Current Concepts in Muscle Disease

American Association of Neuromuscular & Electrodiagnostic Medicine

Anthony A. Amato, MD Timothy M. Miller, MD, PhD Mark B. Bromberg, MD, PhD Gregory T. Carter, MD

2005 AANEM COURSE E AANEM 52nd Annual Scientific Meeting Monterey, California

Anthony A. Amato, MD Timothy M. Miller, MD, PhD Mark B. Bromberg, MD, PhD Gregory T. Carter, MD

2005 COURSE E AANEM 52nd Annual Scientific Meeting Monterey, California AANEM

PRINTED BY JOHNSON PRINTING COMPANY, INC. ii Current Concepts in Muscle Disease

Faculty

Anthony A. Amato, MD Mark B. Bromberg, MD, PhD Associate Professor Professor and Vice-chairman Department of Neurology Department of Neurology Harvard Medical School University of Utah Boston, Massachusetts Salt Lake City, Utah Dr. Amato is currently the chief of the Division of Neuromuscular Disease, Dr. Bromberg began his academic career in basic science research. He director of the Clinical Neurophysiology Laboratory, and vice-chairman of received a doctorate in neurophysiology from the Department of the Department of Neurology at Brigham and Women’s Hospital in Physiology at the University of Vermont and conducted research in the Boston. He is an associate professor of neurology at Harvard Medical somatosensory and motor systems. Dr. Bromberg attended medical school School. Dr. Amato is a graduate of the University of Cincinnati College of at the University of Michigan and also completed his neurology training Medicine. He completed his neurology residency at Wilford Hall Medical and neuromuscular/EMG fellowship there. He was on the faculty at the Center in San Antonio, Texas, and completed his neuromuscular disease University of Michigan until 1994, when he joined the University of Utah, fellowship at the Ohio State University. In addition to co-editing the text- where he is currently a professor and vice-chairman in the Department of book Electrodiagnostic Medicine, Dr. Amato has authored numerous publi- Neurology. Dr. Bromberg is Director of the Neuromuscular Program and cations in the field of neuromuscular disease and electrodiagnostic medi- EMG laboratory, and the Muscular Dystrophy Association clinics. His cine. He has been involved in clinical research trials involving patients with research interests are in quantitative EMG, including motor unit number amyotrophic lateral sclerosis, peripheral neuropathies, neuromuscular estimation (MUNE) and algorithms for automated motor unit analysis, junction disorders, and myopathies. and in clinical aspects of amyotrophic lateral sclerosis.

Timothy M. Miller, MD, PhD Gregory T. Carter, MD Clinical Instructor Clinical Professor Neurosciences Department Department of Rehabilitation Medicine University of California, San Diego University of Washington San Diego, California Tacoma, Washington Dr. Miller earned his medical degree and doctorate from Washington Dr. Carter is Clinical Professor of Rehabilitation Medicine at the University in Saint Louis, Missouri. He then went on to perform an University of Washington, where he co-directs Muscular Dystrophy internship in internal medicine at the University of California, San Association (MDA) clinics and attends in the electrodiagnostic lab. He also Francisco, as well as a neurology residency and a neuromuscular fellowship serves as regional medical director of rehabilitation services for the there. He is currently a clinical instructor and research fellow at the Providence Health System in Southwest Washington. His clinical research University of California, San Diego. Dr. Miller is a member of the is investigating the relationships between pain, physical disability, and American Academy of Neurology and the American Association of quality of life in neuromuscular disease (NMD). His pre-clinical research Neuromuscular & Electrodiagnostic Medicine. He has won several awards, involves studying the role of electromyography and muscle magnetic reso- including the Golseth Young Investigator Award and the Needleman nance imaging as in vivo measurement tools to follow physiological Award for Pharmacology Research. changes in humans with NMD and transgenic mouse models of muscular dystrophy. He has over 100 peer-reviewed publications in these areas. In 1994 he won the Best Research Paper Published by a Physiatrist Award from the American Academy of Physical Medicine and Rehabilitation. In 1998 he received the Excellence in Research Writing Award from the Association of Academic Physiatrists. In 2002, he received the Excellence in Clinical Care Award from the MDA.

Authors had nothing to disclose.

Course Chair: Rahman Pourmand, 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 Current Concepts in Muscle Disease

Contents

Faculty ii

Objectives iii

Course Committee vi

Phenotypes of Myopathies With Inflammation 1 Anthony A. Amato, MD

Skeletal Muscle Channelopathies 19 Timothy M. Miller, MD, PhD

Toxic Drug-Induced Myopathies 29 Mark B. Bromberg, MD, PhD

Hereditary and New Myopathies 37 Gregory T. Carter, MD

CME Self-Assessment Test 53

Evaluation 57

Future Meeting Recommendations 59

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.

O BJECTIVES—As the neuromuscular field continues to advance, the EDX physician not only needs to know the yield of EDX in the evaluation of myopathies, but also needs to understand these diseases as a whole. After attending this course, participants will (1) learn new updates on channelopathies, periodic paralysis, and congenital myotonia with brief clinical presentations and their diagnosis, (2) understand the new classification and diagnosis of inflammatory myopathies as well as the controversies surrounding this topic, (3) learn about iatrogenic myopathies and how the EDX physician can help the referring physician, and (4) know the latest discoveries of new congenital myopathies and muscular dystrophies. P REREQUISITE—This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX prin- ciples. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree. A CCREDITATION S TATEMENT—The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME CREDIT—The AANEM designates attendance at this course for a maximum of 3.25 hours in category 1 credit towards the AMA Physician’s Recognition Award. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he/she actually spent in the activity. The American Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMA PMR category 1 credit. CME for this course is available 9/05 - 9/08. iv

2004-2005 AANEM COURSE COMMITTEE

Kathleen D. Kennelly, MD, PhD Jacksonville, Florida

Thomas Hyatt Brannagan, III, MD Dale J. Lange, MD Jeremy M. Shefner, MD, PhD New York, New York New York, New York Syracuse, New York

Timothy J. Doherty, MD, PhD, FRCPC Subhadra Nori, MD T. Darrell Thomas, MD London, Ontario, Canada Bronx, New York Knoxville, Tennessee

Kimberly S. Kenton, MD Bryan Tsao, MD Maywood, Illinois Shaker Heights, Ohio

2004-2005 AANEM PRESIDENT

Gary Goldberg, MD Pittsburgh, Pennsylvania Phenotypes of Myopathies With Inflammation

Anthony A. Amato, MD Chief, Division of Neuromuscular Disease Director of the Clinical Neurophysiology Laboratory Brigham and Women’s Hospital Associate Professor of Neurology Harvard Medical School Boston, Massachusetts

INTRODUCTION patient’s pattern of weakness is the most important piece of the puzzle. The phenotype constitutes more than just the pat- Dermatomyositis (DM), polymyositis (PM), and inclusion tern of weakness, but also associated clinical features (e.g., body myositis (IBM) are the three major categories of idio- cancer, connective tissue disease, interstitial lung disease), pathic inflammatory myopathy. These inflammatory laboratory features (creatine kinase [CK], antinuclear anti- myopathies are clinically, histologically, and pathogenically bodies, myositis-specific antibodies), and histological features distinct (Table 1).1-3,35,36,47,62 Dermatomyositis is not PM on biopsy. with a rash and IBM is not PM with rimmed vacuoles and inclusions. The annual incidence of these disorders is approximately 1 in 100,000.35,97 There are a few reports of DM, DERMATOMYOSITIS PM, and IBM occurring in parents and children and in sib- lings, including identical twins.4,14,34,63,89,133 There may be a Clinical Features genetic predisposition to developing these disorders, possibly secondary to inherited human leukocyte antigens (HLA) Dermatomyositis can present at any age and females are haplotypes. However, the inflammatory myopathies are best affected more commonly than males. Most childhood cases considered as acquired diseases. present between 5 and 14 years of age,97 but DM can even develop during infancy.26 Although the pathogenesis of There are hereditary forms of inclusion body myopathy, but childhood and adult DM are presumably similar, there are with rare exceptions. The muscle biopsies in these cases lack important differences in some of the clinical features and inflammation and the clinical phenotype (i.e., age of onset, associated disorders. Onset of weakness is typically subacute pattern of weakness) is different from sporadic IBM. On the (over several weeks), although it can develop abruptly (over other hand, inflammatory infiltrate in skeletal muscle is not days) or insidiously (over months).1,3,21,71,139 The neck flex- specific for the primary autoimmune myositis and can be ors, pectoral, and pelvic girdle muscles are the earliest and seen in various forms of muscular dystrophy. most severely affected. As a result, patients complain of difficulty lifting their arms over their heads, climbing steps, and It is important to be able to distinguish the different disor- arising from chairs. Asymptomatic distal extremity weakness ders with inflammation on biopsy from one another because may occasionally be present. Children are more likely to pres- of important differences in prognosis and response to treat- ent with an insidious onset of muscle weakness and myalgias ment. This entails performing a detailed clinical history and which are often preceded by fatigue, low grade fevers, and a examination, laboratory evaluation, and muscle biopsies. The rash. Dysphagia, secondary to inflammation of oropharyngeal 2 Phenotypes of Myopathies With Inflammation AANEM Course

TABLE 1 Idiopathic inflammatory myopathies: clinical and laboratory features

Age of Pattern of Response to Common Associated Disorder Sex Onset Rash Weakness Serum CK Muscle Biopsy IS Therapy Conditions

DM F > M Childhood Yes Proximal > Distal Normal or Perivascular, perimysial, and endomysial Yes Myocarditis, Interstitial and Adult increased inflitrates; Lung Disease, Malignancy, (up to 50x Perivascular / perimysial CD4+ dendritic Vasculitis, normal) cells and B Cells; endomysial PCD MXA, MAC, Ig, C deposition on vessels

PM F > M Adult No Proximal > Distal Increased Perivascular, perimysial , and endomysial Yes Myocarditis, ?Interstitial Lung (up to 50x inflitrates Disease?, normal) Endomysial CD8+ T-cells invade non- Other Connective Tissue necrotic fibers expression MHC1 antigen Diseases Endomysial macrophages, MDC and PC

IBM M > F Elderly No Proximal = Distal; Normal or Perivascular, perimysial, and endomysial None or Sensory europathy (> 50 yrs) Predilection For: Mildly inflitrates; Minimal Paraproteinemia Finger/Wrist Flexors, Increased CD8+ T-cells invade non-necrotic fibers Autoimmune disorders - Knee Extensors (< 10x normal) expression MHC1 antigen; (Sjögren’s syndrome, Muscle fibers with rimmed vacuoles; sarcoidosis, thrombocytopenia) Amyloid deposits; Also COX-negative fibers Endomysial macrophages, MDC, and PC EM: 15-18 nm Tubulofilaments

C= complement; CK = creatine kinase; DM = dermatomyositis; F = female; IBM = inclusion body myositis; Ig = immunoglobulin; IS= immunosuppressive; M = male; MAC = membrane attack complex; MXA = myxovirus resistance 1 protein; PDC = plasmacytoid dendritic cells; PM = polymyositis; MDC = myeloid dendritic cells; PC = plasma cells

From Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615-648, with permission)

