monon- efficacious in brachial plexitis, but has been described as the stan- europathy (CIDM): a focal form of CIDP?. Neurology 2002;58: A303. dard of care in hemiplegic stroke.1,9 Wrist hand orthoses may be 4. Dyck PJB, Engelstad J, Suarez GA, Dyck PJ. Biopsied upper limb beneficial on both hands, either in a neoprene (wetsuit material), nerve provide information about distribution and mechanism in or polypropylene (hard plastic) style, depending on the degree of immune brachial plexus neuropathy. Neurology 2001; 56 (suppl3): movement and level of discomfort present. A balanced forearm A395-396. orthosis may be useful in this case for the right side in particular 5. Dyck PJB, Norell JE. Dyck PJ. Microvasculitis and ischemia in dia- with its more severe proximal weakness. This allows movement of betic lumbosacral radiculoplexus neuropathy. Neurology 1999; 53: the upper arm, commonly to get the hand to the mouth to feed 2113-2121. oneself. If the distal weakness is severe, orthoses are available to 6. Hahn AF, Mauermann ML, Dyck PJB, Keegan BM. A 16-year-old assist patients with activities of daily living (e.g., holding utensils, girl with progressive weakness of the left leg. Neurology 2007; 69: if the distal weakness is this severe, as well as to holding a pen, or 84-90. using a toothbrush). 7. Harper CM Jr, Thomas JE, Cascino TL, Litchy WJ. Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology 1989; 39: 502-506. Pain management can also be addressed with the use of medica- 8. Katz JS, Saperstein DS, Wolfe G, Nations SP, Alkhersam H, Amato tions. Classic medications for neuropathic pain include tricyclic AA, Barohn RJ. Cervicobrachial involvement in diabetic radiculo- antidepressants (such as amitryptyline, taken at bedtime to assist plexopathy. Muscle & Nerve 2001; 24: 794-798. with sleep), gabapentin or pregabalin (taken throughout the day), 9. Klein CJ, Dyck PJB, Friedenberg SM, Burns TM, Windebank SJ, and antiepileptic drugs (including carbamazepine).5,7 Lidocaine Dyck PJ. Inflammation and neuropathic attacks in hereditary bra- patch 5% may assist with pain control as well chial plexus neuropathy. Journal of Neurology, Neurosurgery & Psychiatry. 2002; 73: 45-50. Transcutaneous electrical stimulation (TENS) is frequently recom- 10. Kuhlenbaumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten mended for use of brachial plexus pain, with stimulation above and N, Meuleman J, Watts GDJ, De Vriendt E, Young P, Stogbauer J, below the painful areas, with continuous low frequency current Betz BG, Hor H, Kurlemann G, Bird TD, Airaksinen E, Mononen T, Pou Serradell A, Prats JM, Van Broeckhoven C, De Jonghe P, described, but not proven as beneficial.7 Melzak and Wall demon- Timmerman V, Ringelstein EB, Chance PF. Mutations in SEPT9 strated that the effects of TENS are cumulative, with longer use 8 cause hereditary neuralgic amyotrophy. Nature Genetics 2005; more effective. It has also been described that 8 hours of use daily 37(10): 1044-1046. for at least 1 week should be trialed, then continued for at least 3 11. MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The inci- weeks if effective, with a taper off.4 TENS should not be used near dence and lifetime prevalence of neurological disorders in a prospec- a pacemaker, with someone who has a significant arrythmia, nor tive community-based study in the UK. Brain 2000; 123: 665-676. over insensate areas.7 12. Mauermann ML, Angius A, Spinner RJ, Letendre L, Amrami KK, Dyck PJB. Isolated granulocytic sarcoma presenting as a brachial Biofeedback and relaxation techniques have been advocated, but plexopathy. Journal of the Peripheral Nervous System 2008; 13: not proven efficacious in the treatment of painful brachial plexi- 153-156. tis.5 13. Mauermann ML, Dyck PJ, Kuntz NL, Amrami KK, Spinner RJ, Bosch EP, Engelstad JK, Dyck PJB. Perineurioma: a focal, motor AANEM Course Neuromuscular Update II 9

predominant, benign nerve tumor of the young. Journal of the 12. Rubin DI. Diseases of the Plexus. Continuum 2008;14:156-181. Peripheral Nervous System 2007; 12(Suppl 1): 57-58. 13. Suarez GA, Giannini C, Bosch EP, Barohn RJ, Wodak J, Ebeling 14. Scalf RE, Wenger DE, Frick MA, Mandrekar JN. Adkins MC. MRI P, Anderson R, McKeever PE, Bromberg MG, Dyck PJ. Immune findings of 26 patients with Parsonage-Turner syndrome. American brachial plexus neuropathy: suggestive evidence for an inflammatory Journal of Roentgenology 2007; 189(1): W39-W44. immune pathogenesis. Neurology 1996;46:559-561. 15. Suarez GA, Giannini C, Bosch EP, Barohn RJ, Wodak J, Ebeling 14. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus P, Anderson R, McKeever PE, Bromberg MB, Dyck PJ. Immune neuropathy. Report on 99 patients. Arch Neurol 1972;27:109-117. brachial plexus neuropathy: suggestive evidence for an inflammatory- 15. Van Alfen N. The neuralgic amyotrophy consultation. J Neurol immune pathogenesis. Neurology 1996; 46: 559-561. 2007;254:695-704. 16. Taghavi V, Dyck PJ, Spinner RJ, Amrami KK, Kurtin PJ, Engelstad 16. Van Alfen N, van Engelen BGM. The clinical spectrum of JK, Dyck PJB. Clinical and neuropathological characteristics of pe- neuralgic amyotrophy in 246 cases. Brain 2006;129:438-450. ripheral nerve lymphoma. Journal of the Peripheral Nervous System 2007; 12(suppl 1): 85. REHABILITATION AND TREATMENT REFERENCES 17. Thomas PK, Claus D, Jaspert A, Workman JM, King RHM, Larner AJ, Anderson M, Emerson JA, Ferguson IT. Focal upper limb demy- 1. Bender L, McKenna K. Hemiplegic shoulder pain: defining the elinating neuropathy. Brain 1996; 119: 765-774. problem and its management. Disabil Rehabil. 2001:23(16): 698- 18. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus 705. neuropathy: report on 99 patients. Archives of Neurology 1972; 27: 2. Burt JB. The causes of brachialgia. Proc R Soc Med. 1924; 17:25- 109-117. 29. 19. van Alfen N, van Engelen BGM. The clinical spectrum of neuralgic 3. Dumitru D, Zwarts MJ. Brachial Plexopathies and Proximal amyotrophy in 246 cases. Brain 2006; 129:438-450. Mononeuropathies. In: Dumitru D, Amato AA, Zwarts MJ, editors. 20. Watts GDJ, O'Briant KC, Borreson TE, Windebank AJ, Chance PF. Electrodiagnostic Medicine. 2nd ed. Philadelphia: Hanley & Belfus, Evidence for genetic heterogeneity in hereditary neuralgic amyotro- 2002. p 815-829. phy. Neurology 2001' 56: 675-678. 4. Frampton V. Transcutaneous nerve stimulation and chronic pain. In: 21. Watts DJ, O'Briant KC, Chance PF. Evidence of a founder effect Wells, Frampton, Bowsher, eds. Pain Management by Physiotherapy. and refinement of the hereditary neuralgic amyotrophy (HNA) locus Butterworth Heinemann, 1994. on 17q25 in American families. Human Genetics 2002; 110: 166- 5. Grabois M, McCann MT, Schramm D et al Chronic Pain syndromes: 172. evaluation and treatment. In: Braddom RL, ed. Physical Medicine & Rehabilitation.Philadelphia, WB Saunders Co, 1996, p 876-891. CLINCIAL AND ELECTRODIAGNOSTIC EVALUATION 6. Harris W. The alcohol injection treatment of neuralgia and spasm. REFERENCES Proc R Soc Med. 1909; 2: 77-91. 7. Lee MY, Nelson M, Lee CE. Evaluation and management of 1. Dyck PJB, Engelstad J, Suarez GA, Dyck PJ. Biopsied upper limb brachial plexus injury. In: Lazar RB, ed. Principles of Neurologic nerve provide information about distribution and mechanism Rehabilitation. New York, McGraw-Hill, 1998, p225-235. in immune brachial plexus neuropathy. Neurology 2001;56(suppl 8. Melzak R, Wall PD: The Challenge of Pain. London, Penguin, 3):A395-396. Harmondsworth, 1983. 2. Ferrante MA. Brachial plexopathies: classification, causes, and conse- 9. Yu D. Shoulder pain in hemiplegia. Phys Med Rehabil Clin N Am. quences. Muscle Nerve 2004;30:547-568. 2004; 15(3):683-697. 3. Ferrante MA, Wilbourn AJ. Plexopathies. In Comprehensive Clinical Neurophysiology. Levin KH, Luders HO, Editors. WB Saunders, Philadelphia, PA. 2000. pp. 201- 214. 4. Harper CM, Thomas JE, Cascino TL, Litchy WJ. Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology 1989;39:502-506. 5. Katz JS, Saperstein DS, Wolfe G, Nations SP, Alkhersam H, Amato AA, Barohn RJ. Cervicobrachial involvement in diabetic radiculo- plexopathy. Muscle Nerve 2001;24:794-798. 6. Klein CJ, Dyck PJB, Friedenberg SM, Burns TM, Windebank AJ, Dyck PJ. Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy. J Neurol Neurosurg Pyschiatry 2002;73:45-50. 7. Lederman RJ, Wilbourn AJ. Postpartum neuralgic amyotrophy. Neurology 1996;47:1213-1219. 8. Levin K. Diseases of the nerve roots. Continuum 2008;14:134-155. 9. Moghekar AR, Moghekar AB, Karli N, Chaudhry V. Brachial plexopathies. Etiology, frequency and electrodiagnostic localization. J Clin Neuromusc Dis 2007;9:243-247. 10. Parsonage MJ, Turner JWA. Neuralgic amyotrophy. The shoulder- girdle syndrome. Lancet 1948;973-978. 11. Payne MWC, Doherty TJ, Sequeira KAJ, Miller TA. Peripheral nerve injury associated with shoulder trauma: a retrospective study and review of the literature. J Clin Neuromusc Dis 2002;4:1-6. 10 Neuromuscular Update II AANEM Course 11

Small Fiber Neuropathy

Vinay Chaudhry, MD Jay J. Han, MD Professor Department of Physical Medicine and Rehabilitation Department of Neurology Assistant Professor John Hopkins University School of Medicine University of California Davis Baltimore, Marylan Sacramento, California Dianna Quan, MD Associate Professor Department of Neurology University of Colorado Denver School of Medicine Aurora, Colorado

CASE DESCRIPTION antinuclear antibody, rheumatoid factor, vitamin B12, vitamin E, folate, rapid plasma reagin, thyroid stimulating hormone, and A 52-year-old woman presented with a chief complaint of numb- hemoglobin A1c were normal. ness and pain in the feet. Symptoms became noticeable 2 years before and had been slowly progressive over time. The patient Current Studies characterized the sensation as an underlying burning feeling with frequent but intermittent lancinating pain. These problems af- Nerve conduction studies (NCSs) and needle electromyography fected the feet symmetrically. Symptoms were constant but more (EMG) were normal. Serum protein electrophoresis (SPEP), per- bothersome with prolonged standing or walking and were worse at formed twice, showed mild polyclonal hypogammaglobulinemia the end of the day, interfering with sleep. She described no muscle but was normal on a separate occasion. Quantitative serum im- weakness or back pain. Although her strength was not affected, she munoglobulin measurements showed a mildly reduced IgG level admitted that because of pain, her activity level had diminished, of 669 mg/dL (normal 700-1600 mg/dL) and normal IgA and she had gained weight, and she felt depressed about the change in IgM levels. Immunofixation electrophoresis (IFE) was normal. A her lifestyle. Her previous medical history was notable for hyper- 24-hour urine protein electrophoresis (UPEP) was normal. Two cholesterolemia and mild and well-controlled hypothyroidism, for hour oral glucose tolerance testing showed fasting glucose of 126 which she was taking simvastatin and levothyroxine, respectively. mg/dL and 2-hour glucose level of 256 mg/dL. Simvastatin was started after symptoms began and did not result in any appreciable increase in symptom severity. Differential Diagnosis

Examination This patient had slowly progressive symptoms of both loss of nerve function (numbness) and abnormal positive neuropathic symp- The patient was an overweight woman weighing 249 pounds. toms of burning and lancinating pain. In conjunction with mildly Examination of the cranial nerves and upper extremities was hypoactive Achilles reflexes on examination and loss of pinprick normal. In the legs, strength was normal. Patellar reflexes were sensation in a symmetrical “stocking” distribution, her problem normal, and Achilles reflexes were 1+ bilaterally. Pinprick sensation was most consistent with a distal sensory polyneuropathy (DSP) was diminished below the knees and in the fingertips. Vibratory affecting small fiber more than large fiber modalities. Based on her and proprioceptive sensation was normal. Her gait was normal. early evaluation, this patient was initially considered to have mild idiopathic sensory polyneuropathy. The differential diagnosis in Prior Studies this situation is wide and should be considered in conjunction with more general causes of polyneuropathy, some of which may begin Previous tests including comprehensive metabolic panel, complete with a presentation of DSP and evolve to more extensive large fiber blood count, C-reactive protein, erythrocyte sedimentation rate, sensory and motor involvement. 12 Small Fiber Neuropathy AANEM Course

Endocrine Disorders and Other Systemic Diseases Table 1 Examples of common medications associated with distal sensory polyneuropathy The single most common endocrine disturbance accounting for DSP is diabetes. Other endocrine disorders such as hypothyroidism, hyperthyroidism, and acromegaly are much less Antimicrobial metronidazole common causes of DSP. The association between diabetes and dapsone peripheral neuropathy has long been recognized. The most isoniazid recent American Diabetes Association criteria define diabetes ethambutol as fasting glucose ≥ 126 mg/dL or 2-hour glucose level ≥ 200 after a 75 gram oral glucose load. Impaired fasting glucose Cardiovascular amiodarone (IFG) and impaired glucose tolerance (IGT) are defined re- Chemotherapeutic vincristine spectively as glucose 100-125 mg/dL and 140-199 mg/dL. cisplatinum IFG and IGT may be seen separately or in combination and paclitaxel are likely due to predominant hepatic (IFG) or muscle (IGT) insulin resistance.19 thalidomide Antiepileptic phenytoin In recent years, numerous studies have suggested that IFG and Antiretroviral ddI IGT may also be associated with neuropathy. In some series, ddC 48% to 56% of patients with “idiopathic” or “cryptogenic” sensory predominant polyneuropathy were found to have some Anti-inflammatory colchicine form of impaired glucose metabolism (IGM) when tested in Immune modifying tacrolimus detail. 21,25,27 Others have found no clear association between IGM and sensory polyneuropathy.15 A clear relationship Nonprescription ingested substances such as pyridoxine (vitamin between IGM and sensory polyneuropathy remains to be proven, B6) and ethanol also are associated with sensory neuropathy. therefore studies are underway to examine this question.8 In Pyridoxine doses as low as 100 to 300 mg/day may cause sensory this patient, the normal hemoglobin A1c suggested relatively neuropathy or neuronopathy. Ethanol is a well recognized cause mild diabetes but also suggested that a state of IGM or pre- of sensory polyneuropathy, both independently and in association diabetes was likely present for an unknown duration before its with nutritional deficiencies. Length-dependent sensory loss and identification. In contrast, her hypothyroidism had been mild pain with associated distal axonopathy are common with chronic and well controlled with medication for at least 3 years prior ethanol abuse.17 Arsenic or thallium intoxication are less common to the onset of her neuropathy symptoms, making it a less exposures that may lead to DSP A detailed social history and likely contributor. inquiry into over-the-counter supplements used by the patient revealed no suspicious exposures. Other systemic diseases such as renal failure with uremia may cause a DSP, particularly if serum creatinine is 5 mg/dL or higher.3 Nutritional Deficiencies Polyneuropathy in chronic hepatic failure is also common and may begin with a distal sensory predominant pattern. Primary Deficiencies of B-complex vitamins including thiamine (vitamin biliary cirrhosis may be independently associated with a sensory B1), niacin (vitamin B3), vitamin B6, vitamin B12 may all cause polyneuropathy; distinctive cholesterol laden cells may be found DSP, though large fiber modalities are more often affected in within layers of perineurium, endoneurium, and epineurium. most vitamin B complex deficiencies. Thiamine deficiency is Xanthomas may also be seen. Based on normal screening electro- especially common in alcoholic patients. Folate and vitamin E lyte and metabolic studies, these conditions were not applicable deficiencies are relatively unusual causes of DSP and are almost in this patient. always seen in association with other neurological findings. This patient did not have underlying risk factors such as alcoholism, Drugs and Toxins prior gastric surgery, malnutrition, or unusual diet to suggest these possibilities. Many drugs are implicated in the development of DSP; a few commonly encountered medications are listed in Table 1. The Infections mechanisms of injury vary, but with a few exceptions which may be associated with “coasting” or limited progression of symptoms In industrialized areas of the world, the main infectious consider- after drug discontinuance, most drug-related polyneuropathies ations in the polyneuropathy evaluation include human immuno- stabilize after the drug is withdrawn. Some patients may experi- deficiency virus (HIV), hepatitis C, and Lyme disease. Leprosy and ence improvement after drug withdrawal. In this case, the patient diphtheria, which may also initially appear as DSP, are uncommon was not taking medications that are known to produce sensory in Europe and North America. HIV infection may be associated polyneuropathy. She was taking simvastatin, which some studies with DSP, especially with more severe and longstanding infection. have suggested may possibly contribute to neuropathy.6 However, This effect is independent of dideoxynucleoside treatment, which the simvastatin was started after symptoms began, making it an can cause DSP in some individuals. However, use of these medica- unlikely cause for her problem. tions and highly active antiretroviral therapy does not appear to be AANEM Course Neuromuscular Update II 13

an overall risk factor for the development of DSP, possibly because showed a mild polyclonal hypogamma-globulinemia, which was suppression of HIV infection and improved immunity counterbal- not present on repeat testing. The immunofixation electrophore- ance antiretroviral neurotoxicity.5,24 Polyneuropathy in hepatitis sis (IFE) and urine protein electrophoresis (UPEP) were normal. C is most often seen with cryoglobulinemia, but may also occur Inflammatory markers were unremarkable, making vasculitic or without cryoglobulinemia. Lyme disease related peripheral nervous other inflammatory conditions unlikely. system (PNS) disease typically presents as cranial neuropathy or polyradiculopathy rather than DSP, though a distal, symmetrical Paraneoplastic pattern of involvement has been reported.16 Evidence of infection with the Borrelia bergdorferi spirochete is essential to the diagnosis. Peripheral neuropathy is a common occurrence in the setting of This patient had no risk factors or laboratory results to suggest an malignancies, often as a consequence of chemotherapy toxicity. infectious cause for her neuropathy. Direct infiltration of nerves resulting in DSP is relatively rare but has been reported with lymphoma. Occasionally, the effects of Inflammatory and Immune Mediated Conditions tumors on peripheral nerves are exerted remotely.23 One of the best described syndromes is associated with small cell lung cancer Many inflammatory and immune mediated conditions may cause and the anti-Hu antibody, an antineuronal nuclear antibody DSP. These disorders may involve numerous organ systems or may (ANNA-type 1). Symmetrical sensory loss, paresthesias, and be isolated to the peripheral nervous system. Systemic necrotizing pain, are characteristic and may begin before the identification vasculitic conditions such as Churg-Strauss syndrome, polyarteritis of cancer in many cases. Anti-Hu antibodies have now been nodosa, and Wegner’s granulomatosis, among others, characteristi- described in a wide variety of other carcinomas such as those cally cause multiple mononeuropathies, but occasionally, patients involving breast, prostate, gastrointestinal tract, and thymus, may have a more unusual distal symmetrical sensory presentation. among others. Other paraneoplastic antibodies which may Individuals with other connective tissue disorders such as systemic present with a sensory polyneuropathy include anti-CV2, anti- lupus erythematosis, rheumatoid arthritis, and scleroderma may amphiphysin, and less commonly, anti-Yo and anti-Ri. Sensory more commonly demonstrate DSP, with scleroderma patients more polyneuropathy in this setting often occurs in combination with frequently developing progressive motor nerve involvement and other neurological signs such as encephalopathy, autonomic dys- weakness. Sjogren syndrome is classically associated with a sensory function, and muscle weakness, which may aid in the differential neuropathy or neuronopathy, ranging from mild distal sensory loss, diagnosis of these patients. DSP without an identifiable autoan- paresthesias, and dysesthesias, to disabling sensory loss with sensory tibody may also occur with malignancies, especially that of the ataxia and pseudoathetosis. Concomitant symptoms including xe- lung and also among patients who have experienced significant rophthalmia and xerostomia are usually present. Hypersensitivity weight loss. vasculitides related to cryoglobulinemia, bacterial or viral infections, or drugs may also result in DSP. In patients with multiple myeloma, a painful sensory polyneuropathy may develop related to amyloid protein deposits composed Chronic inflammatory demyelinating polyradiculoneuropathy of insoluable fibrils of immunoglobulin light chains. As disease (CIDP) may occasionally present with predominantly sensory progresses, muscle weakness due to motor nerve involvement is symptoms. Albuminocytological dissociation in the cerebrospi- common. Other associated signs such as macroglossia, auto- nal fluid and demyelinating features on NCS help distinguish nomic dysfunction, renal insufficiency or nephrotic syndrome, or sensory CIDP from inflammatory sensory polyganglionopathy marked weight loss may aid in the diagnosis. This patient had which demonstrates an axonal or neuronal pattern of injury on no systemic symptoms, signs, or laboratory results suggesting un- electrophysiology. derlying malignancy. The patient in this case, had never smoked and was current on her routine health maintenance testing that Monoclonal gammopathies that are not clearly associated with included mammography as well as cervical and gynecological underlying multiple myeloma, macroglobulinemia, lymphoma, or cancer screening. other identifiable syndromes are classified as monoclonal gammopathies of uncertain significance (MGUS). The majority of patients Genetic Conditions have monoclonal IgM, which may bind to myelin associated glyco- protein in up to half of patients. The neuropathy associated with A number of genetic conditions can result in DSP. Disorders such this condition is symmetrical with features of both sensory and as Fabry’s disease and Tangier disease are rare and usually present motor nerve demyelination; sensory complaints often predominate in childhood. Other findings such as angiokeratomas in Fabry’s in the early stages of disease. The exact role of the monoclonal pro- and extremely low levels of high density liproprotein cholesterol teins found in MGUS related neuropathy is uncertain, but in some in Tangier are characteristic. Adults with familial amyloidosis, cases, the antibodies may mediate an autoimmune response. most related to a transythretin (TTR) mutation, may be more difficult to recognize. While the disease is dominantly inherited, the Other rare causes of distal symmetrical sensory polyneuropathy expression of peripheral neuropathy may be highly variable even include sarcoidosis and isolated PNS vasculitis. These conditions among patients with the same mutation. Other organ system most often present asymmetrically. In this patient, one SPEP involvement, such as cardiac or renal dysfunction, may sometimes 14 Small Fiber Neuropathy AANEM Course be present at the time of neuropathy diagnosis. Pain, sensory loss, thermal or chemical), may occur in response to normally non- and eventual weakness beginning distally and moving proximally painful stimuli (allodynia) or increased pain in response to nor- are characteristic. Autonomic fibers are commonly involved and mally painful stimuli (hyperalgesia). Some patients may have lead to orthostatic hypotension and other manifestations of auto- additional or exclusive negative symptoms such as numbness, nomic insufficiency. hypoalgesia, or hypesthesia. Although most patients present with a length-dependent distribution of symptoms (stocking), a Numerous other hereditary neuropathies with prominent sensory few may have symptoms starting in the upper extremities, trunk, loss and pain such as hereditary sensory autonomic neuropathy or face. (HSAN) are well described. Dominant inheritance is most common, and in type I, onset is often in early to mid adulthood. Autonomic symptoms in the form of decreased or increased Patients with HSAN type I may have autonomic disturbances sweating (heat intolerance), dry eyes, dry mouth, erectile dysfunc- (e.g., hyperhidrosis), but the prominent sexual and gastrointestinal tion, urinary incontinence, stomach fullness, diarrhea, dizziness abnormalities characteristic of many TTR amyloid polyneuropathy or light headedness upon standing, or visual blurriness may also variants are relatively uncommon. Also, in contrast to type II he- be described. reditary motor and sensory neuropathy (HMSN II) patients who typically have more prominent motor deficits, individuals with Signs HSAN I have more prominent sensory symptoms, which may be severe enough to result in repetitive mutilation injuries, ulcerations, The examination may be completely normal despite prominent infections, and ultimately bony deformities and necrosis. This symptoms. Small fiber dysfunction in the form of reduced pin- patient had no known family history of neuromuscular disease or prick and reduced thermal sensitivity is often noted, although peripheral neuropathy. allodynia may interfere with this assessment. Large fiber function including vibration sensibility, proprioception, muscle bulk, Idiopathic strength, and muscle stretch reflexes are preserved. Autonomic system examination may show a sluggish or poorly reactive pupil, Although it has been the focus of detailed evaluation, the cause orthostasic hypotension, or tachycardia. of DSP may remain unknown in a significant number of affected individuals. Some studies have suggested that serial follow-up and evaluation may occasionally demonstrate an underlying etiol- DIFFERENTIAL DIAGNOSES ogy, but reversible causes are not often found.12,20 The course of disease in idiopathic DSP is usually relatively benign with minimal Various etiologies of SFN include: diabetes (including impaired progression of symptoms over many years. Severe disability is glucose tolerance), amyloidosis, hereditary sensory neuropathy, uncommon, though a patient’s quality of life may be compromised Tangier disease, Fabry’s disease, HIV, toxic exposure or ingestion due to chronic pain.29 (drugs, toxins, supplements), cryoglobulinemia, nutritional deficiencies, and inflammatory neuropathies.1,13,26