and esophageal muscles, occurs in approximately 30% of (buttocks, knees, elbows) and present as painful, hard nod- DM patients.35,71,113,139 A minority of patients can have mas- ules. Ulceration of the overlying skin with extrusion of calcif- seter weakness causing chewing difficulties.113 Involvement ic debris can be seen in severe cases or in patients who have of the pharyngeal and the tongue muscles may result in been inadequately treated. dysarthria or speech delay in children.113 Sensation is normal and muscle stretch reflexes are preserved until a severe degree Associated Manifestations of weakness has developed. Cardiac Dermatomyositis is easily recognized and diagnosed because of the characteristic rash which may accompany or precede While overt clinical symptoms are uncommon, electrocardio- the onset of muscle weakness.1,71,135 The classic skin manifes- graphic abnormalities including conduction defects and tations include a heliotrope rash (a purplish discoloration of arrhythmias occur frequently in childhood and adult the eyelids) often associated with periorbital edema and DM.13,39,58,65,71,139 Pericarditis, myocarditis, and congestive papular, erythematous, scaly lesions over the knuckles heart failure can occasionally develop.58,71 Echocardiography (Gottron’s papules). In addition, a flat, erythematous, sun- and radionucleotide scintigraphy may demonstrate ventricu- sensitive rash may appear on the face, neck, and anterior lar and septal wall motion abnormalities and reduced ejection chest (V-sign); on the shoulders and upper back (shawl sign); fractions.58 on the hips (holster’s sign); and on the elbows, knees, and malleoli (Gottron’s sign). The nail-beds often have dilated Pulmonary capillary loops and occasionally appear with thrombi or hemorrhage. Interstitial lung disease (ILD) complicates at least 10% of adult DM and can also occur in childhood Calcifications in the subcutaneous tissues occur in 30-70% of cases.41,52,71,113,115,127 Symptoms of ILD (i.e., dyspnea, non- children, while this is an uncommon finding in adults.1,31,113 productive cough) can develop abruptly or insidiously and Cutaneous calcinosis tends to develop over pressure points often precede the development of the characteristic rash and AANEM Course Current Concepts in Muscle Disease 3 muscle weakness. Chest radiographs reveal a diffuse reticu- vasculitis.18 The severity of the inflammatory myopathy does lonodular pattern with a predilection for involvement at the not appear to correlate with the presence or absence of a neo- lung bases. In the more fulminant abrupt-onset cases, a dif- plasm. Treatment of the underlying malignancy sometimes fuse alveolar pattern or “ground-glass” appearance is seen. results in improvement of muscle strength. Pulmonary function tests demonstrate restrictive defects and decreased diffusion capacity, while hypoxemia is evident on The search for an underlying malignancy should include a arterial blood gasses. Antibody directed against t-histidyl comprehensive history and annual physical examinations transfer ribonucleic acid (RNA) synthetase, so-called anti-Jo- with breast and pelvic examinations for women, and testicu- 1, are present in at least 50% of ILD cases associated with lar and prostate examinations for men. This author obtains a inflammatory myopathies.72,91,136 Patients with significant complete blood count (CBC), routine blood chemistries, uri- oropharyngeal and esophageal weakness can develop aspira- nalysis, and stool specimens for occult blood. Chest radi- tion pneumonia. ograph, pelvic ultrasound, and mammogram are the only radiographic studies routinely ordered as well as a Gastrointestinal colonoscopy for anyone over the age of 50 years or those with gastrointestinal symptoms. Inflammation of the skeletal and smooth muscles of the gastrointestinal tract can lead to dysphagia and delayed gastric emptying.113 Vasculitis/vasculopathy of the gastrointestinal Laboratory Features tract is a serious complication which is much more common in childhood DM compared to adult DM.113 The vasculitis Blood Work can result in mucosal ulceration, perforation, and life-threatening hemorrhage. Necrosis of muscle fibers results in elevations of serum CK, aldolase, myoglobin, lactate dehydrogenase, aspartate amino- Joints transferase (AST), and alanine aminotransferase (ALT). Serum CK is the most sensitive and specific marker for mus- Arthralgias with or without arthritis are a frequent presenting cle destruction. Serum CK is elevated in more than 90% of feature. Arthritis is typically symmetric and involves both the DM patients, and levels can be as high as 50 times the nor- large and small joints. The arthralgias and myalgias often ease mal value. However, serum CK levels do not correlate with when the limbs are flexed, which unfortunately leads to the the severity of weakness and can be normal even in marked- development of flexion contractures across the major joints. ly weak individuals, particularly in childhood DM. Flexion contractures at the ankles leading to toe-walking is a Erythrocyte sedimentation rate (ESR) is usually normal or common early finding in childhood DM. only mildly elevated and is not a reliable indicator of disease severity. Vasculopathy Antinuclear antibodies (ANA) can be detected in 24-60% of Besides the skin, muscle, and gastrointestinal system, necro- DM patients.71,91,136 These antibodies are much more com- tizing vasculopathy may affect other tissues including the mon in patients with overlap syndromes (discussed later). eyes (retina and conjunctiva), kidneys, and lungs.115,139 Myositis-specific antibodies (MSAs) deserve special comment Rarely, massive muscle necrosis can lead to myoglobinuria because it has been suggested that they may prove useful in and acute renal tubular necrosis. predicting response to therapy and prognosis.76,91,100,118,136 The MSAs are associated with specific human leukocyte anti- Malignancy gen (HLA) haplotypes, and each patient can have only one type of MSA. However, the MSAs are demonstrated in only There is an increased incidence of underlying malignancy in a minority of patients with an inflammatory myopathy and adult DM, ranging from 6-45%.21,23,28,71,132,139 The associa- have not been studied prospectively in regards to their predic- tion with cancer has not been clearly demonstrated in child- tive value. The pathogenic relationship these antibodies have hood DM. The rare cases of childhood DM associated with to inflammatory myopathies is unknown; they may just rep- malignancies had unusual courses.113 Detection of an under- resent an epiphenomenon. lying neoplasm can precede or occur after the diagnosis of DM; the majority of malignancies are identified within 2 The MSAs include: (1) the cytoplasmic antibodies directed years of the presentation of the myositis. The risk of malig- against translational proteins (i.e., various t-RNA synthetases nancy is similar in males and females and is greater in and the anti-signal recognition particle), and (2) those direct- patients over the age of 40 years. Some studies have suggested against Mi-2 and Mas antigens.91,100,118,136 The most com- ed an increased risk of malignancy in patients with cutaneous mon of the antisynthetases is the anti-Jo-1 antibodies which 4 Phenotypes of Myopathies With Inflammation AANEM Course are associated with ILD and arthritis and are demonstrated in Magnetic resonance imaging may demonstrate signal abnor- up to 20% of patients with inflammatory myopathy.72,91,136 malities in affected muscles secondary to inflammation and The other antisynthetases are much less common and are edema or replacement by fibrotic tissue. Some have advocat- each found in less than 2-3% of inflammatory myopathy ed MRI as a guide to determine which muscle to biopsy.117 patients. The presence of these anti-Jo-1 antibodies has been However, this author has found that MRI adds little to a associated with only a moderate response to treatment and a good clinical examination and needle EMG in defining the poor long-term prognosis.76,118 However, it is the associated pattern of muscle involvement and determining which mus- ILD which is responsible for the less favorable prognosis, not cle to biopsy. just the presence of the anti-Jo-1 antibodies. There has not been a prospective study demonstrating treatment outcomes Muscle Biopsy of myositis-ILD patients with anti-Jo-1 antibodies compared to similar patients without these antibodies. The pathological process is multifocal and the frequency and severity of histologic abnormalities can vary within the mus- Mi-2 antibodies are seen almost exclusively in DM and can cle biopsy specimens. The characteristic histologic feature is be found in 15-20% of DM patients. Mi-2 is a 240 kD perifascicular atrophy.1,35,47 However, in this author’s experi- nuclear protein of unknown function. The anti-Mi-2 anti- ence this is a late histological feature and is seen in less than bodies are associated with an acute onset, a florid rash, a good 50% of cases (particularly less common in adults). The peri- response to therapy, and a favorable prognosis.76,91,118,136 fascicular area contains small degenerating fibers as well as However, it is not known whether DM patients with Mi-2 atrophic and nonatrophic fibers with microvacuolation and antibodies respond differently than DM patients without the disrupted oxidative enzyme staining. Occasionally, wedged- antibody. shaped microinfarcts of muscle fascicles are apparent. Scattered necrotic fibers may be present, however, in contrast Electromyography to PM and IBM, invasion of non-necrotic fibers is not prominent. The inflammatory infiltrate is composed prima- The characteristic electromyographic (EMG) features rily of macrophages, B-cells, and CD4+ cells in the per- observed in myositis patients are: (1) increased insertional imysial and perimysial regions.6,46 However, recent studies and spontaneous activity with fibrillation potentials, positive have demonstrated that there are many more CD 4+ cells in sharp waves, and occasionally pseudomyotonic and complex the endomysium that previously appreciated and that these repetitive discharges, (2) small duration, low amplitude, are for the most part plasmacytoid dendritic cells and not T- polyphasic motor unit action potentials (MUAPs), and (3) helper cells.61 MUAPs which recruit early but at normal frequencies.1,24 Recruitment may be decreased (fast firing MUAPs) in The earliest demonstratable histologic abnormality in DM is advanced disease due to the loss of muscle fibers of entire deposition of the C5b-9 or membrane attack complex motor units. Late in the course of poorly responsive disease, (MAC) on or around small blood vessels.44,83,84 Membrane insertional activity may be decreased secondary to fibrosis. In attack complex precedes inflammation and other structural addition, large duration polyphasic MUAPs may also be seen abnormalities in the muscle on light microscopy and is spe- later in the course reflecting chronicity of the disease with cific for DM. Other complement components (C3 and C9), muscle fiber splitting and regeneration rather than a superim- IgM, and less often gamma G immunoglobulin are also posed neurogenic process. The amount of spontaneous EMG deposited on or around the walls of intramuscular blood ves- activity is reflective on ongoing disease activity. Needle EMG sels.143 The subsequent necrosis of vessels results in a reduc- can be helpful in determining which muscle to biopsy in tion in the capillary density (number of capillaries per area of patients with only mild weakness. In addition, needle EMG muscle).44 Transforming growth factor b (TGF-b) and its may also be useful in previously responsive myositis patients messenger RNA are upregulated in regions of severe who become weaker by differentiating an increase in disease ischemia, which probably accounts for the increased fibrosis activity from weakness secondary to type 2 muscle fiber atro- in these areas.33 Electron microscopy (EM) reveals small phy from disuse or chronic steroid administration. Isolated intramuscular blood vessels (arterioles and capillaries) with type 2 muscle fiber atrophy is not associated with abnormal endothelial hyperplasia, microvacuoles, and cytoplasmic spontaneous activity seen during needle EMG. inclusions; these abnormalities precede other structural abnormalities on EM.14,38 Muscle Imaging Pathogenesis Magnetic resonance imaging (MRI) can provide information on the pattern of muscle involvement by looking at the cross- The immunological studies and other histological features sectional area of axial and limb muscles.51,70,79,114,117 seen with muscle biopsies suggest that DM is a humorally AANEM Course Current Concepts in Muscle Disease 5 mediated microangiopathy. This microangiopathy has been biopsies. Perhaps dysregulated IFN-α production is a central postulated to cause ischemic damage and occasionally infarc- driving problem in the pathogenesis of DM. tion of muscle fibers. Some authorities suggest that the perifascicular atrophy is the result of hypoperfusion to the water- Prognosis shed region of muscle fascicles. However, many questions remain regarding this hypothesis and the pathogenic basis of In the absence of malignancy, prognosis is favorable in DM.60,61 It has never been demonstrated that the perifascic- patients with DM. Poor prognostic features are increased age, ular region is indeed the watershed area in muscle fibers or associated ILD, cardiac disease, and late or previous inade- that the perifasicular fibers are more prone to ischemic dam- quate treatment.30,71,76,107,139,146 Five-year survival rates of age. Of note, perifascicular atrophy is not evident in ischemic adult DM range from 70-93%. The mortality rate in chil- muscle damaged from vasculitis. Further, perifascicular atro- dren is very low.113 phy has not been demonstrated in animal models of small vessel ischemia. On the contrary, such models demonstrate a predilection for the involvement of more centrofascicular INCLUSION BODY MYOSITIS fibers. Clinical Features Deoxyribonucleic acid (DNA) microarray studies of biopsied muscle tissue demonstrate an increased expression of genes Inclusion body myositis is characterized clinically by the induced by interferon-α/β.59,61 Although this is not specific, insidious onset of slowly progressive proximal and distal it is compatible with the hypothesis of a viral infection trig- weakness which generally develops after the age of 50 gering the autoimmune attack. Interferon-α/β has a well- years.1,3,35,62,90,126,145 The slow evolution of the disease defined role in antiviral innate immunity, and this has led to process probably accounts in part for the delay in diagnosis, additional consideration of a hypothesis of chronic persistent averaging approximately 6 years from the onset of symp- viral infection as a cause of juvenile DM. However, there are toms.3,90 Males are much more commonly affected than other possibilities. In particular, interferon-a is synthesized by females, in contrast to the female predominance seen in DM plasmacytoid dendritic cells (PDCs) in response to a serum and PM. The clinical hallmark of IBM is early weakness and factor containing immune complexes of antibody, double- atrophy of the quadriceps, volar forearm muscles (i.e., wrist stranded DNA, and RNA viruses. These cells, also called nat- and finger flexors), and the ankle dorsiflexors.3,62,90 ural interferon producing cells for their ability to secrete mas- Importantly, the manual muscles scores of the finger and sive amounts of IFN-α, can be activated to produce IFN-α wrist flexors are often lower than those of the shoulder by synthetic short palindromic DNA sequences, termed CpG abductors and the muscle scores of the knee extensors are oligodeoxynucleotides. This author and colleagues have often lower than those of the hip flexors in patients with IBM recently demonstrated pyruvate dehydrogenase complex (Tables 2 and 3 and Figures 1 and 2).1 The opposite relation- (PDC) in the muscle biopsies of of patients with DM. ship between muscles scores are present in DM and PM. Pyruvate dehydrogenase complex are CD4+ and comprise a large component of the inflammatory cell infiltrate in DM. In addition, muscle involvement in IBM is often asymmetric, These CD4+ cells were originally thought to be CD4+ T- in contrast to the symmetrical involvement in DM and PM. helper cells, but it was demonstrated that most are CD3- and The presence of slowly progressive, asymmetric, quadriceps thus are PDC and not lymphocytes.61 Increased expression of and wrist/finger flexor weakness in a patient over 50 years of IFN-α inducible proteins such as myxovirus resistance 1 pro- age strongly suggests the diagnosis of IBM.3 tein (MxA) has also been demonstrated on blood vessels and muscle fibers (with a predilection for the perifascicular Dysphagia occurs in up to 40% of patients and can be debil- fibers).61 Interestingly, one postulated function of MxA is to itating requiring cricopharyneal myotomy.37,90,141 Likewise, form tubuloreticular inclusions around RNA viruses. These mild facial weakness can be detected on examination in at inclusions have the same morphology as the tubuloreticular least 33% of IBM patients, however, this weakness is clinical- inclusions seen with EM in blood vessels in DM. Using ly insignificant.3,90 Extraocular muscles are spared. Although immunoelectron microscopy the author and colleagues have most patients have no sensory symptoms, evidence for a gen- demonstrated MxA within inclusions in vessels in DM muscle eralized peripheral neuropathy can be detected in up to 30% 6 Phenotypes of Myopathies With Inflammation AANEM Course of patients on clinical examination and electrophysiological Needle Electromyography and Nerve Conduction Studies testing.3 Muscle stretch reflexes are normal or slightly decreased. In particular, the patellar reflexes are lost early. Increased spontaneous and insertional activity, small polyphasic MUAPs, and early recruitment are usually evident Associated Manifestations during the needle EMG examination.3,90 In addition, large polyphasic MUAPs can also be demonstrated in one-third of Unlike DM and PM, IBM is not associated with myocarditis patients.42,77,90,92 However, large polyphasic MUAPs can also or ILD; nor is there an increased risk of malignancy.28 be seen in DM, PM, and other muscle disorders (i.e., muscu- Autoimmune disorders such as systemic lupus erythematosus lar dystrophies) and probably reflects chronicity of the disease (SLE), Sjögren’s syndrome, scleroderma, thrombocytopenia, process rather than a neurogenic etiology. Nevertheless, nerve and sarcoidosis have been reported in up to 15% of IBM conduction studies reveal evidence of a mild axonal sensory patients.85,90 Diabetes mellitus was reported in 20% of neuropathy in up to 30% of patients.3 patients in one large series.90 Muscle Imaging Laboratory Features Radiological studies demonstrate atrophy and signal abnor- Blood Work malities in affected muscle groups.51,128