EVALUATION AND TREATMENT OF SMALL FIBER It is important to exclude mimickers of SFN and remember that NEUROPATHY foot pain is not synonymous with SFN. Some large fiber neuropathies may present as painful feet; several non-neuropathic condi- Nerve fibers that are <7 μm in diameter are defined as small nerve tions including plantar fasciitis, arthritis, bursitis, tendonitis; tarsal fibers. They include the small myelinated (Aδ) fibers that carry the tunnel syndrome, Morton’s neuroma, and erythromelagia may also cold perception, cutaneous nociception, and autonomic function present as foot pain. Even bilateral lumbar radiculopathy (from (preganglionic fibers); and the unmyelinated fibers (C fibers) that lumbar stenosis) may present as foot pain. carry the warm perception, heat pain, and autonomic function (post ganglionic fibers). It is also important to note that not all patients with SFN will present with painful feet. Patients may present with tight- Symptoms ness, coldness, numbness, or restless leg syndrome. SFN may present in a nonlength-dependent fashion affecting patchy Dysfunction of small fiber neuropathy(SFN) typically present as areas of the body including the face or trunk, without first painful paresthesias that may or may not be stimulus dependent. involving the feet. Finally, SFN may present as acute or sub- The spontaneous or stimulus-independent paresthesias (continu- acute burning pain rather than the typical and chronically ous or intermittent) may be described variously as burning sensa- painful neuropathy. tion (“feet on fire”), electric-shocks, sharp (“knife like, jabbing, pins and needles”), tingling, prickling, shooting-lancinating Testing in Patients With SFN sensations, or aching in toes and feet.9 These symptoms may be mild to excruciatingly painful, are generally worse at night, Laboratory testing is designed to confirm the diagnosis and sever- and may worsen with walking. The stimulus-evoked pain, also ity of SFN, exclude other possibilities, and establish the etiology called stimulus-dependent pain (stimuli may be mechanical, for SFN. AANEM Course Neuromuscular Update II 15

DIAGNOSTIC CONFIRMATION that it is not specific for the peripheral pathway, it is only semi-quanti- The traditional tests for peripheral neuropathy, NCSs and EMG, tative, it is messy, time-consuming, and it requires a special room. are normal in SFN patients, unless there is associated large fiber neuropathy. There have been recent reports that even though Cardiovascular Tests the sural nerve may have a normal amplitude, more distal plantar nerves may show abnormalities in patients with SFN. Cardiovascular tests including heart rate and blood pressure variability with Valsalva maneuver, heart rate variability with deep breathing, Specific tests for small fiber or autonomic function include: sym- and tilt table testing are valuable tests in patients with autonomic pathetic skin response (SSR), quantitative sensory testing (QST), neuropathy. In patients with SFN, up to 57% have been shown to quantitative sudomoter axonal reflex test (QSART), thermo- have heart rate variation with Valsalva or with deep breathing. regulatory sweat tests (TST), cardiovascular reflex testing, axonal flare response, and skin biopsy (measuring intraepidermal fiber Axon Reflex Flare Reaction density).10,11,14,22 Axon reflex flare reaction is a simple bedside test. The clinician lightly scratches the foot area with a pin and inspects for immedi- SSR ate local reddening due to vasodilatation (secondary to the release of histamine), and the surrounding wheal and flare response. This SSR is a response secondary to change in sweat-related skin electri- may be a useful test for impairment of C-fibers although the sensi- cal potential elicited by various electrical or mechanical stimuli. tivity and specificity of this test is not known. The advantage of SSR is that it is widely available, inexpensive, can be performed on routine EMG machines, and it correlates with Skin Biopsy diabetic neuropathy (one study), but not SFN. The disadvantages of SSR are that SSR testing has low sensitivity (10% in one study) Performing a punch biopsy (1 mm thick) of the skin and measur- and low specificity. The response tends to habituate with repeated ing intraepidermal nerve fibers with panaxonal marker PGP 9.5 stimuli. by confocal microscopy or imaging software is considered one of the most sensitive tests for confirming the diagnosis of SFN even though it received only a level C recommendation from the AAN. QST Reduction in small fiber density in the epidermal layer, abnormal axonal swellings, and the distribution of abnormalities may be QST can detect SFN by measuring detection of thermal hot or useful to confirm SFN especially in cases where the presentation cold stimuli or heat pain by giving calibrated stimuli using either is atypical or the examination is normal. The advantages of skin the method of limits or forced choice protocols. The advantages biopsy include the fact that it is simple to perform; multiple sites include its semi-quantitative nature and increased sensitivity can be examined multiple times, and it has been shown to correlate (range 60% to 85%). The disadvantages of QST are that it re- with symptoms, signs, and nerve biopsy. Skin biopsy has been quires patient cooperation, there is a broad range of normal values shown to correlate with QSART, electrophysiology, sural nerve between machines, it includes central pathways, and technical morphometry, and the Gracely pain scale. In addition, it offers an factors need to be strictly controlled. The American Academy of important tool for longitudinal follow up of patients both clinically Neurology (AAN) has given a Level C recommendation to this and for research purposes. The disadvantages of skin biopsy are the mode of testing. training and a large infrastructure needed to conduct this test. In addition, skin biopsy does not currently reveal any etiological information for SFN. In Figure 1, the left panel is normal skin from QSART lower leg and the right panel demonstrates reduced intraepidermal fiber density from a patient with SFN. QSART measures post ganglionic sympathetic sudomotor function. The stimulation of axons is achieved by ACh iontopheresis and the output measured by a sudorometer. The advantages of QSART are that it has fair sensitivity (60% to 80%), it is objective, reproducible, and specific to peripheral nerves. The disadvantages include the fact that the equipment is expensive and it is a somewhat time-consuming test.

TST

TST involves dusting an indicator powder on a patient that will turn purple when the patient sweats on being placed in a hot room. Although TST has high sensitivity (70% to 80%), its disadvantages are Figure 1 Skin biopsy 16 Small Fiber Neuropathy AANEM Course

Nerve Biopsy Prognosis

Nerve biopsy may confirm the presence of SFN if electron micros- Although there are no longitudinal studies of SFN patients the fol- copy is available to show the loss of unmyelinated fibers and prolif- lowing four patterns are recognized: eration of Schwaan cell projections and regeneration. In addition, nerve biopsy may exclude large fiber sensory loss or the presence of Pattern 1: SFN progresses to involve the large fibers and patients inflammation and amyloid. develop the garden variety distal length-dependent sensory motor neuropathy.

INVESTIGATING THE CAUSE Pattern 2: SFN progresses to more manifest involvement of autonomic fibers. History of toxic exposure, medication usage, nutritional deficiencies, supplements (over the counter vitamins), alcohol abuse, and Pattern 3: SFN remains restricted to the small fibers. family history of neuropathy or diabetes are helpful clues in determining etiology. Pattern 4: SFN symptoms resolve.

The standard laboratory studies that may be useful in examining Patterns 3 and 4 are more likely to occur in patients with idiopathic individual circumstances include: 2 hour oral glucose tolerance test SFN. (75 gm load), serum and urine immunofixation electrophoresis, HIV, antinuclear bodies, SSA, SSB, lip biopsy, transthyretin genetic testing, thiamine levels," galactosidase A levels, lipid panel, anti-Hu REHABILITATION TREATMENT ISSUES IN SFN antibody, tissue transglutaminase, and nerve biopsy may be useful in individual circumstances.10,13 Rehabilitation treatment concerns in regards to SFN deals primarily with pain symptom management issues. Pain associated with TREATMENT OF SFN SFN can be severe and can have significant impact on mobility function and quality of life. Pharmacological treatment options Attempts to treat painful SFN can be divided into those directed may offer some relief from intense pain. at treating the underlying etiology, and those directed toward symptom suppression based on neural mechanisms. Currently, there are no specific guidelines on therapy regimen or therapeutic modalities to be used in SFN. The treatment plan may Even though painful neuropathies may not contribute to increased include a combination of medications, physical or occupational mortality, the pain may be so severe that it severely impairs the therapy, nerve blocks, and psychological interventions. Beyond quality of life including normal work, activities of daily living, the pharmacological treatment options, desensitization training mood, and sleep. Treatment of neuropathic pain may improve the by a therapist (physical therapy or occupational therapy), cogni- patients’ quality of life. tive behavioral treatment by a psychologist specializing in pain management, meditation techniques, or acupuncture treatments The first line therapy for neuropathic pain includes the tricyclic are available. antidepressants and the antiepileptic drugs. The antidepressants include: the tricyclics (amitriptyline, nortriptyline, imipramine, Although no studies have specifically examined the role of desen- desimipramine, doxepin (10-150 mg qd), serotonin-noradrenaline sitization training in patients with allodynia associated with SFN, reuptake inhibitors (NRIz): duloxetine (60-120 mg qd), and venla- studies suggest its potential role in complex regional pain syn- faxine (150-225 mg qd). The antiepileptics include carbamazepine drome (CRPS).2,28 Desensitization therapy comprises the essential 100-800 mg qd, oxcarabazepine 1200-2400 mg qd, lamotrigine therapeutic core element in the physical or occupational therapist’s 200-400 mg qd, topiramate 300-400 mg qd, gabapentin 900-3600 management of allodynia in CRPS to restore functional use of the mg qd, pregabalin 150-600 mg qd, and valproic acid 1000-1500 affected body parts. Somatosensory desensitization therapy for al- mg qd. lodynia generally involves having the patient rub the affected body region over time with a series of progressively coarser and more The second line therapies include the opiates: oxycodone 40-160 irritating tactile stimuli. A treatment protocol may span 10 to 15 mg qd, morphine 90-360 mg po qd, Tramadol 50-400 mg qd, fen- weeks, including home practice sessions and weekly clinic rechecks. tanyl patch 2-75 μg/hr q 2-3 days; the antiarrythmics: mexiletine 2,29 The working mechanism of desensitization has not yet been 600-1200 mg qd; topical treatments such as capsaicin 0.075% established and the available research findings lack substantial ef- topical qid, lidocaine 5% patch, or isosorbide dinitrate spray 30 ficacy data, as most involve case reports without the use of adequate mg qhs. Other treatments to consider include clonidine 0.1-2.4 mg control subjects. qd, memantine 55 mg qd, dextromethorphan 400 mg, levodopa 100 mg tid, alpha-lipoic acid (thioctic acid) 600 mg, spinal Physical therapy approaches such as warm paraffin bath dips or cord stimulators, transcutaneous electrical nerve stimulator units, cold soaks followed by massage may be utilized; however, patients and acupuncture. should exercise caution due to a risk of impaired thermal and pain AANEM Course Neuromuscular Update II 17