Serum CK is normal or only mildly elevated (less than 10- Muscle Biopsy fold above normal).3,62,90 Autoantibodies are usually absent except for the occasional patients with concurrent connective The characteristic light microscopic findings are endomysial tissue disease, although some series have reported positive inflammation, small groups of atrophic fibers, eosinophilic ANAs in approximately 20% of their IBM patients.85,91 cytoplasmic inclusions, and muscle fibers with one or more There is a significant incidence of the HLA DR3 phenotype rimmed vacuoles lined with granular material.3,62,90 Amyloid (*0301/0302) in IBM.55

Table 2 Clinical features of inflammatory myopathies AANEM Course Current Concepts in Muscle Disease 7

Table 3 Pattern of weakness in the inflammatory myopathies

Figure 1 Pattern of weakness in DM, PM, and IBM

DM = dermatomyosits; IBM = inclusion body myositis; PM = polymyositis 8 Phenotypes of Myopathies With Inflammation AANEM Course

Figure 2 Pattern of weakness in IBM and PM based on responsiveness to treatment

PM = polymyositis; IBM = inclusion body myositis

deposition is evident on Congo red staining using polarized Similar to PM, the inflammation in IBM is predominantly light or fluorescence techniques.9,99 The number of vacuolat- endomysial and composed of macrophages and CD8+ cyto- ed and amyloid-positive fibers may increase with time in toxic/suppressor T-lymphocytes which invade non-necrotic individual patients.17 An increased number of ragged red fibers.46 Major histocompatibilty complex class 1 antigens are fibers and cytochrome oxidase (COX)-negative fibers are also expressed on necrotic and non-necrotic muscle fibers.43 evident in IBM compared to DM and PM patients and age- Investigations of the T-cell receptor repertoire demonstrate matched control subjects.120 Electron microscopy demon- an oligoclonal pattern of gene rearrangement, although there strates 15-21 nm cytoplasmic and intranuclear tubulofila- is heterogeneity in the CDR3 domain.94,110 These findings ments, although a minimum of three vacuolated fibers may suggest that the T-cell response is not directed against a mus- need to be scrutinized to confirm their presence.90 Vacuolated cle-specific antigen, although the response could be triggered fibers also contain cytoplasmic clusters of 6-10 nm amyloid- by a superantigen. Recently, others have found persistent like fibrils.9,62 Because of sampling error, repeat muscle biop- clonal restriction of T-cell receptors in infiltrating lympho- sies may be required to identify the rimmed vacuoles and cytes on repeated muscle biopsies in some patients suggesting abnormal tubulofilament or amyloid accumulation in order that there is a continuous antigen driven attack against the to histologically confirm the diagnosis of IBM.3 This sam- muscle fibers.5 Gene expression studies in muscle demon- pling error probably accounts for IBM being misdiagnosed as strated up-regulation of immunoglobulin genes.59 This PM or “inflammatory myopathy with COX-negative muscle author and colleagues have found large numbers of fibers.”20,88 endomysial plasma cells sometimes surround muscle fibers. AANEM Course Current Concepts in Muscle Disease 9

Myelodendritic cells that in part function to present antigens observed in Alzheimer patients.56 However, other studies of to both T-cells and B-cells are abundant in the endomysium IBM patients reported no significant increase in apolipopro- as well. tein E ε4 allele frequency.12,64 Askanas and colleagues have also described increased acetylcholine receptor, PrPc, and B- Pathogenesis APP mRNAs in IBM vacuolated fibers.62,125 Thus, increased prion and B-amyloid deposition in these muscle fibers prob- The pathogenesis of IBM is unknown. Whether IBM is a pri- ably result, in-part, from increased transcription of the PrPc mary inflammatory myopathy like DM and PM, or a myopa- and B-APP genes. Muscle fibers transfected in vitro with B- thy in which the inflammatory response plays a secondary APP cDNA using a recombinant-deficient adenovirus vector role is the subject of intense research.62 The histological and results in Congo red positive, vacuolated fibers with immunological studies previously described provides evi- tubulofilaments, and abnormal mitochondria typical of that dence that IBM may be an autoimmune disorder mediated observed in IBM. by cytotoxic T-cells. The autoinvasive T-cells in IBM contain perforin granules. Upon release of these granules, pores form Interestingly, B-amyloid and prion proteins can induce apop- on the muscle membrane, resulting in osmolysis.57 Pruitt and tosis of neurons invitro. In this regard, regenerating and colleagues reported the frequency of invaded fibers was degenerating muscle fibers express Fas and Fas ligand, a pro- greater than either necrotic or amyloidogenic fibers suggest- apoptotic complex.19,53 However, there is no evidence that ing that the inflammatory response plays a more important apoptosis plays a role in muscle fiber destruction in IBM.75 role than the accumulation of vacuoles or amyloidogenic fil- Perhaps as in PM, the demonstrated increased co-expression aments in the pathogenesis of IBM.119 Although antibodies of the anti-apoptotic protein, Bcl-2, in muscle fibers protects have not been demonstrated binding to muscle fibers, it is against the potential apoptotic effect of Fas/Fas ligand.19 clear that the humoral wing of the immune system is also Although intriguing, the pathogenic relationship of the upregulated, as evidenced by the plasma cell infiltrate. “Alzheimer-characteristic proteins” in IBM to the pathogenesis of the myopathy is not clear. The accumulation of these The lack of significant clinical response with various proteins in IBM vacuolated muscle fibers may be an epiphe- immunosuppressive therapies alone or in combination argues nomena rather than the primary pathogenic defect of IBM. against IBM being a primary autoimmune disorder. Eight patients were treated with IBM for 6-24 months with Besides the accumulation of rimmed vacuoles and tubulofil- immunosuppressive medications. Their response to treat- aments, mitochondrial abnormalities as indicated by ragged ment was evaluated and their pre- and post-treatment muscle red fibers and mitochondrial DNA mutations are more fre- biopsies were analyzed.17 None of the patients improved in quent in IBM patients than in the other inflammatory strength or function despite lower serum CK levels and myopathies.62,111,120 However, these mitochondrial abnor- reduced inflammation on the post-treatment muscle biop- malities are believed to be secondary changes and not the pri- sies. Interestingly, the amount of vacuolated muscle fibers mary cause of the myopathy. In addition, increased and fibers with amyloid deposition were increased in the fol- immunoreactivity for nitrotyrosine and both the inducible low-up biopsies suggesting that inflammation may play a sec- and nuclear forms of nitric oxide synthase (NOS) have been ondary role in the pathogenesis of IBM, while the accumula- demonstrated in vacuolated muscle fibers.144 These findings tion of vacuoles and amyloid may have a more significant suggest that nitric oxide-induced oxidative stress may play a role. role in muscle fiber destruction in IBM. αB crystalin expression, a member of the heat-shock protein family, is increased Another line of evidence which suggests that IBM could be a in normal as well as abnormal appearing IBM muscle fibers degenerative disorder of muscle rather than an autoimmune suggesting that there is a pathologic stressor acting upstream inflammatory myopathy is the accumulation of “Alzheimer- from to the development of structural abnormalities includ- characteristic proteins” in vacuolated muscle fibers.62 ing the accumulation of Alzheimer-like proteins, NOS Abnormal accumulation of B-amyloid, C- and N-terminal expression, and mitochondrial abnormalities.15 epitopes of B-amyloid precursor protein (B-APP), prion protein (PrPc), apolipoprotein E, α1-antichymotrypsin, ubiqui- A viral etiology has also been speculated in the pathogenesis tin, hyper-phosphorylated tau protein and neurofilament of IBM. Chronic persistent mumps was previously hypothe- heavy chain similar to that observed in the brains of sized based on immunostaining of inclusions by anti-mumps Alzheimer’s patients is evident within IBM vacuolated antibodies.29 This was subsequently rejected after in-situ fibers.7-12 Interestingly, a study of 14 IBM patients reported hybridization and polymerase chain reaction studies failed to a significant increase in the apolipoprotein E ε4 frequency as confirm mumps infection.78,86,109 Interestingly, histologic 10 Phenotypes of Myopathies With Inflammation AANEM Course abnormalities on muscle biopsy similar to IBM have been seen in patients with retroviral infections and post-polio syn- Table 4 Bohan and Peter’s criterial for PM and DM drome. 1. Symmetrical Weakness of the limb girdle muscles and anteripr neck Prognosis flexors, progressiving over weeks to months, with or without dysphagia or respiratory muscle involvement. Most IBM patients are older and life expectancy does not 2. Muscle biosy evidence of necrosis of myofibers, phagocytosis, appear to be significantly altered. Progressing slowly, IBM regeneration with basophils, large vesicular sarcolemmal nuceli. does not respond well to immunosuppressive medications. Anlsoprominent nucleoli, atrophy in a perifasciuclar distribution, Most patients remain ambulatory, although they frequently variaqbtion in fiber size and an inflammatory exudate, often perivascular. require or at least benefit from a cane or a wheelchair for long distances. However, some patients become severely incapaci- 3. Elevation in serum skeletal muscle enzymes, particularly the CK and tated and require a wheelchair or become bed-ridden within often aldolase AST, ALT, and LDH. 10-15 years.90 4. Needle EMG triad of short, small polyphasic motor units, fibrillation potentials, positive sharp waves, insertial irritability, and complex Many patients with steroid-resistant or “refractory” PM even- repetitive discharges. tually are diagnosed with IBM. Importantly, there are Three out of four of the above features are needed for a diagnosis of PM. patients who clinically resemble IBM, but in whom a defini- The diagnosis of DM is made if the patient also has characteristic rash. tive diagnosis cannot be confirmed with muscle biopsy.3 These patients are diagnosed with “possible” or “probable” ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine IBM.3,62 kinase; DM = dermatomyositis; EMG = electromyography; LDH = lactate dehydrogenase; PM = polymyositis.

POLYMYOSITIS

Background restricted, antigen-specific, cell-mediated immune response What had been described in the literature as “polymyositis” is directed against muscle fibers. most likely a heterogenious group of disorders.2,36,140 Despite what one might suspect from reading the literature, PM is the This author believes there is a clinical spectrum of dermato- least common of the major idiopathic inflammatory myositis with respect to muscle and skin involvement (Figure myopathies. There are definitely cases of PM, but it is impor- 3). tant to realize that many cases of so-called PM in the literature are in fact IBM, dystrophies with inflammation, and Most patients with classic dermatomyositis have a combina- perhaps even DM. The reasons for the erroneous diagnosis tion of skin and muscle involvement. It is appreciated by are multiple. many authorities that some patients have the characteristic rash but never develop weakness—so called myopathic der- Misdiagnosed Dermatomyositis? matomyositis or dermatomyositis sine myositis.48,134 What about the converse? Are there patients with dermatomyositis Most published papers regarding epidemiology and treat- sine dermatitis? Traditionally, such patients have been diag- ment of PM have used Bohan and Peter’s criteria for PM and nosed as having PM based on Bohan and Peter’s criteria. DM (Table 4).21,22 These criteria were fine in 1975, but as However, if one looks carefully at the muscle biopsies, the one can see a muscle biopsy is not required for the diagnosis features are more similar to DM than PM. of PM and DM, and the only feature distinguish the PM from DM is the presence of a rash in DM. Further, the biop- In this regard, some have tried to classify the myositis on the sy abnormalities as listed are nonspecific (except for perifasci- basis of so-called MSAs.91,100,118,136 These studies suggested cular atrophy—a finding specific for DM, but not seen in that antibodies such as anti- signal recognition particle (SRP) PM) and do not help in distinguishing PM from DM or any were specific for PM or that anti-Jo-1 antibodies could be myopathy with necrosis, including muscular dystrophies. seen in either PM or DM. However, no details regarding the Importantly, the histological criteria do not take into account histopathology was ever mentioned in these early papers and the advances in histopathology, particularly in regard to the diagnosis of DM apparently was made only because the immunohistochemistry. It is now appreciated that DM is a characteristic rash was not present or at least not appreciated. humerally mediated microangiopathy, while PM is an HLA- In studies that have made the diagnosis of PM or DM based AANEM Course Current Concepts in Muscle Disease 11

of muscular dystrophy (i.e., congenital, facioscapulohumeral, Figure 3 Clinical spectrum of dematonyositis limb-girdle, and the dysferlinopathies). Myositis with perinatal onset was first described in Japan.81,82,108,112 Subsequently, Amyopathic DM Classic DM Adermatopathic DM there have been several reports in the western hemisphere of infantile myositis or congenital inflammatory myopathy.123,131,137 The myopathy is characterized by the antenatal or perinatal presentation of hypotonia and generalized weakness and the presence of inflammation on muscle biopsy. Serum CK is usually elevated and needle EMG is myopathic. However, careful review of the clinical features in these reported patients are suggestive of a congenital muscular dystrophy (i.e., Fukayama-type, Walker-Warburg syndrome, or the occidental type) in most. Only one case where the patient had perifascicular atrophy and immunoglobulin and complement deposition on the biopsy characteristic of DM, and the Modified from Sontheimer RD. Current Op Rheum 1999;11:465-482. patient improved with steroids was strongly suggestive of a 123 DM = dermatomyositis primary myositis. Most of the reported children did not significantly improve with corticosteroids. In addition, the biopsies had dystrophic features in addition to the inflammatory infiltrates. Finally, there have been several reports of upon currently accepted histological criteria, myositis associ- patients with the occidental type of congenital muscular dys- ated with anti-SRP and anti-Jo-1 antibodies all had histolog- trophy with hypomyelination whose muscle biopsy showed ical features of a humorally mediated microangiopathy simi- prominent inflammation and merosin (alpha-2 laminin) lar to DM.59-61,101,105 No patient has been reported with his- deficiency.98,103,116 It is suspected that the majority of infants tolopathological abnormalities of PM. with inflammation seen on muscle biopsy have a form of congenital muscular dystrophy rather than a primary myosi- Misdiagnosed Inclusion Body Myositis tis.