6. de Langen JJ, van Puijenbroek EP. HMG-CoA-reductase inhibitors sensitivity with SFN. In addition, prior to the use of either super- and neuropathy: reports to the Netherlands Pharmacovigilance ficial mild heat or cold treatments, patients should be adequately Centre. Netherlands J of Med 2006;64:334-338. educated and prepared for such trials as increased sensitivity to 7. Dyck PJ, Dyck PJB, Klein CJ, Weigand SD. Does impaired glucose such modalities may occur with potential exacerbation of pain metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study. Muscle symptoms. Alternative treatment methods for neuropathic pain Nerve 2007;36:536-541. have not yet clearly demonstrated efficacy in studies. Yet, efficacy 8. Elftman NW. Orthotic management of the neuropathic limb. Phys may vary depending on individual patients and the combination Med Rehabil Clin N Am. 2006 Feb;17(1):115-157. of treatment modalities used. Thus, a variety of different treat- 9. Fink E, Oaklander AL. Small-fiber neuropathy: answering the ment options should be explored in consultation with individual burning questions Sci Aging Knowledge Environ. 2006; 2006:e7. patients. The general rehabilitation principles guiding the care of 10. Gibbons CH, Griffin JW, Polydefkis M, Bonyhay I, Brown A, Hauer patients with SFN include preservation of function, minimizing PE, McArthur JC. The utility of skin biopsy for prediction of complications, and improved quality of life while managing pain progression in suspected small fiber neuropathy. Neurology 2006; symptoms. 66:256-258. 11. Goodman BP. Approach to the evaluation of small fiber peripheral Pure SFN does not demonstrate significant muscle wasting, weak- neuropathy and disorders of orthostatic intolerance Semin Neurol 2007; 27:347-355. ness, or reflex changes. However, some sensory or sensorimotor 12. Grahmann F, Winterholler M, Neundorfer B. Cryptogenic poly- polyneuropathies are thought to begin with small fiber involve- 18 neuropathies: an out-patient follow-up study. Acta Neurol Scand ment and later evolve to affect large fibers. Therefore, within this 1991;84:221-225. context of evolutionary patterns of peripheral neuropathy, more 13. Hoitsma E, Reulen JP, de BM, Drent M, Spaans F, Faber CG. Small advanced SFN may also display sensory numbness and motor fiber neuropathy: a common and important clinical disorder. J weakness. Impaired pain and thermal sensitivity that accompanies Neurol Sci 2004; 227:119-130. SFN places the patients at great risk for developing foot ulcer- 14. Horowitz SH. The diagnostic workup of patients with neuropathic ations, subsequent gangrene, and amputations. With concomitant pain Med Clin North Am 2007; 91:21-30. sensory deficits and motor weakness, the medical care plan will 15. Hughes RA, Umapathi T, Gray IA, Gregson NA, Noori M, Pannala need to include foot care and education, and appropriate orthotics AS, et al. A controlled investigation in the cause of chronic idio- as needed. pathic axonal polyneuropathy. Brain 2004: 127:1723-1730. 16. Kindstrand E, Nilsson BY, Hovmark A, Nennesmo I, Pirskangen R, Solders G, Asbrink E. Polyneuropathy in late Lyme borreliosis—a A more detailed discussion of orthotic and rehabilitation manage- 4,8 clinical, neurophysiological and morphological description. Acta ment of peripheral neuropathy in general is reviewed elsewhere. Neurol Scand 2000;101:47-52. As a general rule, and in particular with SFN with its sensory 17. Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol impairments, prefabricated orthotics are not appropriate. Patients 2006;19:481-486. should be evaluated and fitted with custom-molded orthoses. A 18. Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002 variety of orthotic options are available to meet the individual Aug;26(2):173-188. patient’s needs. The different orthotic options include: in-shoe 19. Nathan DM, Davidson MB, deFronzo RA, Heine RJ, Henry RR, inserts versus more extensive ankle foot orthoses (AFOs), ankle Pratley R, Zinman B. Imparied fasting glucose and impaired glucose foot orthosis (with/without ankle joint articulation); different ma- tolerance. Diabetes Care 2007;30:753-759. terial (double metal upright versus thermoplastic); anterior versus 20. Notermans NC, Wokke JH, Franssen H, Vermeulen M, Busch HF, Jennekens FG. Course of chronic idiopathic polyneuropathy posterior trimlines, dorsiflexion assist and stop; orthopedic shoes during middle age and older: 2-year follow-up study. Ned Tijdschr with wide toe box; rocker bottom shoes, and as necessary for ulcer Geneeskd 1994;138:1281-1285. healing, a total contact protected weight bearing orthosis such as 21. Novella SP, Inzucchi SE, Goldstein JM. The frequency of undi- total contact AFOr CROW (Charcot-Restraint Orthotic Walker). agnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001;24:1229-1231. 22. Polydefkis M, Hauer P, Griffin JW, McArthur JC. Skin biopsy as a REFERENCES tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 2001; 3:23-28. 1. Al-Shekhlee A, Chelimsky TC, Preston DC. Review: small-fiber neu- 23. Rudnicki SA and Dalmau J. Paraneoplastic syndromes of the periph- ropathy. Neurologist 2002; 8:237-253. eral nerves. Curr Opin Neurol 2005;18:598-603. 2. Allen RJ. Physical agents used in the management of chronic 24. Schifitto G, McDermott MP, McArthur JC, Marder K, Sacktor N, pain by physical therapists. Phys Med Rehabil Clin N Am. 2006 Epstein L, Kieburtz K, Dana Consortium on the Therapy of HIV May;17(2):315-345. Dementia and Related Cognitive Disorders. Incidence of and risk 3. Bazzi C, Pagani C, Sorgato G, et al. Uremic polyneuropathy: a factors for HIV-associated distal sensory polyneuropathy. Neurology clinical and electrophysiological study in 135 short and long-term 2002;58:1764-1768. hemodialyzed patients. Clin Nephrol 1991;35:176-181. 25. Singleton JB, Smith AG, Bromberg MB. Increased prevalence of im- 4. Carter GT. Rehabilitation management of peripheral neuropathy. paired glucose tolerance in patients with impaired glucose tolerance. Semin Neurol. 2005 Jun;25(2):229-237. Muscle Nerve 2001;24:1225-1228. 5. de Freitas MRG. Infectious neuropathy. Curr Opin Neurol 26. Smith RG. Painful diabetic peripheral neuropathy. J Am Podiatr Med 2007;20:548-552. Assoc 2007; 97:394-401. 18 Small Fiber Neuropathy AANEM Course

28. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The 30. Wolfe GI, Baker NS, Amato AA, Jackson CE, Nations SP, Saperstein spectrum of neuropathy in diabetes and impaired glucose tolerance. DS, Cha CH, Katz, JS, Bryan WW, Barohn RJ. Chronic cryptogenic Neurology 2003;60:108-111. sensory polyneuropathy: clinical and laboratory characteristics. Arch 29. Walsh MT, Muntzer E. Therapist’s management of complex regional Neurol 1999; 56:540-547. pain syndrome (reflex sympathetic dystrophy). In: Macklin EJ, editor. Rehabilitation of the hand and upper extremity. 5th ed. St. Louis (MO): Mosby; 2002. p. 1707–1724. 19

Metabolic Myopathy

Yadollah Harati, MD Jay J. Han, MD Professor Department of Physical Medicine and Rehabilitation Department of Neurology and Neuromuscular Diseases Assistant Professor Baylor College of Medicine University of California Davis Houston, Texas Sacramento, California Justin Y. Kwan, MD Research Fellow EMG Section National Institutes of Health Bethesda, Maryland

CASE DESCRIPTION I have not had any major episodes since then until the ones I describe below. I have helped multiple times with moving heavy An intelligent 24-year-old female patient documents her own items and being out all day tailgating. medical history in a letter prior to her visit to Baylor College of Medicine as follows: In May of this year, I attended a NASCAR race where I tailgated during the day and drank lots of water. When we walked to the “I am seeking help in diagnosing a neuromuscular disease. I cur- track I could barely walk because my thighs were rock hard, and I rently live in Virginia and I am moving back to Texas. I have had had trouble bending my knees. During the race I began to feel light- problems off and on since I was fifteen, but it seems that whatever headed and nauseous. I went down to the first aid center and was it is might be getting worse and becoming a problem. I would like given four Motrin pills and told to drink water. Around midnight help diagnosing this or refer me to someone who would be more that night, I vomited and noticed my urine was the color of coke. suited to helping me. This was on a Saturday night and on Sunday I went to a prime care facility where they performed a urinalysis. They were unsure of what My first episode was when I was fifteen and I helped move a was the problem. I spent that Sunday, Monday, and Tuesday barely piece of furniture in my theatre class. My right forearm started able to urinate and vomiting. I couldn’t eat or drink anything. They to hurt, but by that night it had become rock hard and swelled. sent me to an internist on that Tuesday. He admitted me into the It had become painful to move and I went to the hospital hospital for severe dehydration. I was seen by several doctors and was emergency room. I was diagnosed with having compartments told that I had elevated creatine. I was also told I had rhabdomyoly- syndrome and was admitted overnight. The doctors had me sis and acute renal failure. I was put on dialysis and constant fluids. sleep all night with my right arm in the air so that the swelling I stayed in the hospital for a week and was then put on outpatient di- would go down. The next morning it was back to normal, and I alysis three times a week. I lost around 20 pounds within two weeks. went home. I stayed on dialysis until the first of June. My kidney function had returned to normal, and I was told to take it easy. Not until I was twenty-one did this happen again. My left forearm swelled up and had the symptoms as last time. I went to the ER On July 22, I lifted a small box of clothes that weighed around and was given a muscle relaxer and sent home. Everything was ten pounds. My left forearm started to swell and become hard. I back to normal again in the morning. was having trouble keeping the arm straight because of the pain. 20 Metabolic Myopathy AANEM Course

I decided to go to the hospital around ten o’clock that night due Glycogen Storage Diseases to what happened in May. I was also starting to lose sensation in my fingers and was experiencing shooting pains. They performed Patients with GSDs frequently develop symptoms during brief an ultrasound to see if I had any blood clots, which they did not physical exertion of maximal intensity or sustained high intensity find. They discovered that my CPK was off their charts. They told submaximal exercise due to the muscle’s normal dependence on me their machine only went to 8000 and I was way over that. I anaerobic glycolysis and carbohydrate oxidation. GSDs most was admitted into the hospital until my CPK went down so that I often cause dynamic findings rather than static or fixed weakness. would not go into renal failure again. They also rigged my left arm Some patients initially experience recurrent and reversible muscular into the air so that it could drain to avoid surgery since that had symptoms that are exercise induced, but later develop fixed weak- worked before. By Sunday morning my arm was somewhat better. ness in distributions mimicking acquired or hereditary myopathies. I continued to have tingling and numbness in my fingers until Table 1 includes a list of currently identified GSDs. about Monday or Tuesday. A neurologist, told me to follow-up with him after this episode had passed and my CPK came down. The most common GSD is myophosphorylase deficiency, also My CPK fell to around 2300 and I was released. known as McArdle’s disease or glycogenosis type V. Initial onset of symptoms often occurs during childhood and consists of poor I saw the neurologist on August 15th and he has referred me down to endurance, fatigue, and exercise induced cramps and myalgia that Baylor since I am moving. He performed blood work and my CPK mainly affects active muscle groups. Myoglobinuria may also be was around 600. He has told me that it is very important to get in absent during childhood with the prevalence of fixed muscle weak- with a neuromuscular specialist and let them start the work up.” ness increasing as a patient ages. Symptoms can be precipitated by activities such as lifting heavy weights or climbing long flights of Upon her visit to the author’s clinic, further information was ob- stairs. The “second wind” phenomenon is characteristic of this dis- tained. She had a history of hypothyroidism and what has been order. With the onset of myalgia, patients who rest briefly are then termed temporomandibular joint disorder due to her “jaw locking able to continue their physical activity with few or no symptoms. on occasion when chewing.” There was no family history of similar McArdle’s disease is an autosomal recessive disorder with mutation neuromuscular symptoms. Several members of the family had in the gene that encodes muscle phosphorylase localized to chro- hypothyroidism. The review of other systems was entirely normal. mosome 11q13. The normal function of muscle phosphorylase is A detailed examination revealed an only mild (5-/5) proximal to catalyze the removal of 1,4-glucosyl residues from glycogen to weakness of upper and lower limbs. An electromyography (EMG) produce glucose-1-phosphate. Its absence leads to decreased meta- revealed short duration polyphasic units in the deltoids, iliopsoas, bolic substrate for glycolysis to produce adenosine triphosphate. and left middle thoracic paraspinous muscles. There was no evidence of muscle membrane irritability. Serum creatine kinase (CK) Table 1 Glycogen storage disease was 1088 IU/L. Serum lactate, pyruvate and all other blood tests were normal. Nonlysosomal Glycogenoses Phosphorylase b kinase deficiency* What is the most likely diagnosis?

Myophosphorylase deficiency* DIFFERENTIAL DIAGNOSIS Phosphofructokinase deficiency* Phosphoglycerate kinase deficiency* The constellation of symptoms consisting of exercise intolerance, muscle weakness, and myoglobinuria are most commonly associ- Phosphoglycerate mutase deficiency* ated with metabolic myopathies. These symptoms are the result Lactate dehydrogenase deficiency* of failure in energy production stemming from impaired lipid or Debrancher enzyme deficiency glycogen metabolism, or mitochondrial dysfunction. The three Brancher enzyme deficiency main groups of metabolic myopathies are glycogen storage disease (GSD), fatty acid oxidation (FAO) defects, and mitochondrial Aldolase A deficiency cytopathies. Each group is clinically and genetically heteroge- β Enolase deficiency neous. The various disorders can have distinct neurological and Triosephosphate isomerase deficiency systemic manifestations in addition to the muscular symptoms in Lafora disease different age groups. Furthermore, both transient and permanent muscle dysfunction can occur. Patients presenting with symptoms suggestive of these complex disorders can represent a diagnos- Lysosomal Glycogenosis tic challenge for clinicians due to overlapping symptomatology Acid maltase deficiency among the various metabolic myopathies, as well as similarities Lysosome associated membrane protein-2 deficiency to other acquired and genetic muscle diseases; however, a detailed patient history and laboratory testing can provide clues leading to *Disorders in which exercise intolerance, cramps, and myoglobinuria are the most the diagnosis. prominent presenting symptoms. AANEM Course Neuromuscular Update II 21

CK is persistently elevated even between episodes of myoglobinuria. enzyme deficiency IIIa is an autosomal recessive disorder and the Electrodiagnostic (EDX) studies show normal nerve conduction gene is localized to chromosome 1p21. EDX testing can be normal studies. EMG is normal when patients are asymptomatic, but can or reveal mixed myopathic and neuropathic features that suggest a show myotonic discharge and fibrillation potentials during an acute neurogenic contribution to phenotype. The type IIIb form of deb- attack. Diagnosis can be made by demonstrating the absence of my- rancher enzyme deficiency does not have muscular manifestations. ophosphorylase on the muscle biopsy or genetic mutation analysis. Other GSDs including branch enzyme deficiency (glycogenosis The myopathic variant of phosphorylase b kinase (PBK) defi- type IV) and acid maltase deficiency (glycogenosis type II) typically ciency (glycogenosis type VII) is similar to myophosphorylase cause progressive and static muscular symptoms. Exercise intoler- deficiency in that patients experience exercise intolerance, cramps, ance and activity induced symptoms are not prominent features and myoglobinuria. It is caused by a defect in phosphorylase b in these disorders. In addition to the myopathic findings, other kinase, a key regulator of glycogen metabolism. PBK deficiency neurological or systemic conditions are frequently present. can be transmitted as an X-linked or autosomal recessive disorder. Phosphofructokinase (PFK) deficiency (glycogenosis type Disorders of FAO VII) is clinically indistinguishable from myophosphorylase deficiency. The main clinical features include exercise intolerance, Myopathic symptoms such as myalgias, muscle fatigue, weakness, myalgia, cramps, and exercise induced myoglobinuria. Despite the and myoglobinuria are most commonly induced by prolonged similarities, PFK can be differentiated from McArdle’s disease by physical exertion in patients with FAO defects. This is due to the routine laboratory testing. PFK is a tetrameric enzyme encoded dependence of the muscle on stored lipid as the metabolite for by different combinations of three subunits located on separate energy production during long endurance activities. In addition to chromosomal loci. The muscle (M) subunit is on chromosome 1, sustained activity, patients with this group of disorders frequently liver (L) subunit is on chromosome 21, and platelet subunit is on have muscular symptoms precipitated by prolonged fasting, infec- chromosome 10. The muscle expresses only the M isoform and tion, general anesthesia, and states of metabolic stress. The exact erythrocytes express both M and L isoforms. A complete absence trigger for myopathic symptoms is sometimes unknown. Unlike of the M isoform results in partial PFK deficiency in erythrocytes, adults, infants and young children with FAO defects have systemic causing hemolytic anemia. This is reflected in laboratory studies involvement including hepatic dysfunction, cardiomyopathy, hy- as elevated reticulocyte count and hyperbilirubinemia. Other clues poketotic hypoglycemia, and generalized metabolic perturbation for PFK deficiency include the presence of polyglucosan, in ad- which can overshadow the myopathic symptoms. dition to glycogen deposits on the muscle biopsy. Polyglucosan stains intensely with periodic acid-Schiff reaction, but is resistant Carnitine palmitoyltransferase (CPT) 2 deficiency is the most to diastase. PFK deficiency, like McArdle’s disease, causes impaired common cause of recurrent myoglobinuria in adults. The adult onset glycolysis, but the metabolic block is in the downstream glycolytic myopathic form of CPT2 deficiency typically manifests as recurrent pathway. PFK deficient muscle cannot utilize glucose, and high paroxysmal myoglobinuria, muscle aches, and stiffness induced by carbohydrate meals exacerbate the exercise intolerance resulting in sustained exercise. The myopathic attacks can also be triggered by the “out of wind” phenomenon. febrile illness, prolonged fasting, cold temperature, or emotional stress. The precipitant is not identified in 20% of cases. The “second Phosphoglycerate kinase (PGK) deficiency (glycogenosis type IX) wind” phenomenon is not a feature of this disorder, and patients are causes exercise intolerance and myoglobinuria. In addition, pa- able to participate in brief strenuous physical activities. Significant in- tients may have central nervous system dysfunction such as mental volvement of other organ systems is not characteristic of this disorder. retardation, seizure, and hemolytic anemia. PGK deficiency also Between episodes of myoglobinuria, patients with CPT2 deficiency distinguishes itself as an X-linked disorder. The primary manifesta- are essentially normal, and the development of fixed muscle weakness tion of phosphoglycerate mutase deficiency (glycogenosis type X) is uncommon. Men appear to be more affected than women. is exercise intolerance, exertion induced myalgia, cramp, and myoglobinuria. It is an autosomal recessive condition. Lactate dehy- CPT2 deficiency is an autosomal recessive disorder, and the causative drogenase (LDH) deficiency (glycogenosis type XI) is a rare cause gene is localized to chromosome 1p32. Diminished CPT2 activity of exercise intolerance and myoglobinuria. It is due to mutation in results in failure to transport long-chain fatty acids across the mito- the muscle specific subunit localized to chromosome 11. Patients chondrial membrane into the matrix where FAO takes place. This have myoglobinuria, elevated serum CK, but low LDH. ultimately leads to impaired energy production. Rare cases of clinically affected heterozygote with partial CPT2 deficiency have been Debrancher enzyme deficiency (glycogenosis type III) represents reported. Routine laboratory studies between myopathic attacks may 25% of all GSDs. In the IIIa subtype, branching enzymes are absent be normal or show elevated serum CK. EDX testing reveals normal in both muscle and liver. The most common presentation is child- nerve conduction studies and low-amplitude short duration motor hood onset of liver dysfunction, hepatomegaly, failure to thrive, unit action potentials on EMG. Routine histochemical studies of delay in motor skills development, and fasting hypoglycemia that the muscle biopsy including sections evaluating glycogen and lipid resolves by puberty. Subsequent static weakness in the distal more content in an asymptomatic individual may be normal. The diag- than proximal muscles occurs during the third and fourth decade of nosis can be made by demonstrating reduced CPT2 enzyme activity life. Cases with exercise intolerance have been reported. Debrancher from the muscle specimen or fibroblast culture. 22 Metabolic Myopathy AANEM Course