Bohan and Peter’s criteria do not take into account the exis- Inflammation on biopsies is not specific for the congential tence of IBM. This myopathy was not well-appreciated until muscular dystrophies, but is also evident in dys- the late 1980s and early 1990s, particularly in regard to it trophinopathies, facioscapulohumeral dystrophy, dysfer- being the most common inflammatory myopathy in patients linopathy, and other forms of limb-girdle muscular dystro- over 50 years of age. Further, although more physicans are phy.54,96,106,124,129 This author has seen many patients with aware of IBM now, they still do not realize that because of muscular dystrophy misdiagnosed as PM and subjected to sampling error, any given biopsy may lack definitive histolog- long-term complications associated with immunosuppressive ical criteria for IBM.3 Thus, many patients with IBM are therapy. There are clinical features that may help distinguish erroneously diagnosed as PM. dystrophy with inflammation from a primary inflammatory myopathy. Scapular winging, prominent facial weakness, and One group of investigators has tried to define a distinct sub- asymmetrical involvement is common in facioscapulohumer- group of PM on the basis of the presence of COX-negative al muscular dystrophy (FSHD), but is not in PM. Patients fibers on muscle biopsy and a modest response to methotrex- who have severe proximal weakness (i.e., Medical Research ate in a small number of patients.20,88 The clinical features of Council grade 3 or less) but normal strength distally (wrists this subgroup are male predominance, age over 50 years, and ankles) would be more likely to have a form of a limb gir- prominent quadriceps weakness, mildly elevated serum CK dle muscular dystrophy (LGMD) as opposed to PM. levels, and poor response to corticosteroid treatment. As illus- Dysferlinopathies can manifest with a LGMD pattern of trated above, these are the characteristic features of IBM, weakness, early gastrocnemius weakness and atrophy, tibalis which are believed to be the most likely diagnosis of this anterior weakness, or any combination of the above and “subgroup” of patients.2,62 markedy elevated serum CK levels.

Misdiagnosed Muscular Dystrophies Muscle biopsy features can also be helpful in distinguishing a dystrophy from PM. Although endomysial inflammatory cell Occasionally, prominent endomysial inflammatory cell infil- infiltration and necrotic fibers can be seen in dystrophies, trates are evident on biopsies of patients with different forms unlike PM there should be no invasion of non-necrotic muscle 12 Phenotypes of Myopathies With Inflammation AANEM Course fibers by the mononuclear inflammatory cells. Also, deposition Associated Manifestations of MAC may be seen on the sarcolemma of scattered non- necrotic fibers in FSHD, LGMD, and dysferlinopathies, but The cardiac and pulmonary complications of PM are report- not in PM, DM, or IBM.22,135 Further, there is often edly similar to those previously described for DM. Myositis increased endomysial connective tissue in the dystrophies with secondary congestive heart failure or conduction abnor- prior to the muscle end-stage. malities occur in up to one-third of patients, but again histopathologic confirmation of true PM is lacking in most Necrotizing Myopathy of these studies.13,39,58,65,68,71,80,139 Anti-SRP antibodies have been associated with myocarditis and had been noted to be The idiopathic necrotizing myopathy are often diagnosed as specific for PM.91,100,118,136 However, in studies in which PM by Bohan and Peter’s criteria.25,45,87,142 Nevertheless, the detailed immunohistochemistries were performed, the biop- pathogenic basis appears to be quite distinct from PM and in sies were not suggestive of PM but rather resembled DM.101 other reported cases more closely resembles humorally mediated microangiopathy. As in DM, deposition of MAC on Also, ILD has been reported to occur in at least 10% of PM small blood vessels and depletion of capillaries can be seen. patients with at least half having Jo-1 antibod- However, these patients do not have a characteristic rash, ies.41,52,91,100,118,127,136,139 However, as has been noted, these biopsy shows no perifascicular atrophy, perivascular inflam- studies did not define PM histologically, and subsequent mation is sparse, and tubuloreticular inclusions in endotheli- biopsy specimens from patients with Jo-1 antibodies demon- um are not commonly seen on EM. So-called pipestem cap- strated features again more similar to DM then PM. illaries may be evident on routine histochemistry and EM.45 Necrotizing myopathy should lead to a search for an under- Polyarthritis has been reported in as many as 45% of PM lying connective tissue disease (usually scleroderma or mixed patients at the time of diagnosis.139 The risk of malignancy connective tissue disease) and cancer. Muscular dystrophies with PM is lower than that seen in DM, but it may be slight- and toxic myopathies (e.g., statin myopathies) also need to be ly higher than expected in the general population.23,28,139 But excluded. However, many cases of necrotizing myopathy are again, the diagnosis of PM in these studies was not based on idiopathic. histopathology so if there actually is an increased risk of malignancy in PM, it is unclear. For the various reasons previously listed, it is impossible to determine from the literature the true incidence of PM, asso- Laboratory Features ciated laboratory abnormalities, medical conditions (e.g, CTD, ILD, myocarditis, cancer) that may accompany it, and Blood Work prognosis. Prospective trials using currently histopathological criteria for PM are needed to address this issue. Serum CK level is elevated 5 to 50 fold in the majority of PM cases. Serum CK can be useful in monitoring response to Clinical Features therapy, but only in conjunction with the physical examination. The serum CK level does not correlate with the degree Polymyositis generally presents in patients over the age of 20 of weakness. Erythrocyte sedimentation rate (ESR) is normal years and is more prevalent in females.3,21,23,71,97,139 Diagnosis in at least half the patients and does not correlate with disease is often delayed compared to DM, because there is no associ- activity or severity.22 ated rash which serves as a “red-flag” to patients and their physicians. Patients present with neck flexor and symmetric Positive ANAs are reportedly present in 16-40% of PM proximal arm and leg weakness, which typically develops over patients.71,91,139 Again the exact relationship of ANAs and several weeks or months. Distal muscles may also become CTD in patients with histologically defined PM is unclear. involved but are not as weak as the more proximal muscles. Muscle pain and tenderness are frequently noted. Dysphagia Electromyography and Muscle Imaging reportedly occurs in approximately one-third of patients secondary to oropharyngeal and esophageal involvement. Mild Electromyography is usually abnormal in PM with increased facial weakness occasionally may be demonstrated on exami- insertional and spontaneous activity, small polyphasic nation. Sensation is normal and muscle stretch reflexes are MUAPs, and early recruitment.1,24 Muscle imaging studies usually preserved. can suggest areas of inflammation in affected muscles.51,117 AANEM Course Current Concepts in Muscle Disease 13

Muscle Biopsy forin granules, which are orientated to the surface of the muscle fibers.57 When released by exocytosis, these granules The histologic features of PM are distinct from DM. The induce pore formations on the sarcolemma and result in predominate histologic features in PM are variability in fiber osmolysis of muscle fibers. Although regenerating and degen- size, scattered necrotic and regenerating fibers, and erating muscle fibers express Fas and Fas ligand (a pro-apop- endomysial inflammation with invasion of non-necrotic totic complex),19,53 there is no evidence that apoptosis plays muscle fibers.1 All of the invaded and some of the noninvad- a role in muscle fiber destruction. The increased expression of ed muscle fibers may express major histocompatibility com- Bcl-2, an anti-apoptotic protein may protect against the plex class 1 antigen which is not normally present in the sar- potential apoptotic effect of Fas/Fas ligand. colemma of muscle fibers.43 The endomysial inflammatory cells consist primarily of activated CD8+ (cytotoxic), alpha, Prognosis beta T-cells, and macrophages.6,46,47 A single case of PM with CD4- CD8- gamma/delta T-cell inflammation has been The majority of patients with PM respond favorably to reported in detail.74 Investigations of the T-cell receptor immunosuppressive therapies, but usually require life-long (TCR) repertoire of endomysial T-cells in PM demonstrate treatment.1,3,30,69,71,73,76,146 Some retrospective studies suggest an oligoclonal pattern of gene rearrangements and a restrict- that PM does not respond to immunosuppressive agents as ed motif in the CD3R region of the TCR suggesting the well as DM. However, interpretation of the results of these immune response is antigen-specific.94 Finally, in contrast to retrospective series is difficult as the diagnosis of PM was usu- DM, there is no evidence of immune deposits (MAC, com- ally made on the basis of Bohan and Peter’s criteria rather plement, or immunoglobulins) on the microvasculature in than more current criteria based on strict clinical and histo- PM. Gene expression studies in muscle demonstrated upreg- logical criteria. ulation of immunoglobulin genes.59 It has been demonsrated that large numbers of endomysial plasma cells sometimes surround muscle fibers. Myelodendritic cells that in part func- OVERLAP SYNDROMES tion to present antigens to both T-cells and B-cells are abundant in the endomysium as well. The overlap syndromes apply to a group of disorders in which DM or PM is associated with another well-defined Pathogenesis CTD such as scleroderma, mixed connective tissue disease, Sjögren’s syndrome, systemic lupus erythematosus, and The histologic and immunologic features seen by the muscle rheumatoid arthritis. Whether or not PM is associated with biopsy suggest that PM is the result of a HLA-restricted, anti- CTD is not clear as the histology in such patients was not gen-specific, cell-mediated immune response directed against described—just that they did not have an obvious DM rash. muscle fibers. The trigger of this autoimmune attack is not known. A viral etiology has been speculated, but there is no Scleroderma conclusive evidence supporting this theory.1,86 Most class 1 molecules on the surface of cells express endogenous self-pep- Proximal muscle weakness is common in scleroderma, how- tides. Viral antigens and genomes have not been identified in ever, most of the patients have normal serum CKs and nor- the muscle fibers suggesting that the immune response may mal needle EMG findings. Muscle biopsies may demonstrate be directed against endogenous self-antigens rather than mild variability in fiber size with atrophy of type 2 muscle processed viral antigens. Nonetheless, viral infection could fibers and perimysial fibrosis. However, active myositis has indirectly trigger an autoimmune response secondary to been reported in 5-17% of patients with scleroderma and can cross-reactivity with specific muscle antigens, altering the occur in either of its two major forms—progressive systemic expression of self-antigens on muscle fibers, or by the loss of sclerosis or calcinosis cutis, Raynaud’s phenomenon, physiologic self-tolerance.47 Interestingly, PM can develop as esophageal dysfunction, sclerodactyly and telangiectasia a complication of human immunodeficiency virus (HIV) (CREST) syndrome.49,95,121,138 Scleroderma-myositis and human T-lymphocyte virus 1 (HTLV-1) infections.35,47 patients have increased serum CK levels, and irritable and In these cases, the myositis appears to be the result of such myopathic EMGs. indirect triggering of the immune response against muscle fibers. Anticentromere antibodies are seen in the majority of patients with CREST syndrome, while anti-Scl-70 antibod- The cytotoxic T cells appear to induce cell death via the per- ies are common in patients with progressive systemic sclero- forin pathway. The autoinvasive T-cells in PM contain per- sis. In addition, approximately 25% of North American 14 Phenotypes of Myopathies With Inflammation AANEM Course patients with scleroderma-myositis have anti-PM-Scl (also anti-U1 RNP antibodies are common in MCTD, these anti- called anti-PM-1) antibodies. Anti-PM-Scl is not specific for bodies but can also be detected in SLE. this disorder, because only 50% of patients with this antibody have the scleroderma-myositis overlap syndrome. In Japan, the scleroderma-myositis syndrome is associated with FOCAL MYOSITIS anti-Ku antibodies, rather than anti-PM-Scl antibodies. In North America, anti-Ku antibodies are not associated with Clinical features myositis, but can be demonstrated in some patients with systemic lupus erythematosus. Focal myositis is a rare disorder which can develop in infancy to late adult life.27,32,66,67,102,104 It presents as a solitary, Sjögren’s Syndrome painful, and rapidly expanding skeletal muscle mass which often mimics a malignant soft tissue tumor. The legs are the Sjögren’s syndrome is characterized by dryness of the eyes and most common site of involvement but it can also affect the mouth (sicca syndrome) and other mucosal membranes. upper extremities, abdomen, head, and neck. There are rare Muscle pain and weakness are common in Sjögren’s syn- cases of focal myositis generalizing to more typical drome, however, actual myositis is rare. Weakness is usually polymyositis.67 The disorder needs to be distinguished from due to disuse atrophy secondary to arthritis and pain. sarcoidosis, Bechet’s syndrome, muscle infarction secondary Nonetheless, there are reports of both DM and PM associat- to diabetes or vasculitis, and soft tissue tumors. The lesions ed with Sjögren’s syndrome.40,122,136 About 90% of patients may resolve spontaneously or with corticosteroid treatment. have ANAs directed against ribonucleoproteins, specifically SS-A (Ro) and less commonly SS-B (La) antibodies.122,134 Laboratory Features