Childhood onset of hypoketotic hypoglycemia and multiple meta- a careful review of the circumstances and provocative factors as- bolic disturbances is the most common presentation for acyl-coA sociated with the patient’s muscular symptoms. Extensive labora- dehydrogenase deficiencies. Recurrent myoglobinuria triggered by tory testing, EDX evaluation, muscle biopsy with biochemical exercise or fasting is an uncommon phenotype of very long chain studies, and genetic mutation analysis may all be necessary before acyl-CoA dehydrogenase (VLCAD) deficiency. Isolated muscle an exact diagnosis can be established. Despite an exhaustive involvement tends to have a later onset when compared to patients effort, the underlying etiology may still elude even the most with generalized metabolic derangement. VLCAD deficiency is assiduous clinician. an autosomal recessive disorder caused by mutation in the gene ACADVL mapped to chromosome 17p13. Other rare cases of exertion-related myoglobinuria and episodic weakness with rhab- TREATMENT domyolysis have been described in medium chain acyl-coA dehydrogenase (MCAD) deficiency and long chain acyl-coA dehydrogenase Currently, there is no effective cure for any of the metabolic (LCAD) deficiency. MCAD is localized to chromosome 1p31, myopathies. Lifestyle modification such as endurance training may and LCAD is mapped to chromosome 2q34. Recurrent episodes improve exercise capacity in some patients with GSD. A regimen of exertion-induced myoglobinuria associated with a sensorimotor of moderate aerobic exercise can be tolerated by patients with polyneuropathy have been described as an uncommon phenotype McArdle’s disease without adverse muscle symptoms or elevation of mitochondrial trifunctional protein (MTP) deficiency. MTP is a in serum CK. The improvement in oxidative and work capacity multimeric enzyme with four α-subunits and four β-subunits. The with physical conditioning may be due to increased mitochon- α-subunits have long-chain 2-enyol-coA hydratase and long-chain drial enzyme level and cardiac output. Ingestion of sucrose prior L-3-hydroxyacyl-CoA dehydrogenase activities. The genes that to physical exercise can also increase exercise tolerance in patients encode α- and β-subunits are both localized to chromosome 2p23. with McArdle’s disease. Patients with FAO disorders and mitochondrial cytopathies are encouraged to avoid fasting and exercise Mitochondrial Cytopathy during fasting or acute illnesses. Dietary changes and supplements have not produced sustained long-term functional improvement. Mitochondrial cytopathy represents one of the most complex groups Patients who have FAO disorders should avoid prolonged sustained of disorders. Although the human mitochondrial genome is only exercise. Enzyme replacement therapy and gene therapy are among 16.5 kb and encodes 13 structural proteins, many different clinical the potential innovative therapeutic options that may revolutionize syndromes can result from mutations in these genes. The complex- treatment for these disorders. ity of mitochondrial disorders stems from three unique features of mitochondrial genetics. First, all mitochondria and mitochondrial deoxyribonucleic acid (DNA) are derived from the oocyte. Second, REHABILITATION TREATMENT ISSUES IN MCARDLE’S mitochondria with different DNA sequences can coexist in a cell or DISEASE tissue in a phenomenon known as heteroplasmy. When all of the mitochondrial DNA in a cell or tissue is the same sequence, it is McArdle’s disease (GSD type V) results from the absence of the known as homoplasmy. Heteroplasmy is important in mitochon- muscle glycolytic enzyme, myophosphorylase. This enzyme de- drial disorders because mutant mitochondrial DNA can be present ficiency leads to a muscle’s inability to break down glycogen for in different proportions in various cell populations. The pathogenic energy generation during anaerobic metabolism. In addition, a effect of the mutation will only be manifested when a critical level lack of myophosphorylase also impacts energy generation during of mutant mitochondrial DNA is reached. This is known as the aerobic metabolism due to decreased substrate generation (pyru- threshold effect. Third, mutant and normal mitochondrial DNA vate) for the citric acid cycle. Glycogen is the most important segregate randomly during cell division, thus changing the propor- source of energy for the muscle during early exercise and at high tion of mutant DNA in the different cells over time. exercise intensities. The decrease in oxidative capacity of McArdle’s disease muscle is at less than half of normal muscle in the first few Although exercise intolerance, myalgia, and recurrent myoglobi- minutes of moderate exercise. More vigorous activity will trigger nuria can be symptoms of mitochondrial disorders, the myopathic muscle cramps, pain, and myoglobinuria. Therefore, the block- symptoms may occur in isolation or coexist with other neurologic age of glycogen breakdown in muscle results in a complex clinical and systemic conditions. Progressive fixed muscle weakness can pattern of exertional intolerance, muscle cramps, myalgia, second develop in addition to the paroxysmal muscular symptoms. The wind phenomenon, rhabdomyolysis, and myoglobinuria, as seen in genetic mutations responsible for myopathies can also cause multi- McArdle’s disease. systemic disorders. Due to the risk for severe and potentially dangerous rhabdomyolysis associated with exercise, many patients with McArdle’s disease EVALUATION have traditionally been advised to avoid exercise. However, sedentary and inactive lifestyles for these patients results in The possible causes of exercise intolerance and myoglobinuria deconditioning, which can further complicate and worsen the are extensive. To determine the specific diagnosis, a detailed disease by decreasing cardiovascular and circulatory capacity. developmental and family history is critical in combination with With deconditioning and decline in circulatory capacity, the AANEM Course Neuromuscular Update II 23 delivery of much needed bloodborne energy fuels such as glucose the severity of exercise intolerance correlates with insertion/deletion and free fatty acids to muscle becomes impaired in a clinical polymorphic variants of angiotensin-converting enzyme (ACE).4 scenario where muscle energy imbalance is already compromised Ramipril 2.5 mg orally daily showed possible benefit in McArdle’s by the inborn error of glycogen breakdown. Research has also disease patients with the D/D ACE haplotype.3 shown that deconditioning reduces levels of muscle mitochondria and mitochondrial enzymes that are necessary for metabolizing Currently, there is no specific guideline for a physical therapy or energy sources. Thus, avoidance of physical activity and adop- an exercise program. A reasonable approach may be to discuss tion of an inactive lifestyle in McArdle’s disease patients for fear with the patient current knowledge in regards to exercise, sucrose, of muscle injury may result in a downward spiral of decreased nutrition, and pharmacological treatment options in McArdle’s exercise tolerance and aerobic capacity. In turn, this further disease. A moderate aerobic exercise program with or without pre- lowers the threshold of physical activity, producing muscle injury exercise oral sucrose can be recommended. If the patient would and cramps. like to pursue an exercise program, several things should be considered to provide the patient with the best chance for success. It Given these issues, recent studies have examined whether exercise is recommended that a structured exercise program be designed in training and aerobic conditioning can help ameliorate the symptoms a consultation with an experienced physical therapist who will be of McArdle’s disease. Haller and collegues have demonstrated the monitoring the patient and will be in contact with the physician. beneficial effects of a moderate intensity aerobic exercise program The exercise regimen should be an aerobic program, preferably in improving average work capacity (36%), oxygen uptake (14%), either walking/treadmill or stationary cycle program, starting at low cardiac output (15%), and citrate synthase and beta-hydroxyacyl intensity (30% to 40%) during warm up period (5 to 15 minutes) coenzyme A dehydrogenase enzyme levels (80% and 62%, respec- with gradual progression to a goal of 60% to 70% maximal heart tively) without causing pain, cramping, or increasing serum CK rate. Isometric, maximal effort, and high-weight, low-repetition levels.2 The exercise regimen entailed cycle ergometry for 30-40 exercises are to be avoided and listed under precautions for exercise minutes per day, 4 days per week for 14 weeks, at an intensity of prescription. Exercise duration should be about 30 to 40 minutes approximately 60% to 70% maximal heart rate. The investigators per day, and 4 to 5 days per week. Initially, heart rate and per- found that moderate aerobic exercise is well tolerated and when ceived exertional effort should be monitored and recorded. The performed regularly, leads to adaptations that substantially increase physical therapist can instruct the patient in heart rate monitor- oxidative and work capacity in patients with McArdle’s disease. A ing as well as provide feedback about concordance with perceived favorable response was also noted in a similar but longer (8 month) exertional effort. This will prepare the patient for transition to a exercise training program study.5 Other case reports and studies self-monitored, home-based, long-term exercise program. If ap- also support the benefit of a moderate intensity aerobic exercise propriate on clinical grounds, a sports drink containing 30 grams and activity program in patients with McArdle’s disease to improve of oral sucrose just prior to the exercise session can be administered exercise tolerance, work capacity, and overall health status.6,7,8 The as a preventative measure for muscle cramps and exercise-induced beneficial effects of the exercise program are thought to occur myoglobinuria, especially during the first 5 to 10 minutes of the through increasing cardiovascular fitness and improving circulatory exercise program. delivery capacity, as well as increased mitochondrial enzyme level and improved metabolic efficiency. BIBLIOGRAPHY Researchers have shown that ingestion of sucrose prior to an exercise program improves work capacity and exercise tolerance in pa- 1. Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly tients with McArdle’s disease.1,5,10 It appears that smaller amounts before exercise on work capacity in McArdle disease. Arch Neurol. (30 to 37 grams) of sucrose just prior to an exercise session may be 2008 Jun;65(6):786-9. as effective as a large amount (75 grams) ingested 30 to 40 minutes 2. Cwik VA. Disorders of lipid metabolism in skeletal muscle. Neurol before exercise. It should be cautioned that when used regularly Clin. 2000 Feb;18(1):167-84. and in large amounts well in-advance of planned activities, sucrose 3. Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; ingestion may result in unintended side effects of weight gain and part I. Pediatr Neurol. 2000 Feb;22(2):87-97. 4. Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; a potential for diabetes. part II. Pediatr Neurol. 2000 Mar;22(3):171-81. 5. Devries MC, Tarnopolsky MA. Muscle physiology in healthy men A recent Cochrane Review on pharmacological and nutritional treat- and women and those with metabolic myopathies. Neurol Clin. 2008 ment for McArdle’s disease concluded that there is no evidence of Feb;26(1):115-48 significant benefit from any specific nutritional or pharmacological 6. DiDonato S, Taroni F. Disorders of lipid metabolism, in Engel AG, treatment in McArdle’s disease.9 There is a lack of evidence to show Franzini-Armstrong C (eds): Myology, 3rd ed. New York: McGraw- benefit from supplementation with branched chain amino acids, Hill; 2004, 1587-1621. 7. DiMauro S, Andreu AL. Mutations in mtDNA: are we scraping the depot glucagon, dantrolene sodium, verapamil, vitamin B6, high-dose oral D-ribose, or high-dose creatine. Low-dose creatine conferred a bottom of the barrel? Brain Pathol. 2000 Jul;10(3):431-41 modest benefit on ischemic exercise testing, while high-dose creatine 8. DiMauro S, Hays AP, Tsujino S. Nonlysosomal glycogenoses, in was found to worsen symptoms.9 A diet rich in carbohydrates may Engel AG, Franzini-Armstrong C (eds): Myology, 3rd ed. New York: McGraw-Hill; 2004, 1535-1558. be better than a protein rich diet. Recent research has indicated that 24 Metabolic Myopathy AANEM Course

9. DiMauro S, Lamperti C. Muscle glycogenoses. Muscle Nerve. 2001 3. Martinuzzi A, Liava A, Trevisi E, Frare M, Tonon C, et al. Aug;24(8):984-99. Randomized, placebo-controlled, double-blind pilot trial of ramipril 10. Haller RG, Wyrick P, Taivassalo T, Vissing J. Aerobic condition- in McArdle's disease. Muscle Nerve. 2008 Mar;37(3):350-7. ing: an effective therapy in McArdle's disease. Ann Neurol. 2006 4. Martinuzzi A, Sartori E, Fanin M, Nascimbeni A, Valente L, et Jun;59(6):922-8. al. Phenotype modulators in myophosphorylase deficiency. Ann 11. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, Mora Neurol. 2003 Apr;53(4):497-502. M, Riggs JE, Oh SJ, Koga Y, Sue CM, Yamamoto A, Murakami 5. Maté-Muñoz JL, Moran M, Pérez M, Chamorro-Viña C, Gómez- N, Shanske S, Byrne E, Bonilla E, Nonaka I, DiMauro S, Hirano Gallego F, et al. Favorable responses to acute and chronic exercise in M. Primary LAMP-2 deficiency causes X-linked vacuolar car- McArdle patients. Clin J Sport Med. 2007 Jul;17(4):297-303. diomyopathy and myopathy (Danon disease). Nature. 2000 Aug 6. Ollivier K, Hogrel JY, Gomez-Merino D, Romero NB, Laforêt P, 24;406(6798):906-10. Eymard B, Portero P. Exercise tolerance and daily life in McArdle's 12. Ørngreen MC, Schelhaas HJ, Jeppesen TD, Akman HO, Wevers RA, disease. Muscle Nerve. 2005 May;31(5):637-41. Andersen ST, ter Laak HJ, van Diggelen OP, DiMauro S, Vissing J.Is 7. Pérez M, Foster C, González-Freire M, Arenas J, Lucia A. One-year muscle glycogenolysis impaired in X-linked phosphorylase b kinase follow-up in a child with McArdle disease: exercise is medicine. deficiency? Neurology. 2008 May 13;70(20):1876 Pediatr Neurol. 2008 Feb;38(2):133-6. 8. Pérez M, Maté-Muñoz JL, Foster C, Rubio JC, Andreu AL, et al. Exercise capacity in a child with McArdle disease. J Child Neurol. REHABILITATION TREATMENT REFERENCES 2007 Jul;22(7):880-2. 9. Quinlivan R, Beynon RJ, Martinuzzi A. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type 1. Andersen ST, Haller RG, Vissing J. Effect of oral sucrose shortly V). Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003458. before exercise on work capacity in McArdle disease. Arch Neurol. 10. Vissing J, Haller RG. The effect of oral sucrose on exercise toler- 2008 Jun;65(6):786-9. ance in patients with McArdle's disease. N Engl J Med. 2003 Dec 2. Haller RG, Wyrick P, Taivassalo T, Vissing J. Aerobic condition- 25;349(26):2503-9. ing: an effective therapy in McArdle's disease. Ann Neurol. 2006 Jun;59(6):922-8. 25