Systemic Lupus Erythematosus Serum CK and ESR are usually normal. Magnetic resonsance imaging and CT imaging demonstrate edema within the Systemic lupus erythematosus (SLE) is an autoimmune dis- affected muscle groups.27,102,104 order affecting multiple organ systems. Weakness is not unusual in SLE, but is most often the result of disuse atrophy. Histopathology Inflammatory myositis is uncommon in SLE. However, some series have reported that up to 8% of DM and PM patients Mononuclear inflammatory cells composed of CD4+ and have SLE.50,136 CD8+ T-lymphocytes and macrophages are present in the endomysium.27 Necrosis and phagocytosis of necrotic fibers The majority of patients with SLE have positive ANA titers is apparent. Nonspecific myopathic features such as fiber size which are directed against native DNA (highly specific for variablity, split fibers, increased centronuclei, and endomysial SLE) and ribonuclear proteins (RNP). The anti-RNP anti- fibrosis are also described. One report noted that MHC class bodies are present in less than half of SLE patients and 1 antigens were not expressed on muscle fibers, in contrast to include anti-SS-A and anti-SS-B (also present in Sjögren’s polymyositis where these antigens are typically abnormally syndrome), anti-U1 RNP (also present in mixed connective expressed on the fibers. tissue disease), and anti-Sm (specific for SLE). Pathogenesis Rheumatoid Arthritis The etiology is unknown. Immunological studies suggest the Rheumatoid arthritis (RA) has been reported in up to 13% disorder is distinct from PM and not the result of a cell-medi- of patients with DM and PM, although the incidence of ated attack directed against a muscle specific antigen.27 inflammatory myopathy in patients with RA is much less.136 The most common etiology of weakness in RA is type 2 muscle fiber atrophy from chronic steroids or disuse secondary to SUMMARY arthralgias. Dermatomyositis, PM, and IBM are clinically, histologically, Mixed Connective Tissue Disease and pathogenically distinct categories of idiopathic inflammatory myopathy. Features of DM and PM can overlap with Mixed connective tissue disease (MCTD) has clinical features those of other autoimmune connective tissue diseases. Other of scleroderma, SLE, RA, and myositis.130 Dermatomyositis types of inflammatory myopathy are much less common but is more common than PM, although both have been are clinically and histologically distinguishable. described in association with MCTD.93,130,136 High titers of Dermatomyositis is a humorally-mediated microangiopathy, AANEM Course Current Concepts in Muscle Disease 15 while PM is a T-cell mediated disorder directed against mus- 18. Basset-Seguin N, Roujeau JC, Gherardi R, Guillaume JC, Revuz J, cle fibers. The pathogenesis of IBM is unknown. Touraine R. 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Skeletal Muscle Channelopathies

Timothy M. Miller, MD, PhD Clinical Instructor Neurosciences Department University of California San Diego, California

INTRODUCTION Disorders secondary to mutations in skeletal muscle ion channels are among the best characterized channelopathies Selecting which charged molecule and how much of that and will be the focus in this manuscript. Recognizing the typ- charged molecule should be allowed to enter or exit a cell or ical presentation of these disorders avoids the risks and costs its subcompartments is a critical task accomplished through of further diagnostic testing and has clear implications for numerous ion channels. Proper regulation of ions may be treatment. The skeletal muscle channelopathies include particularly important for nerve and muscle given the hypokalemic periodic paralysis (HOPP), hyperkalemic peri- demands of electrical excitability. Indeed, dysfunction of odic paralysis (HYPP), Andersen-Tawil syndrome, paramy- these channels (“channelopathy”) has been linked to a wide otonia congenita (PC), Becker’s myotonia congenita (MC), variety of inherited diseases of the nervous system and mus- and Thomsen’s MC. Malignant hyperthermia and congenital cle,8,10,20,22 including periodic paralysis, myotonia congenita, myasthenic syndromes may also be linked to dysfunction of episodic ataxia, familial hemiplegic migraine, and episodic muscle ion channels. ataxia (Table 1). Presumably, sporadic disorders with similar phenotypes may also be related to ion channel function, though this remains less well established. The majority of this MUSCLE PHYSIOLOGY AND ION CHANNELS manuscript will focus on the genetic syndromes since those are the best characterized. Nerve input to skeletal muscle depolarizes the outer muscle membrane, which in turn triggers an action potential that is One strikingly common feature of the diverse group of disor- propagated through the muscle membrane. The action ders secondary to mutations in ion channels is the paroxys- potential begins by an inward sodium current mediated by mal nature of the symptoms. Many patients are normal in the rapid opening of voltage-gated sodium channels. between attacks. Although some triggers of attacks such as Inactivation of sodium channels as well as outward flow of certain foods or temperature have been well defined by potassium through potassium channels leads to repolariza- patients, how exactly these trigger symptoms and why the tion of the membrane. Repolarization is also dependent on disease is episodic remain a mystery. Many of the chan- high chloride conductance. Propagation of the action poten- nelopathies start in infancy or childhood and worsen in ado- tial through the muscle membrane causes release of the of cal- lescence or young adult life. Some improve in the middle to cium ions from the sarcoplasmic reticulum. This burst of cal- late adult years. A common set of medications is effective in cium triggers muscle contraction. treating these disorders. Carbonic anyhdrase inhibitors improve attack frequency and severity in periodic paralysis, Abnormal sodium channel inactivation in vitro first implicat- episodic ataxia, and migraine headache. ed sodium channels as a possible cause for HYPP. Subsequent 20 Skeletal Muscle Channelopathies AANEM Course

Myotonia congenita is caused by mutations in the CLCN1 Table 1 Human channelopathies gene, the major skeletal muscle chloride channel.9 These mutations shift the membrane potential to the depolarizing range. The sustained depolarization allows a new premature Skeletal Muscle Channelopathies action potential, which results in skeletal muscle hyperex- Disorder Gene Channel citability.4,6,7,24,25 On needle electromyography (EMG) this is Paramyotonia congenita SCN4A Sodium channel represented by myotonic runs. Patients with MC experience Potassium aggravated myotonia SCN4A Sodium channel muscle hyperexcitability as stiffness and weakness. Hyperkalemic periodic paralysis SCN4A Sodium channel Hypokalemic periodic paralysis CACNA1S Calcium channel CLINICAL PRESENTATIONS Andersen-Tawil syndrome KCNJ2 Potassium channel Myotonia congenita CLCN1 Chloride channel Periodic Paralyses

Congenital myasthenic CHRNA Acetylcholine receptor Periodic paralyses are a group of dominantly inherited disor- syndrome ders characterized by episodic weakness of skeletal muscles CHRNB Acetylcholine receptor without effects on the central nervous system or respiratory CHRNE Acetylcholine receptor function.