Progressive Asymmetrical Weakness

Kerry H. Levin, MD Jay J. Han, MD Chairman Department of Physical Medicine and Rehabilitation Department of Neurology Assistant Professor Cleveland Clinic University of California Davis Professor of Medicine (Neurology) Sacramento, California Cleveland Clinic Learner College of Medicine Cleveland, Ohio Anthony A. Amato, MD Professor of Neurology, Harvard Medical School Department of Neurology Brigham Women’s Hospital Boston, Massachusetts

CASE DESCRIPTION Electrodiagnostic Studies A previously healthy 50-year-old man began to develop difficulty The results of the nerve conduction studies (NCSs) for the upper arising from a chair and climbing stairs. By the time of his first and lower extremities can be found in Table 1. The needle electro- neuromuscular evaluation at age 54, he needed both arms to lift myography (EMG) results are located in Table 2. himself from a chair, both arms to pull himself up the stairs, and both hands to open a car door. He denied symptoms of myelopathy. The patient described some degree of numbness over digits DIFFERENTIAL DIAGNOSIS 4 and 5 of the left hand. He occasionally had difficulty clearing his throat, and on questioning, described occasional coughing on In summary, the patient presented with slowly progressive, painless particulate or dry foods. muscle weakness. He had predominantly distal weakness in the arms (sparing of the shoulder girdle and triceps but involvement of At age 54, on motor examination of the upper body, neck flexion the wrist and finger flexors and extensors), but proximal and distal was graded 4/5, shoulder abduction 4.5/5, arm external rotation weakness in the legs (involvement of hip girdle, knee extensors, and 4.5-4.8/5, elbow extension 4.5-4.8/5, and elbow flexion 3/5 on the ankle dorsiflexion and plantar flexion). There was also asymmetry right, 2.5-3/5 on the left. Wrist flexors and extensors were graded in muscle strength, particularly distally. Sensory examination was 4/5, with left wrist extension 3.5/5. Ulnar intrinsic hand muscles normal but he did have mild symptoms in the distribution of the were graded 4.5/5 on the right and 3/5 on the left. Distal and prox- left ulnar nerve. Muscle stretch reflexes were normal and plantar imal finger flexion was graded 3.5/5 on the right and 3/5 on the responses were normal. left, as was left thumb flexion, while thumb abduction was 4-4.5/5. In the legs, hip abduction, adduction, flexion, and extension, and In approaching patients with neuromuscular problems, the three knee flexion were graded 4/5. Knee extension was graded less than main goals include localizing the site of the lesion, identifying the 2/5 on the right and 2/5 on the left. Foot dorsiflexion was graded cause of the disorder, and successfully treating the patient. 4/5 on the right and 2/5 on the left. Foot inversion and eversion were grade 4/5 and plantar flexion was 3/5, somewhat worse on the The last goal is the most important to the patient and should be left. Muscle stretch reflexes were zero to trace throughout. There considered in determining how aggressively to pursue a work-up to was marked thinning of musculature in the forearms, somewhat identify the exact etiology of a disorder. For example, the physician more prominent in the flexor compartment, and there was atrophy may be able to make a diagnosis of Charcot-Marie-Tooth (CMT) of ulnar intrinsic hand muscles, more prominent on the left. In the Type 1 on clinical examination and electrodiagnostic (EDX) testing legs, there was prominent atrophy of the quadriceps muscle groups. and could order genetic testing to see if there is CMT1A, IB, 1C, Fasciculation and percussion myotonia were absent. No definite etc., but this may not be important to a patient, especially if they sensory deficits could be identified. have to bear some of the costs and find that there is no specific 26 Progressive Asymmetrical Weakness AANEM Course

Table 1 Nerve conduction studies for the upper and lower extremities

Upper Extremities NERVE AmplitudeRight/Left Lateral Right/Left Conduction Velocity Bold= abnormal Right/Left Ulnar Sensory 10/8 µv 3.2/3.3 ms 50/NR m/s Below Elbow (BE) --/not recorded (NR) Above Elbow (AE) 4/NR Doral Ulnar Sensory 10/6 3.0/2.9 Ulnar first dorsal 15/8 mv 4.1/4.2 interosseous (FDI) BE --/6 --/49 AE 13/5 50/42 Ulnar abductor digiti 10/8 3.0/3.0 minimi (ADM) BE --/7 --/48 AE 9/7 51/41 Axilla (AX) --/7 --/44 Lower Extremities Sural Sensory -- / 8.0 Supficial Peroneal (Per) Sensory NR/NR Per extensor digitorum 5.2/3.2 4.2/5.5 brevis (EDB) Popliteal Fossa (PF) 4.0/3.2 44/43 Per tibialis anterior (TA) 3.0/1.8 3.0/4.0 PF 77/72 treatment for any of the subtypes. Make certain this is discussed o distal myopathies/ muscular dystrophies, myofibrillar with a patient before such tests are ordered. myopathy, glycogen storage diseases (e.g., acid maltase, debrancher, branching enzyme, phosphorylase kinase The key to localizing the lesion is to assess the pattern of involve- deficiencies), amyloidosis, polymyositis/dermatomyositis ment and perform confirmatory EDX testing and laboratory (rare), sarcoidosis/granulomatous myositis, and inclusion evaluation.2 In the process, the exact diagnosis may be made or body myositis(IBM). additional testing such as a muscle or nerve biopsy, genetic testing, or serological studies can be ordered. The lack of sensory abnormalities on examination or any sensory symptoms (except for the possible left ulnar distribution numb- In the patient presenting with asymmetric, predominantly motor ness), makes a polyradiculopathy/plexopathy or peripheral neu- weakness, affecting distal greater than proximal muscles in the ropathy less likely. The pattern of weakness was diffuse in this arms and legs, the following disorders need to be considered: patient and not in the distribution of individual nerves, so it would seem that MMN is unlikely. About 5% of myasthenics will • anterior horn cell have predominately distal weakness but most patients have ocular o motor neuron disease (i.e., amyotrophic lateral involvement of some type (ptosis, blurred or double vision) and sclerosis [ALS], spinal muscular atrophy, fluctuations in their weakness that the patient did not exhibit.17 and poliomyelitis) Furthermore, because profound atrophy is not usually seen in MG • polyradiculopathies as seen in this patient, MG does not seem likely in this case. o cervical and lumbosacral, syrinx, tumors of cord, Lyme disease, sarcoidosis, and tumor infiltration On the basis of the history and clinical examination, it is sus- • plexopathies pected that the patient has either an anterior horn cell disease or • peripheral nerve myopathy. In regards to motor neuron (MN) disease, there was no o CMT, multifocal motor neuropathy (MMN) and history of an acute febrile illness to suggest poliomyelitis (plus the multifocal acquired demyelinating sensory and motor progressive nature suggests this is not polio). There is no history of neuropathy , vasculitis, cancer, and amyloidosis,toxic/ previous poliomyelitis to suggest a post-polio syndrome. The most metabolic/endocrine common anterior horn cell disease would be ALS. The patient has • neuromuscular junction no apparent cramps, fasciculations, or upper motor neuron find- o rare cases of myasthenia gravis (MG) ings that would further assist in localizing the lesion to the anterior • muscle horn cells and diagnosis of ALS. It is important to note that some forms of MN disease remain purely lower MN by symptoms and signs. Thus, MN diseases such as ALS remains a possibility. AANEM Course Neuromuscular Update II 27

Table 2 Needle electromyography results for the upper and lower extremities

Muscle Fibrillation Other Recruitment MUAP Duration MUAP Amplitude Config L=Left R=Right L FDI ++ ↓↓ ↑↑ ↑↑ R FDI 0-+ ↓ ↑ ↑ L APB + NL NL NL L FPL + ↓ Some ↑ Some ↑ L EIP + NL NL NL L FCU ++ NL Some ↑ Some ↑ L PT ++ NL Some ↑ + Serrated L BR ++ MTP Poor ↓↓ ↓ and ↑ + Polyphasic activation L Triceps ++ Poor ↓ ↓ and ↑ + Polyphasic activation L Biceps +++ Poor ↓↓ ↓ ++ Polyphasic activation L Deloid 0-+ NL NL NL NL L Infra 0-+ NL NL NL NL

L EDB + ↓↓ ↑ ↑ L TA +-++ CRD Poor ↓↓↓ ↓ ++ Polyphasic activation L MG +-++ Poor ↓↓ ↓ + Polyphasic activation L RF ++ MTP Poor Some ↑ ↓ ++ Polyphasic activation L Iliac +++ Poor Some ↑ NL ++ Polyphasic activation L CPS ++ CRD -- ↓ ↓ + Serrated

APB = abductor pollicis brevis; BR = brachioradialis; CPS = cervical paraspinal; CRD = complex repetitive discharge; EIP = extensor indicis proprius; FCU = flexor carpi ulnaris; FPL = flexor pollicis longus; Infra = infraspinatus; MTP = myotonic potentials; MUAP = motor unit action potentials; NL =Normal; PT = pronator teres; RF = rectus femoris

There are various types of myopathy that present in this age EMG usually shows fibrillation potentials, positive sharp waves, range and with this pattern of weakness. The most common and occasionally complex repetitive discharges and myotonic/ myopathy presenting after age 50 is IBM.11 About two-thirds pseudomyotonic discharges. A mixture of short duration, low of patients exhibit a characteristic pattern of weakness with early amplitude polyphasic motor unit action potentials (MUAPs) and weakness and atrophy of the volar forearm muscles (wrist and long duration, high amplitude, polyphasic MUAPs is often ap- finger flexors) with relative sparing of the deltoids.4 In the legs, preciated. The larger MUAPs may lead to the erroneous impres- there is early weakness and atrophy of the quadriceps in addi- sion of chronic denervation with reinnervation, but in reality are tion to the hip girdle and anterior tibial muscles. Asymmetric secondary to the chronic myopathy. A way to help distinguish involvement is commonly seen. At least 30% to 40% of patients if large MUAPs are secondary to a myopathic versus neurogenic have dysphagia. The myopathy is very slowly progressive, so process is examine the recruitment pattern. In neurogenic disor- it fits well with the description. It is important to note that ders, MUAP recruitment is decreased (fewer units are seen and NCSs can sometimes demonstrate low amplitude sensory nerve they fire fast) while with a myopathy, the pattern of recruitment action potentials (SNAPs) suggestive of an underlying axonal is usually early (many units firing at a normal rate are seen with neuropathy even though patients are typically asymptomatic. minimal power). 28 Progressive Asymmetrical Weakness AANEM Course

Other myopathies are also possible and must be distinguished from biopsy. It is also recommended to biopsy a muscle that was not IBM with a muscle biopsy. studied by EMG. A vastus lateralis would probably be ideal in this case. On the biopsy, the focus would be on finding endomysial inflammation and invasion of non-necrotic muscle fibers, rimmed EVALUATION vacuoles, ragged red fibers/cytochrome oxidase negative fibers, amyloid deposition on Congo red or 15-21 nm tubulofilaments Serum creatine kinase (CK) can be helpful if markedly elevated but that would support the impression of IBM. Granulomas suggest- mild elevations may be seen in anterior horn cell disease (e.g., ALS) ing sarcoidosis or granulomatous neuromyoathy should be sought. and normal CK can be seen in myopathies. So the serum CK of The biopsy should also be helpful in distinguishing IBM from 1100 U/L is not particularly helpful. other myopathic disorders in the differential diagnosis (e.g., myofibrillar myopathy, dystrophy, and glycogen storage disorders). In attempting to differentiate an anterior horn cell disorder from a myopathy, the most useful tests would be EMG/NCSs. The NCS revealed absent superficial pernoneal and borderline to low ampli- FOLLOW-UP tudes for the ulnar SNAPs bilaterally. The left ulnar-first dorsal interosseous compound muscle action potential (CMAP) had an Biopsy of the vastus lateralis muscle showed marked interstitial amplitude almost half the size of the right side. There was perhaps fibrosis and fat infiltration in atrophic muscle, focally and mark- mild slowing of the left ulnar motor conduction velocity across the edly infiltrated by lymphocytes. Other findings included numerous elbow, but not enough to declare it definitely abnormal. The left rimmed vacuoles and prominent intranuclear and cytoplasmic in- peroneal-tibialis anterior CMAP amplitude was also reduced, but clusions surrounded by vacuolar space. Granulomas were not seen. interestingly, the peroneal-extensor digitorum brevis CMAP was Acid and alkaline phosphatase reactions were intense in degenerat- normal. This finding would be atypical for a peripheral neuropa- ing and regenerating fibers. The pathological diagnosis confirmed thy, but might suggest reduction secondary to a distal myopathy. the clinical diagnosis of IBM.

The EMG revealed marked numbers of fibrillation potentials, posi- The patient enrolled in an experimental trial of cyclosporine , but tive sharp waves, complex repetitive discharges, and myotonic dis- he noticed no difference in strength. At age 57 years, he underwent charges. Notably, fasciculation potentials were not observed, which a left ulnar transposition at the elbow for focal neuropathy without would be atypical for ALS. Myotonic discharges should lead to subsequent benefit. There was continued generalized decline in the consideration of myotonic dystrophy (DM1 and DM2), myo- strength and activities of daily living (ADLs), with accentuated fibrillar myopathies, and glycogen storage diseases (acid maltase, weakness in the left hand and left foot dorsiflexors. He developed debrancher, branching enzyme deficiencies), but they can be seen progressive dysphagia with occasional symptoms of aspiration. occasionally in the inflammatory myopathies, including IBM. He enrolled in a National Institute of Health sponsored trial of EMG of proximal muscles showed mainly small MUAPs. Some of a combination of prednisone, methotrexate, and azathioprine for the distal muscles had large MUAPs and decreased recruitment, sug- the treatment of IBM, and continued on that regimen for about gestive of a possible superimposed neurogenic process (but could be 6 years, the last 3 of which were after completion of the study. seen in very severe myopathic weakness). The recruitment pattern During these years, there was steady progression of weakness, and was difficult to assess in many muscles due to poor activation or all drugs were gradually tapered and withdrawn. effort. The only strong evidence of a neurogenic process by EMG was in the ulnar-innervated muscle in the left arm. The EMG/NCS At age 66, an otolaryngologist identified pooling of oral secretions results were most consistent with a chronic necrotizing/irritative in the piriformis sinuses and evidence of aspiration. This patient myopathic process, perhaps with superimposed left ulnar neuropa- obtained modest benefit from an oral regimen of guaifenesin, but thy and generalized axonal sensory polyneuropathy which are likely had recurrent frightening episodes of choking from thick secre- incidental to the myopathy, which is the primary problem. tions he could not mobilize from his oropharynx, due in part to a weak cough. At age 67, he underwent cricopharyngeal myotomy A neuromyopathy related to sarcoidosis or granulomatous disease with marked symptomatic improvement of dysphagia and degluti- would need to be considered. Amyloidosis that can cause a myo- tion. By age 73, dysphagia had returned and spirometry identified pathy and/or neuropathy could also be considered, although the hypoventilation on a restrictive basis. He started bilevel-positive patient did not have symptoms suggestive of amyloid polyneuropa- pressure ventilation at that time to allow rest in the supine position thy. Again, the clinical examination, laboratory testing, and EDX at night. The patient died at age 74. features are all consistent with a diagnosis of IBM, which is the most common myopathy in patients over age 50. It is likely that Treatment for IBM IBM would be on the top of the differential diagnosis. To date, there are no clearly effective treatments that reverse, To support this impression, a muscle biopsy of a clinically affected stabilize, or slow the progression of IBM. Many retrospective muscle would need to be performed. It is important to biopsy a and few prospective studies have assessed the value of various im- muscle that is weak but not too weak, as severely weak muscles munosuppressant treatments. Several studies have documented secondary to a neurogenic disorder can resemble a dystrophy on improvement in elevated CK levels, but this was not associated AANEM Course Neuromuscular Update II 29

Rehabilitation Treatment Issues in IBM with sustained clinical improvement. An unblinded prospective study was performed on 11 patients, comparing prednisone plus Since there is no cure for IBM, most of the current treatment strat- either oral or IV methotrexate. Over 6 months, there was no egies are designed to maximize mobility and dexterity functions, significant change in clinical status, but serum CK levels dropped minimize falls and other potential complications related to the significantly.14 disease, and aim for improved quality of life for the patients.

Intravenous immunoglobulin (IVIg) is clearly effective in the treat- A multi-disciplinary team approach to treating patients with IBM ment of dermatomyositis.7 However, two prospective, double-blind, (as it is often the case with other neuromuscular diseases) is recom- placebo-controlled studies have failed to demonstrate effectiveness mended whenever possible. Even though IBM is a primary muscle in IBM.8,9 Methotrexate, which is effective in dermatomyositis and disease, the functional and quality of life impact it has on patients polymyositis, has also been shown to be ineffective in IBM as part with IBM can be quite significant. Although not all disciplines of controlled trials.6 need to be involved at once or initially in the disease course, as the disease progresses, a coordinated care plan needs to incorporate Two randomized controlled studies of ß-Interferon-1a, each in 30 various clinical specialists including: a physical therapist, an occu- patients over a 6 month period, produced no significant improve- pational therapist, an orthotist, a speech therapist, a rehabilitation ment in strength or muscle mass.15,16 A trial of total body irradia- psychologist, a social worker, a pulmonologist, a gastroenterologist, tion in IBM was ineffective and may have caused acceleration of a nutritionist, and an otolaryngologist. Examples of the various the disease.13 clinical specialists and their roles in the multidisciplinary team are shown (Table 3). Often a physical medicine and rehabilitation spe- Progressive dysphagia is a frequent complication of IBM. Medical cialist or a neurologist will lead the treatment team and coordinate treatment includes maneuvers such as chin tucking to maximize a comprehensive, goal-oriented care plan. esophageal mechanics and the avoidance of offending foods, such as dry and particulate foods. Swallowing studies in some Often, the affected muscle groups in IBM are primarily finger patients with progressive dysphagia demonstrate cricopharyngeal flexors and knee extensors. The progressive weakness affecting dysfunction, otherwise known as cricopharyngeal achalasia. The the finger flexors have great impact on ADLs and self-care (oro- cricopharyngeus muscle (upper esophageal sphincter) is normally facial hygiene, grooming, dressing, feeding, and bathing), while in a state of contraction, except when it relaxes in sequence with knee extensor weakness results in impaired mobility with frequent pharyngeal propulsion during the swallowing maneuver, to allow falls due to knee buckling. Adaptive equipment such as built-up passage of the bolus into the esophagus. Primary cricopharyngeal handle utensils, electric toothbrushes or razors, handheld shower, dysfunction occurs when the muscle remains contracted during grabbers, and sockaids can help improve patient’s independence. swallowing. This can occur on an idiopathic basis, but also An AFO with articulated ankle joint with dorsiflexion assist and develops in the setting of some neurological disorders, such as anterior stop can help with weak tibialis anterior muscle as well oculopharyngeal dystrophy, ALS, inflammatory myopathies, IBM, as quadriceps muscle weakness. During the swing phase of the and stroke. gait, the dorsi-assist action of the AFO will help with toe clearance while during the stance phase, the anterior dorsiflexion stop A number of pathological disorders in the oropharynx and esopha- will help to keep the knee from buckling by prevention of ankle gus develop in patients with polymyositis, dermatomyositis, and dorsiflexion. Another option may be a lightweight non-articulated IBM, predisposing them to dysphagia and aspiration. These (solid ankle) AFO with ankle joint at neutral position. A forearm include dysfunctional pharyngeal wall motion (leading to poor style crutch with built-up handle (to compensate for finger flexor bolus formation and transit in the oral phase), poor laryngeal weakness) may also be used in select ambulatory patients with IBM elevation due to suprahyoid muscle weakness (impairing complete to improve their gait and balance. Wheeled walkers or quad canes closure of the vestibule of the epiglottis and complete opening of may also help, depending on the degree and pattern of weakness. the upper esophageal sphincter), inadequate hypopharyngeal pres- As the disease progresses, mobility and ADL functions decline, sure generation to trigger relaxation of the cricopharyngeus, and the risk of falls increases. Timely and appropriate prescription for cricopharyngeal hypertrophy (resulting from fibrosis of the muscle), mobility and transfer equipment (with help from therapists) will that leads to narrowing at the esophageal inlet.10 Fluoroscopic swal- improve safety and independence while decreasing complications. lowing studies may demonstrate a “bar” during the swallowing maneuver that represents the hypertrophied cricopharyngeus and Until recently, active physical exercise in patients with inflamma- narrowing of the entry to the esophagus. For this reason, some tory myopathies was discouraged for fear of exacerbating muscle patients benefit from cricopharyngeal myotomy, during which the inflammation. Although exercise studies are limited in IBM and muscle is sectioned to relieve the obstruction.10,19 report only a few subjects1,5,18, there appears to be an overall trend towards achieving health benefits and reducing physical impair- Most of the treatment strategies for IBM aim to maximize mobility ment with improved strength measures, without significant ag- and dexterity, and minimize falls. Utensils with wide grips allow gravation of muscle inflammation. A moderate intensity 20 min patients to feed themselves. Ankle-foot orthoses (AFOs) improve home exercise program combined with a 15 minute walk 5 days gait stability, but do not prevent falls from knee buckling. For that a week for 12 weeks showed that while strength was not signifi- reason, most patients eventually lose the ability to ambulate. cantly improved after the exercise program, none of the patients 30 Progressive Asymmetrical Weakness AANEM Course

Table 3 Examples of clinical specialists and roles in multidisciplinary team

Evaluation/Education Treatment/Equipment Physical Therapist (PT) Mobility assessment Manual wheelchair Exercise and ROM education Power wheelchair Transfer eval and education Lift mechanisms Occupational Therapist (OT) ADL assessment Built-up handle utensils Adaptive equipment evaluation Static orthosis/Universal cuff Home evaluation Bathroom equipment Architectural or in-home mod. Orthotist Evaluation, manufacture, and AFOs (ankle foot orthosis) fitting of orthosis Static hand orthosis Speech Therapist Swallowing evaluation Dysphagia diet modification Safe swallowing techniques Psychologist Adjustment to disease Therapy sessions Depression Referral to psychiatrist Social worker Community and work resources Provide support and information End of life issues Assist with community integration Work related issues Pulmonologist/respiratory therapist Pulmonary function tests BIPAP Nocturnal pulse oximetry Cough assist machines Evaluation for RLD Interface/mask fitting\ Discussion re: prolonged Flu/pneumovax vaccine| ventilation options Gastroenterologist/nutritionist Nutritional assessment PEG placement Diet counseling Monitor diet and calories Otolaryngologist Tracheostomy evaluation Tracheostomy care followup Dysphagia evaluation Surgical treatment options for dysphagia

ADL = activities of daily living; AFOs = ankle foot orthesis; BIPAP = bilevel positive airway pressure; PEG = percutaneous endoscopic gastrostomy; RLD = restrictive lung disease; ROM = range of motion

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