Other Neurological Diseases Patients with inherited periodic paralysis typically present in Spinocerebellar ataxia type 6 CACNA1A Calcium channel childhood with episodic weakness. In general, those with Familial hemiplegic migraine CACNA1A Calcium channel HYPP present at an earlier age (infancy) than those with ATP1A2 Sodium-potassium HOPP (pre-teen). Onset of symptoms after age 20 is strik- 15 transporter ingly unusual for the inherited form of the disease. The attacks of weakness range from mild to full tetraplegia, last- Episodic ataxia with myokymia KCNA1 Potassium channel ing from several minutes to 24 hours. The frequency of Episodic ataxia with nystagmus CACNA1A Calcium channel attacks is highly variable, with some patients only having a Hereditary hyperekplexia GLRA1 Glycine receptor few attacks per year, while others experience attacks daily. In general, attacks for HOPP occur infrequently (1 per week or Cardiac Disease month), but when they do occur, they are severe and the Long QT syndrome patient is unable to get out of bed for hours to a full day. Type 1 KVLQT1 Potassium channel Attacks in HOPP often occur upon first awakening. For HYPP or PC the attacks may occur daily, lasting only sever- Type 2 HERG Potassium channel al minutes and causing some disability, but still allowing the Type 3 SCN5A Sodium channel patient to move. The large variability in frequency, severity, Type 4 ANK2 Ankyrin B and duration has made this generalization difficult to formal- Type 5 minK Potassium channel ly quantify. Some of this variability among patients may be related to behavioral modification, in that attacks are often Type 7 KCNJ2 Potassium channel provoked. Rest after exercise is a common precipitant to an attack for all periodic paralyses. Diet also influences attacks, QT = quick time. but with different effects. Missing meals commonly provokes an attack in HYPP whereas eating a large carbohydrate meal provokes attacks in HOPP. Certain foods may also provoke attacks. Anesthesia is a well-known precipitant for paralytic genetic studies and functional analysis proved this hypothesis attacks. For patients with PC, the attacks of episodic weak- correct5,18,19 and helped establish the group of channelopathy ness are usually much less prominent than the myotonia. diseases. The specific gene defects associated with the disor- Some HOPP and HYPP patients describe cold as a precipi- ders are listed in Table 1. Sodium channel dysfunction is also tant. For PC, worsening with cold exposure is a nearly uni- responsible for PC and a small subset of HOPP. The majori- versal phenomenon, often associated with significant weak- ty of HOPP is caused by mutations in calcium channels. An ness as well as increased myotonia. The myotonia in HYPP inwardly rectifying potassium channel has been linked to and PC is “paradoxical” in that it is worsened by activity Andersen-Tawil syndrome. rather than improved with activity. In MC, the myotonia AANEM Course Current Concepts in Muscle Disease 21 improves with continued activity, termed the “warm-up” cal trial.27 Acetazolamide is also commonly used. During an phenomenon. acute attack for HOPP, replacing potassium often helps restore strength. Education regarding typical triggers in the Neurological examination between attacks in younger disease may help prevent attacks, although in the inherited patients with periodic paralysis may be entirely normal, with forms of the disease, the triggers are usually well-known to the exception of myotonia in patients with HYPP or PC. As the patients. noted earlier, the myotonia is paradoxical. In older patients with periodic paralysis, a surprising number of patients will Andersen-Tawil Syndrome have evidence of proximal weakness,2,12,13,15 which in some is severe. Andersen-Tawil syndrome is associated with the triad of cardiac arrhythmias, dysmorphic features, and periodic paraly- Laboratory testing has found that potassium does indeed sis. The episodic weakness may be similar to periodic paraly- help distinguish HYPP and HOPP especially if potassium is sis. There is no myotonia. The distinguishing features are the tested during one of the attacks. Hyperkalemic periodic other manifestations of the disease including dysmorphisms paralysis or PC has normal or slightly elevated potassium. such as clinodactyly, syndactyly, hypertelorism, and low set Hypokalemic periodic paralysis patients have low potassium ears. The dysmorphisms may be subtle and not easily recog- during the attacks. Needle EMG is strikingly different nized. The part of the disease that causes the most concern is between HYPP and HOPP or PC. Electrical myotonia is the cardiac abnormalities, which sometimes cause malignant common in HYPP and PC and almost never found in ventricular arrhythmias. It is the cardiac problems with this HOPP. On muscle biopsy, a vacuolar myopathy is the most disorder that strongly argues for checking an electrocardio- common finding. gram (EKG) in all patients suspected to have periodic paralysis, especially since the dysmorphic features may be very As will be discussed in more detail, the exercise test shows a subtle. The EKG findings in Andersen-Tawil syndrome may decrement in HOPP, HYPP, and PC. In general, HOPP and include prolonged quick time interval (common early sign), HYPP do not show an objective cold effect; PC patients do bigeminy, and ventricular tachycardia. Some patients require have an objective cold effect. In occasional patients with PC cardioverter defibrillators. Andersen-Tawil syndrome is or HYPP, there may be some overlap in the exercise test and caused by a mutation in potassium channel KCNJ2.17 objective cold effect. Administration of potassium will provoke attacks in HYPP, although this test is not routinely per- Potassium-Aggravated Myotonia formed. Similarly driving potassium into cells by giving insulin and glucose simultaneously may provoke an attack in Potassium administration “aggravates” or brings on myotonia HOPP, although this is also not routinely performed. in patients with potassium-aggravated myotonia. They also experience random, episodic myotonia without any associat- Genetic testing for periodic paralysis is performed by some ed weakness. The myotonia is not sensitive to cold and is specialized laboratories. The easiest way to find such most prominent about 20 minutes after exercise. Like HYPP resources may be by logging on to http://www.genetests.org/. and PC, the disorder is linked to sodium channel dysfunc- Most laboratories will only test for the common mutations. tion.21 Typically HOPP shows mutations in the calcium channel gene CACNA1S, most commonly R528H and R1239H, Inherited Periodic Paralysis of Uncertain Etiology although disease-causing sodium channels and potassium channel mutations are recognized. There are some differences There is a group of patients that have some of the features of between the various mutations, e.g., HOPP secondary to periodic paralysis, but no demonstrable mutation in sodium, sodium channels is often less responsive to acetazolamide calcium, or potassium ion channels.15 Some of these patients therapy. Two mutations in the sodium channel SCN4A gene, also have a convincing family history. In general, patients T704M and M1592V, account for the majority of HYPP. without evidence of ion channel mutations are older at dis- Mutations in the sodium channel are also responsible for PC; ease onset. In addition, these patients rarely describe diet as a residues R1448C and T1313M are the most commonly precipitant for an attack, a common trigger for those with affected. mutations. Finally, patients with mutations often show vacuolar myopathy on muscle biopsy. Patients without muta- Treatment with carbonic anhydrase inhibitors decreased tions often have nonspecific, abnormal muscle biopsies. attack severity and frequency in both HYPP and HOPP. The Despite the less typical features, these patients also respond to efficacy of dichlorphenamide was demonstrated in one clini- carbonic anhydrase treatment. All of these patients with less 22 Skeletal Muscle Channelopathies AANEM Course typical features and especially those without a family history ion channels. There are often less typical features in these need to have a thorough investigation of secondary (metabol- patients and myotonia is less prominent on needle EMG. ic) causes of periodic paralysis. On examination, patients often have preserved strength with Metabolic Periodic Paralysis hypertrophied muscles that seem at odds with their physical limitation. Masseter muscle hypertrophy may produce a The most common metabolic derangement associated with characteristic facial appearance. Percussion myotonia may be HOPP is thyrotoxicity. At first presumed to only effect readily demonstrated. Myotonia improves with repeated Asians, it is now recognized among a large number of ethnic movement. groups. Despite the fact that thyrotoxicosis is more common among women, thyrotoxic periodic paralysis is much more General laboratory findings are normal, except creatine phos- common among men (20:1 ratio). The second to fourth phokinase may be slightly elevated. Needle EMG shows decade is the typical age presentation for thyrotoxic periodic prominent, widespread myotonia. paralysis. The genetic contribution and how the thyrotoxicity triggers the HOPP remains unknown. The attacks in this A subset of patients with MC may have a decrement on the disorder are commonly provoked by rest after exercise or a exercise test.1,11 There is no objective cold effect, although large carbohydrate meal, and are associated with signs of electrical myotonia may increase with cooling. Mutations in hyperthyroidism and a low serum potassium. Returning the chloride channels are responsible for MC. Why the various patient to a euthymic state treats the disorder. Potassium mutations cause either dominant or recessive disease remains replacement aids recovery of strength, but should be moni- a mystery. In fact, the same mutation may cause recessive tored closely, especially if given intravenously, as rebound (Becker’s) or dominant (Thomsen’s) disease. There are few hyperkalemia may occur.26 All patients with suspected peri- laboratories performing routine genetic testing for MC. The odic paralysis should be checked for thyroid disease. website http://www.genetests.org/ may be the best resource to find current testing. Chronic potassium wasting, e.g., with diuretics or because of renal tubular acidosis, can also cause periodic paralysis. In Many patients with MC do not need or seek treatment for patients without a family history of the disease and no evi- their myotonia. However, for others the symptoms are dis- dence of the thyroid disease, especially in older patients, a full abling. Although there are no approved medications for the search for chronic potassium wasting should be sought. treatement of MC, the myotonic symptoms are best treated with mexilitene, an orally absorbed lidocaine derivative that Myotonia Congenita functions as a use-dependent sodium channel blocker. Quinine, procainamide, phenytoin, and carbamazepine have Myotonia congenita presents in infancy to childhood. Both also been used with some success. forms of MC, Thomsen’s MC, and Becker’s MC present with nearly identical phenotypes. They are distinguished by their mode of inheritance. Thomsen’s MC is dominant while SPECIALIZED TESTING Becker’s MC is recessive. Some physicians have noted that Becker’s MC tends to present somewhat later (age 4-12) than Exercise Test Thomsen’s MC (infancy) and that Becker’s MC patients have more severe symptoms.22 While the attacks of myotonia are The exercise test and provocative cold test are two straightfor- often described as being associated with mild weakness, stiff- ward examinations that can be performed in any electrodiag- ness (myotonia) is the predominant symptom. The myotonia nostic (EDX) laboratory. A protocol for the exercise test and in MC differs clinically from that found in PC or HYPP. In provocative cold test are provided in Tables 2 and 3. The HYPP or PC, the myotonia worsens with continued activity. exercise test, as first described by Phil McManis14 shows a In MC, myotonia improves with continued activity and this decrement of the compound muscle action potential so called, “warm-up” phenomenon is characteristic. Attacks (CMAP) when the CMAP is tested over time following 5 of myotonia may be provoked by rest after exercise or cold, as minutes of sustained exercise. The test is positive in both with the periodic paralyses. However, triggers for the myoto- HOPP, HYPP, and in PC. A positive test is defined as a nia are usually a less prominent feature of the disease than greater than 40% drop in CMAP. Both metabolic and famil- with the periodic paralyses. As with periodic paralyses, there ial cases are likely to be positive. The decrease in patients with are patients with a positive family history and some features PC differs qualitatively from HOPP and HYPP. In PC, fol- of the disease who do not have demonstrable mutations in lowing exercise, there is a rapid fall in the amplitude followed AANEM Course Current Concepts in Muscle Disease 23 by a slow increase back to baseline over the next 60-90 min- show decreased electrical activity during needle EMG and a utes. In HOPP and HYPP, the amplitude may be mildly low remarkable decrease in CMAP amplitude. Patients with MC at rest, increase slightly, and then fall by greater than 40% will show an increase in myotonia with cooling, but the over the next 15-30 minutes. Some cases of MC also show a CMAP amplitude will not be effected. Typically HOPP and decrement on the exercise test as well, but this is not consis- HYPP do not show any changes with cooling. However, tent. The response to the exercise test is summarized in Figure some “overlap” cases of HYPP do show an objective cold 1. effect.

Provocative Cold Test Differential Diagnosis

Patients with PC often describe weakness and stiffness pro- Table 4 summarizes the clinical features of MC and Table 5 voked by cold. This may be a direct effect on the muscles and summarizes the clinical findings in MC. With these tables in can be reproduced in the EDX laboratory.16,23 A protocol for mind, often the correct diagnosis can be reached by the provocative cold test is provided in Table 3 and a positive history/physical and relatively few diagnostic tests. Figure 2 test is defined as an objective cold effect with a decrease in outlines one approach to patients with episodic weakness. CMAP amplitude greater than 75%. The most specialized piece of equipment not standard to many EDX laboratories The approach to patients with suspected MC is often less is a basic, long thermometer that can be submerged in water. challenging than periodic paralysis. In clinical practice, it The “old style” with a column of fluid works best. The may make little difference whether the patient is labeled as CMAP is recorded before and after cooling the hand in a having Thomsen’s MC versus Becker’s MC, though some bucket of cool (15˚ C) water. Patients with PC may initially authors have argued that Becker’s is more severe than show increased myotonia with mild cooling, but will then Thomsen’s. The first important step is to establish that there

Table 2 Exercise test Table 3 Provocative cold test

1. Rule out compressive or other lesion affecting nerve to be 1. Rule out compressive or other lesion of nerve to be studied studied 2. Record CMAP from APB, ADM or if needed EDB 2. Record CMAP of EDB, APB, or ADM Hand muscles preferable 3. Be sure that recording electrode is secured well 3. Use indelible marker to mark exactly where the recording 4. Exercise patient by sustained contraction of muscle for 5 minutes electrode is placed Rest breaks of a few seconds are allowed for patient It is useful to draw a box/circle around the entire electrode 5. Following exercise, Record CMAP every 1 minute for 5 minutes 4. Remove electrodes 6. After first 5 minutes, record CMAP every 5 minutes for 30 to 60 5. Place patient’s hand (or foot) in a basin with water cooled to minutes approximately 15˚ C 7. Test is positive if CMAP area decreased greater than 40% This should be monitored closely with a thermometer. Much 8. Note that CMAP may increase slightly in the first few minutes colder than 15˚ C is uncomfortable (and possibly harmful) 9. See Figure 1 and text for interpretation and much warmer than 15˚ C may be produce a false negative result

ADM = adductor digiti minimi; APB = abductor pollicis brevis; CMAP = compound 6. Ask patient to self regulate the temperature by occasionally muscle action potential; EDB = extensor digitorum brevis. adding ice to the water 7. Cool hand for 15-30 minutes in the water bucket 8. Dry off hand (foot) 9. Replace electrodes in exact same location as was first recorded 10. Record CMAP 11. The test is positive if the CMAP decreases by >75% after cooling

ADM = adductor digiti minimi; APB = abductor pollicis brevis; CMAP = compound muscle action potential; EDB = extensor digitorum brevis. 24 Skeletal Muscle Channelopathies AANEM Course

Table 5 Clinical features of the familial periodic paralyses

HOPP HYPP PC Age at onset, years 5 to 20 <10 Infancy Attacks Frequency Infrequent Frequent Frequent Duration, hours >24 <24 < 24 Precipitants Exercise Exercise Exercise High Hunger Cold carbohydrates Salt Potassium-rich foods Myotonia No Yes Always Weakness Yes Yes Yes Figure 1 Exercise test. Potassium level Low Normal to Normal High Response to Relieves acute Causes No effect Changes in compound muscle action potential (CMAP) in response to 5 potassium paralysis weakness minutes of exercise. The amplitude increases minimally in normal subjects with a return to baseline over 5 minutes. In paramyotonia Objective cold effect None None Causes congenita, there is a precipitous decline in CMAP amplitude with a slow weakness return towards baseline. In periodic paralysis, there is an initial increase Muscle biopsy Vacuolar Vacuolar Variable in CMAP amplitude followed by a slow decline over 15 to 30 minutes. myopathy myopathy Lambert-Eaton syndrome shows a low amplitude at rest and a prominent (usually > 200%), nonsustained increase in amplitude following exercise. HOPP = hypokalemic periodic paralysis; HYPP = hyperkalemic periodic paralysis; PC = paramyotonia congenital.

Modified from a chapter by P. McManis in: Neuromuscular function and disease: Table 5 is reproduced from Miller and colleagues, Neurology 2004;63(9):1647- 3 basic, clinical, and electrodiagnostic aspects, ed. Brown, Bolton, Aminoff, 2002. 165515 with permission from Lippincott Williams & Wilkins.

Table 4 Clinical features of myotonia congentia

Age of onset Infancy to childhood Myotonia Always present and with “warm up” phenomenon Weakness Mild weakness during attack of myotonia Precipitants Cold, exercise Physical Muscle hypertrophy, myotonia examination findings AANEM Course Current Concepts in Muscle Disease 25

Figure 2 Diagnosis of periodic paralysis.

Periodic paralyses can usually be diagnosed by following the above list of questions and examinations, especially if the patient presents during one of the paralytic episodes.

Figure 2 is reproduced from Miller and colleagues.,15 Neurology 2004;63(9):1647-1655 with permission from Lippincott Williams & Wilkins. 26 Skeletal Muscle Channelopathies AANEM Course is indeed myotonia, both clinically and by needle EMG. The 12. Links T, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ. next step is to exclude other myotonic disorders, such as Permanent muscle weakness in familial hypokalaemic periodic paral- myotonic dystrophy. ysis. Clinical, radiological and pathological aspects. Brain 1990;113:1873-1889. 13. Links TP, Smit AJ, Molenaar WM, Zwarts MJ, Oosterhuis HJ. Familial hypokalemic periodic paralysis. Clinical, diagnostic and ther- CONCLUSION apeutic aspects. J Neurol Sci 1994;122:33-43. 14. McManis PG, Lambert EH, Daube JR. The exercise test in periodic Current management of patients with periodic paralysis and paralysis. Muscle Nerve 1986;9:704-710. 15. Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, MC depends on an accurate clinical diagnosis, one in which Tawil R, McManis P, Griggs RC, Angelini C, Servidei S, Petajan J, the EDX consultant often plays an important role. Further Dalakas MC, Ranum LP, Fu YH, Ptacek LJ. Correlating phenotype studies of ion channel mutations and their functional conse- and genotype in the periodic paralyses. Neurology 2004;63:1647- quences may lead to a better understanding of skeletal mus- 1655. cle channelopathies and other episodic neurological disor- 16. Nielsen VK, Friis ML, Johnsen T. Electromyographic distinction ders, as well as guide future therapies. between paramyotonia congenita and myotonia congenita: effect of cold. Neurology 1982;32:827-832. 17. 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Toxic Drug-induced Myopathies

Mark B. Bromberg, MD, PhD Department of Neurology University of Utah Salt Lake City, Utah

INTRODUCTION This manuscript will focus on toxins and metabolic states in skeletal muscle (and will exclude primary cardiomyopathies). Toxic and metabolic myopathies are considered to be rare dis- The list of possible agents will be narrowed to those that orders. Or are they? Their incidence is not known, and given could be encountered in the outpatient clinic and inpatient the large number of available drugs, the frequency of consultation service. It will consider primary causes but not polypharmacy and its effect on drug metabolism, and other secondary causes such as drugs that induce coma resulting in variables such as genetic differences in metabolism, it is like- muscle compression. Primary genetic disorders will not be ly that the incidence is much higher than suspected. Since discussed. Tables 1 and 2 include lists of toxins and metabol- toxic and metabolic myopathies are potentially treatable, it is ic states, respectively, for reference. Toxic myopathies have important to recognize them at an early stage. Some of the been tabulated by a mixed list of headings, including those challenges in assessing a patient for such a myopathy relate to based on muscle biopsy findings (necrotic, inflammatory), the many possible variables that could cause the myopathy. on organelle involvement (mitochrondrial), on class of drug For example, there are known toxins, toxins that rarely cause (lipid-lowering agents), and a variety of other headings. It is muscle disease, and some that are possible toxins in certain difficult to improve upon this disparate scheme. For most, situations. Similarly, there are known metabolic states that the mechanism of toxicity is unknown, and general descrip- cause muscle disease, some that rarely do, and others that tions have to suffice. appear on lists of metabolic disorders with little firm clinical data. Clinically, the definitions of symptoms supporting toxicity vary among incidence reports, and there are patients DEFINITIONS OF MUSCLE DISEASE who present with clear weakness, some with ill-defined fatigue or muscle pain, and some who have normal strength The spectrum of symptoms used to support a toxic and meta- but an elevated serum creatine kinase (CK) level discovered bolic myopathy is broad and influences the interpretation of on a random blood test panel and who are also taking a list- the literature. Examples of definitions are: “myopathy” as any ed drug. Given these factors, assessment of potential toxins muscle complaint; “myositis” as symptoms plus an elevated and metabolic states must always be considered in the differ- CK; and “rhabdomyositis” when the CK is greater than ential diagnosis of any muscle disorder. 10,000 IU/L and the creatinine level is elevated.19 28 Toxic Drug-Induced Myopathies AANEM Course

Table 1 List of drugs implicated in muscle disease. Table 2 List of metabolic abnormalities implicated in muscle disease. Necrotizing Cholesterol-lowering agents Glucocorticoid Diseases HMG-CoA reductase inhibitors Excess Atorvastatin Cushing disease Fluvastatin Corticosteroid drugs Lovastatin Deficiency Pravistatin Adrenal insufficiency Rosuvastatin Thyroid Disease Simvastatin Excess Fibric acid derivatives Thyrotoxicosis Gemfibrozil Thyrotoxic periodic paralysis Probucol Deficiency Clofibrate Hypothyroidism Epsion-aminocaproic acid Growth Hormone Immunophilins Acromeglay Cyclosporine Tacrolimus Propofol Ethanol VULNERABILITY OF MUSCLE Amphiphilic Chloroquine Skeletal muscle is susceptible to a variety of toxic and meta- Hydroxychloropuine bolic insults. Direct pressure and vascular insufficiency are Aminodarone obvious examples, but will not be considered. Muscle is a complex structure. Macroscopically, muscles are made up of Antimicrotubular innumerable fibers that run the length of the whole muscle. Colchicine Microscopically, muscle fiber cytoplasm (sarcoplasma) is con- Vincristine tained and separated from extracellular and vascular environ- Drug-induced mitochondrial myopathy ments by a bi-lipid membrane (sarcolemma). The membrane Zidovudine is composed of a variety of lipids, including cholesterols. Other HIV-related antiretrovirals Further, the sarcolemma is not a simple tubular structure, but Hypokalimic has an extensive network of invaginations of the membrane into the middle of the fiber (transverse tubules), and the over- Diuretics all square area of the sarcolemma is tremendous. Within the Laxatives sarcoplasma are the contractile proteins actin and myosin. Impaired protein sythensis There is an extensive endoplasmic reticulum that participates Emedine (Ipecac syrup) in the release of calcium required for contractile function. Unknown mechanism There is also an important series of proteins that may be vul- Critical illness nerable in toxic and metabolic myopathies. These include proteins that link actin to the basal lamina, and include dys- Omeprazole trophin and the sarcoglycan complex, and other protein com- Cyclosporine plexes that are involved in muscle function.

HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-methyl-glutaryl- coenzyme A. Energy requirements of muscle are high, and muscles at rest consume approximately 35% of total energy, and with vigor- ous activity a much greater percentage. The internal ionic environment of muscle is tightly regulated, particularly for AANEM Course Current Concepts in Muscle Disease 29 calcium, and its regulation has a major role in the contraction which further increases the diagnostic difficulties. Muscle process. Adenosine triphosphate (ATP) is the source of ener- weakness is usually assessed by brief testing in the clinic based gy for these regulatory processes. Energy is supplied by three on the Medical Research Council (MRC) scale that has a metabolic pathways. The first, immediate availability ATP, wide range for normal (grade 5), and factors for gender, age, comes from the combining of phosphocreatine with adeno- physical build, and degree of conditioning must be included, sine diphosphate (ADP). This reaction is rapid but is used up or mild degrees of weakness can be missed. The time course within minutes with intense exercise. The second most avail- of symptoms varies from acute (rare) to subacute over sever- able source is anerobic metabolism from glycogen through its al months (most common), to insidious over years (least conversion to glucose, and on to pyruvate. The energy from common). glycogen via anerobic metabolism is limited for two reasons; (1) glycogen stores in muscle are modest, and can be con- Among laboratory tests, serum CK is felt to be a good mark- sumed within 2 hours of active exercise; (2) only a net two er for sarcolemmal disruption. However, values vary between ATP molecules are generated from each molecule of glucose. genders and among ethnic groups.6 Serum CK is occasional- Aerobic metabolism results in a greater yield of ATP. Pyruvic ly high (>10 x upper limb of normal [ULN]) to extraordinar- acid, through the tricyclic acid cycle, generates 36 ATP mol- ily high (1000+ x ULN) in acute cases, and may be mildly ecules. The third metabolic pathway is the metabolism of elevated (2 x ULN) in asymptomatic individuals who are triglycerides which can yield up to 129 ATP molecules implicated because they are taking a listed drug. The signifi- through the electron transport system. cance of incidental mild elevations (approximately 2 x ULN) is not clear.20 Needle EMG is a sensitive tool for assessing Another issue is that the enzymes responsible for anerobic structural (architectural) alterations of muscle fibers. metabolism are located in the sarcoplasm, while those for aer- Abnormal spontaneous activity (positive sharp waves and fib- obic metabolism are located in mitochondria. Mitochondria rillation potentials) and complex motor unit action potentials are complex in that there are transport proteins that are nec- (polyphasic and polyturn) with rapid recruitment are find- essary for the shuttling of molecules back and forth across the ings supporting a myopathic process (Figure 1).2 However, inner and outer membranes. Evidence for the key roles that in less severe cases, and with abnormalities of energy metab- mitochondrial production of energy play in contraction are olism, such changes do not occur and the EMG may be nor- the large number of mitochondria in muscle and their loca- mal. Muscle biopsy findings are helpful in several ways. It is tion close to contractile proteins. Thus, there are many steps the most sensitive tool for making a diagnosis of a myopathy where disturbances of muscle metabolism could lead to mus- because subtle morphologic changes can be detected, and his- cle dysfunction. tochemical stains can directly measure enzymatic activity and identify specific abnormalities (Figure 2). However, in cases with mild symptoms, the biopsy may be normal or minimal- CLINICAL AND LABORATORY FEATURES ly abnormal with only nonspecific findings.

There are a number of clinical and laboratory symptoms and findings that suggest a toxic or metabolic disorder of muscle. DIAGNOSIS Unfortunately, none are specific, and some toxic or metabolic disorders are largely silent. The symptom list includes mus- A diagnostic algorithm is advantageous, but there are few cle pain, soreness, swelling, fatigability, and weakness. The clear nodal points (Figure 3). In general, the history and laboratory findings are an elevated serum CK, myoglobin- physical examination determines whether there is weakness uria, needle electromyography (EMG) abnormalities, and and its pattern (proximal for a myopathy, proximal and dis- pathologic changes in biopsied muscle tissue. Muscle pain or tal for a neuromyopathy), an electrodiagnostic (EDX) study soreness is not specific, making it challenging to determine to determine if there is a defect in neuromuscular junction whether they represent a metabolic or toxic disorder when transmission or altered muscle fiber architecture (necrotic symptoms are unaccompanied by true weakness, elevated and inflammatory myopathies), and a serum CK level. CK, and EMG abnormalities. Similarly, nonspecific fatigabil- Assessment for myoglobinuria and renal failure are required ity without other clinical features is challenging, and disor- in severe cases. A muscle biopsy can define the type of pathol- ders of the neuromuscular junction (myasthenia gravis and ogy (necrotic, inflammatory, mitochondrial, myosin dissolu- Lambert-Eaton syndrome) must be excluded. Nonspecific tion). Laboratory studies for underlying metabolic causes and symptoms are also part of the chronic fatigue syndrome, contributing factors (renal and hepatic failure, thyroid dys- 30 Toxic Drug-Induced Myopathies AANEM Course

Figure 1 Needle electromyography (EMG) findings in myopathic disorders. Left: Normal muscle. EMG findings are no abnormal spontaneous activity and normal motor unit waveforms. Right: Muscle with segmental degeneration. EMG findings are abnormal spontaneous activity with fibrillation potentials and positive waves and complex motor unit waveforms.

agents with myalgias reported in 2-7%, weakness or elevated CK in 0.1-1%, and severe myopathy in 0.08%.28 There are associated factors that may increase the risk in subpopula- tions of patients, and many risk factors are interrelated (Table 3). For example with lipid-lowering agents, advanced age is associated with other diseases that may raise lipid levels and lead to a greater need for such agents. Further, there may be needs for additional medications to treat concurrent age- Figure 2 Left: Vacuolar changes. Right: Ragged red fibers related diseases, resulting in polypharmacy. Multiple drugs supporting mitochondrial changes. also increase the chances of affecting the cytochrome P-450 (CYP) enzyme system, the major detoxification pathway for many drugs. Advanced age and other diseases may reduce renal and hepatic function, altering metabolism. function) are appropriate. Finally, careful consideration for possible interactions of multiple drugs, including ones not The CYP system is responsible for oxidative metabolism of a specifically listed, should be considered for their effect on large percentage of drugs (Table 4). However, drugs may drug metabolism. either induce or inhibit CYP enzymes.31 Inhibition occurs from other drugs, and also with natural foods (grapefruit juice). Further, there are genetic differences in the CYP sys- TREATMENT tem in greater than 1% of the population due of polymor- phisms or variant alleles that can increase or reduce drug oxi- Treatment is relatively straightforward for most toxic dation. myopathies—removal of the toxic drug and treatment of the metabolic abnormalities. Associated metabolic consequences, such as rhabdomyolisis and renal failure, must be appropri- CHOLESTEROL-LOWERING AGENTS ately managed.30 Muscle has a high capacity to regenerate, and recovery of strength will take time. HMG-CoA Reductase Inhibitors

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) RISK FACTORS FOR TOXIC AND METABOLIC MYOPATHIES reductase is the rate-limiting step in the synthesis of cholesterol, and catalyzes the formation of mevalonic acid. There The overall incidence of muscle toxicity from prescription are another dozen enzymatic steps from mevalonic acid to drugs is low. This has been assessed for cholesterol-lowering cholesterol. While it was initially thought that drugs inhibit- AANEM Course Current Concepts in Muscle Disease 31

Table 3 Factors and their effects on drug metabolism that may Symptoms suggestive of muscle disease: lead to myotoxicity. Myalgias Cramps Factors Effect Fatigue Advanced age Concomitant diseases Weakness Polypharmacy Increases or decreases P-450 metabolism Hepatic insufficiency Reduced metabolism

Review medications: Renal insufficiency Reduced elimination Discontinue or reduce dose of suspected medications P-450 enzyme system Increased or decreased drug metabolism Diet P-450 inhibition by grapefruit juice

Initial laboratory studies: Serum CK TSH Creatinine Table 4 List of common drugs and their effect on the CYP3A family of cytochrome P-450 enzyme system (modified from EMG Wilkinson G.).

If CK > 10,000: SUBSTRATES INHIBITORS INDUCERS Check for myoglobinuria Treat thyroid disease Calcium-channel Calcium-channel Rifamycins blockers blockers If creatinine high: Diltiazem Diltiazem Rifampin Fluids Nifedipine Verapamil Verapamil

If symptoms mild and CK mildly elevated: Immunosuppressant Axole antifungal Anticonvulsant agents agents agents Follow patient Cyclosporine Ketoconazole Carbamazepine If symptoms marked and CK high: Tacrolimus Phenobarbital Muscle biopsy Phenytoin Benzodiazepines Microlide antibiotics Figure 3 Algorithm for evaluation and treatment of toxic and Alprazolam Clarithomycin metabolic myopathies. Midazolam Erythromycin Triazolam CK = creatine kinase; EMG = electromyography; TSH = thyroid stimulating hormone. Statins Atorvastatin Lovastatin ing HMG-CoA reductase could contribute to decreased sar- Anti-HIV agents Anti-HIV agents Anti-HIV agents colemmal cholesterol content leading to destabilization and eventual destruction of the membrane, there are newer data Indinavir Delavirdine Efavirenz to implicate a more complex pathology involving steps along Nelfinavir Indinavir Nevarapine the way.1 Ritonavit Ritonavit Saquinavir Saquinavir Clinical features vary from asymptomatic elevations in serum Miscellaneous Miscellaneous Miscellaneous 28 CK to myalgias to weakness. The drug cervistatin is an Sildenafil Mifepristone St John’s wort example of a drug that produced a much higher incidence of Grapefruit juice rhabdomyolysis leading to mortality and morbidity in the setting of renal failure, and was subsequently taken off the HIV = human immunodeficiency virus market. Needle EMG in weak patients shows abnormalities consistent with muscle fiber damage, but is usually normal in 32 Toxic Drug-Induced Myopathies AANEM Course asymptomatic patients with only elevated CK levels. Muscle reduced recruitment) in distal muscles. Serum CK levels are biopsy shows fiber necrosis and regeneration, and subsar- elevated. Muscle biopsy shows autophagic vacuoles. colemmal accumulation of autophagic lysosomes in electron Pathogenesis is attributed to drug interaction with the mus- micrographic examination. In general, symptoms and signs cle fiber membrane. reverse with removal of the drug.

ANTIMICROTUBULAR MYOPATHIES FIBRIC ACID DERIVATIVES Colchicine In fibric acid derivatives, the mechanism is not known, but is postulated to destabilize muscle fiber membrane leading to Colchicine can cause a neuromyopathy and symptoms devel- degeneration.24 The clinical, needle EMG, and biopsy fea- op usually after long-term use. Renal insufficiency is a pro- tures vary as they do with HMG-CoA reductase inhibitors. moting factor.13 Weakness develops slowly, and the neuropathy is mild. Nerve conduction studies show distal slowing and reduced sensory and motor responses. Needle EMG IMMUNOPHILINS shows a proximal myopathic and distal neuropathic pattern, and may include myotonic discharges.22 Serum CK levels Cyclosporine and tacrolimus are immunosuppressive agents vary from mildly to markedly elevated. Muscle pathology used particularly for organ transplant patients. Cyclosporine shows a vacuolar pattern. Disruption of microtubular trans- may cause myalgias and weakness.7 Rhabodmyolysis has been port of lysosomes is felt to be the underlying pathologic described with concurrent use of cholesterol-lowering agents process. (including HMG-CoA reductase and fibric acid derivatives). Tacrolimus has also been associated with rhabdomyolysis.10 Mechanisms of muscle fiber damage are unknown, but pos- DRUG-INDUCED MITOCHONDRIAL MYOPATHIES tulated to destabilize the membrane in a similar manner as with cholesterol-lowering agents, thus explaining the Anti-human Immunodeficiency Virus Drugs increased risk with the combination of drugs. Zidovudine is an antiretroviral drug used for human immunodeficiency virus (HIV) infections, and causes myalgias in PROPOFOL 20-50% of patients and proximal weakness with or without an elevation of serum CK in patients at all stages of HIV Propofol is used in intensive care settings for sedation of ven- infection.26 The muscle biopsy is significant for ragged red tilated patients and treating status epilepticus. There are fibers and cytochrome oxidase-negative fibers. Other findings reports of rhabodmyolysis and myoglobinuria primarily in are fiber necrosis, cytoplasmic bodies, nemaline rods, and children.8 Given the intensive care setting, concomitant fac- microvaculoated fibers. A clinical challenge in diagnosing tors such as acute quadriplegic myopathy must be consid- antiretrovial-induced myopathy is that HIV itself can cause ered. an inflammatory myopathy, a necrotizing myopathy without inflammation, and type 2 muscle fiber atrophy from a wasting syndrome. Drug-induced myopathy from anti-retroviral AMIODARONE drugs is slowly progressive, and should be differentiated from the acute rhabdomyolysis characterized by myalgias, weak- Amiodarone is unique in that it can cause a neuropathy and ness, and high CK levels (>1500) secondary to antiretroviral myopathy (neuromyopathy).5,17 Thus there may be distal drug toxicity. Needle EMG will show similar myopathic pat- weakness from the neuropathy and proximal weakness from terns for all myopathies in HIV, and thus will be unable to the myopathy. Accordingly, nerve conduction studies are differentiate these diagnoses. Accordingly, a muscle biopsy is consistent with an axonal neuropathy, but in cases with acute important to help determine which or whether there are sev- onset there may be initial demyelinating features similar to eral superimposed pathologic processes.27 The source of those recorded in Guillain-Barré syndrome. Needle EMG pathology is thought to result from a mitochondrial cytopa- will show abnormal spontaneous activity and motor units thy, and electron microscopy shows such abnormalities. will likely have a myopathic pattern in proximal muscles and Azidothymidine acts as a false substitute for viral reverse tran- a neuropathic pattern (high amplitude potentials with scriptase not only for cellular deoxyribonucleic acid (DNA) AANEM Course Current Concepts in Muscle Disease 33 polymerse but also for mitochondrial DNA polymerase, Diverse factors related to sepsis may also contribute to break- which is felt to account for mitochondrial abnormalities on down. biopsy.

ALCOHOL MYOPATHY EMATINE Ethanol can cause a variety of myopathic conditions, includ- Ematine is extracted from the ipecac root and has been used ing: (1) acute necrotizing myopathy; (2) acute hypokalemic as an amebicide and emetic. Its greatest potential for toxicity myopathy; (3) chronic myopathy; and (4) asymptomatic is misuse for weight control in people with eating disorders. myopathy.15,25 The acute necrotizing form occurs in the set- Overuse over a few days can cause in marked weakness of ting of high ethanol consumption usually associated with a skeletal and cardiac muscle.18 Serum CK levels are mildly ele- binge, and includes marked muscle pain, tenderness to palpa- vated and the needle EMG is mildly abnormal. Muscle biop- tion, swelling, marked weakness and elevated CK levels. sy shows necrosis, moth-eaten fiber perimeter, and partial Muscle pathology shows fiber necrosis. Acute hypokalemic clearing of oxidative enzymes in a targetoid pattern. Electron myopathy has similar clinical features to other types of microscopy shows degeneration of contractile proteins. hypokalemic myopathy, and is associated with serum potassi- Ematine interferes with protein synthesis, although the um levels between 1.4 and 2.1 meq/L. Biopsy findings in the mechanism for the changes in muscle is not clear. acute phase show vacuoles. Chronic alcoholic myopathy has an insidious onset and affects primarily leg muscles. Biopsy findings are not specific and include atrophy, necrosis, and CRITICAL ILLNESS MYOPATHY regenerating fibers. An asymptomatic alcoholic myopathy loosely designates a condition with elevated serum CK levels. Quadriplegia can occur in the setting of critical illness from The mechanism of ethanol toxicity is not known, and is com- a variety of causes, including a myopathy. There are a num- plicated because many such patients are malnourished and ber of terms used, including acute quadriplegic myopathy, have vitamin deficiencies. acute illness myopathy, critical illness myopathy, and myopathy associated with myosin destruction. Another factor is an axonal neuropathy that may present as a similar clinical pic- THYROTOXIC MYOPATHY ture of weakness, and critical illness neuropathy may co-exist with critical illness myopathy. Given the complexity of criti- The incidence of weakness in patients with thyrotoxicosis is cally ill patients, several factors have emerged, and include high. Serum CK is normal. Needle EMG shows no abnormal use of high-dose intravenous corticosteroids with or without spontaneous activity, but motor unit recruitment may be nondepolarizing neuromuscular blocking drugs, although increased and motor units complex. Muscle biopsy findings the use of these drugs is not required for the development of are variable, and may include inflammatory changes.9 There critical illness myopathy11 Weakness develops over days, and is a small increased association between thyroid disease and failure to wean from the ventilator is a major clinical issue. myasthenia gravis. Thyroid hormones have many metabolic Serum CK levels are normal or mildly elevated. Needle EMG influences affecting a number of aspects of muscle func- may show abnormal spontaneous activity, but assessment of tions—specific mechanisms causing weakness are not clearly motor units is hampered by the patient’s inability to recruit known. motor units. The electrophysiologic technique of direct muscle stimulation may be helpful in separating critical illness myopathy from neuropathy.21 In this technique, muscle THYROTOXIC PERIODIC PARALYSIS fibers are directly activated by an intramuscular stimulating needle electrode and compared to the response to stimulation Episodic weakness that is clinically similar to that of familial of the nerve. With critical illness neuropathy, the response to hypokalemic periodic paralysis occurs in association with direct muscle stimulation should be of good amplitude and thyrotoxicity, most commonly, but not exclusively, in Asian that to stimulation of the nerve of low amplitude, while with populations.29 Attacks are associated with ingestion of carbo- critical illness myopathy, the response to stimulation of either hydrate-rich meals and weakness may be profound. Serum site should be the same. Muscle biopsy shows atrophy of type potassium values range from 1.1 to 3.4 mmol/L, and phos- 2 fibers as well as loss of ATPase staining in type 1 and 2 phate values are frequently low.16 Thyrotoxic periodic paral- fibers. By electron microscopy there is loss of myosin.14 The ysis is usually a sporadic condition and resolves with treat- mechanism is not known, but calcium-activated proteases ment of hypokalemia, and does not recur with treatment of may be enhanced and thus contribute to myosin breakdown. the thyroid disorder. 34 Toxic Drug-Induced Myopathies AANEM Course

HYPOTHYROID MYOPATHY 4. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry When the symptoms of myopathy are expanded to include 2000;68:750-755. fatigability, pain, stiffness, cramps, and weakness the inci- 5. Gledhill R, Van Der Merwe C, Greyling M, Van Niekerk M. Race- dence of myopathy can be up to 80%.4 Serum CK may or gender differences in serum creatin kinase activity: a study among may not be elevated. South Africans. J Neurol Neurosurg Psychiatry 1988;51:301-304. 6. Grezard O, Lebranchu Y, Birmele B, Sharobeem R, Nivet H, Bagros P. Cyclosporin-induced muscular toxicity. Lancet 1990;335:177. 7. Hanna J, Ramundo M. Rhabdomyolysis and hypoxia associated with CORTICOSTEROID MYOPATHY prolonged propofol infusion in children. Neurology 1998;50:301- 303. The incidence of weakness due to the use of corticosteroids is 8. Hardiman O, Molloy F, Brett F, Farrell M. Inflammatory myopathy difficult to access, in part because corticosteroids are fre- in thyrotoxicosis. Neurology 1997;48:339-341. quently given for disorders that themselves cause weakness, 9. Hibi S, Misawa A, Tamai M, Tsunamoto K, Todo S, Sawada T, Imashuku S. Severe rhabodmyolysis associated with tacrolimus. and the balance of positive and negative effects is usually to Lancet 1995;346:702. improved strength, thus masking a negative drug effect on 10. Hirano M, Ott BR, Raps EC, Minetti C, Lennihan L, Libbey NP, strength. A reasonable estimate of 10% comes from patients Bonilla E, Hays AP. Acute quadriplegic myopathy: a complication of with brain tumors treated with corticosteroids or those with treatment with steroids, nondepolarizing blocking agents, or both. asthma.3,23 It appears that fluorinated corticosteroids (dex- Neurology 1992;42:2082-2087. amethasone) are more likely than prednisone to cause weak- 11. Khaleeli AA, Levy RD, Edwards RH, McPhail G, Mills KR, Round JM, Betteridge DJ. The neuromuscular features of acromegaly: a clin- ness. Weakness is not highly correlated with corticosteroid ical and pathologic study. J Neurol Neurosurg Psychiatry peak or accumulative dose. Serum CK levels are usually nor- 1984;47:1009-1015. mal, as is the EMG. Muscle biopsy is remarkable primarily 12. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper for type 2 fiber atrophy. Corticosteroids have a number of M. Colchicine myopathy and neuropathy. N Engl J Med roles in muscle metabolism, and when in excess, their effect 1987;316:1562-1568. 29 13. Lacomis D, Giuliani MJ, Van Cott A, Kramer DJ. Acute myopathy on protein catabolism is likely a major factor. of intensive care: clinical, electromyographic, and pathologic aspects. Ann Neurol 1996;40:645-654. 14. Lafair JS, Myerson RM. Alcoholic myopathy: with special reference GROWTH HORMONE MYOPATHY to significance of creatine phosphokinase. Arch Intern Med 1968;122:417-422. Acromegaly is associated with a myopathy in 50% of 15. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic fea- 12 tures of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med patients. Weakness is mild and serum CK values are normal 1999;159:601-606. or mildly elevated. Myopathic EMG findings were mild. 16. Martinez-Arizala A, Sobol S, McCarty G, Nichols B, Rakita L. Muscle biopsy findings are type 2 atrophy. Amiodarone neuropathy. Neurology 1983;33:643-645. 17. Palmer EP, Guay AT. Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N Engl J Med SUMMARY 1985;313:1457-1459. 18. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and The challenge in assessing for toxic and metabolic safety of statins. Circulation 2002;106:1024-1028. myopathies is not to miss them. This is difficult because of 19. Reijneveld JC, Notermans NC, Lissen WH, Wokke JH. Benign the ill-defined symptoms, the vulnerability of muscle to prognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000;23:575- insults, and the growing frequency of polypharmacy. It is 579. 20. Rich MM, Bird SJ, Raps EC, McCluskey LF, Teener JW. Direct mus- always wise to discontinue a suspicious medication, or to cle stimulation in acute quadriplegic myopathy. Muscle Nerve substitute with a different type of medication. Finally, when 1997;20:665-673. there are doubts, a muscle biopsy is clinically wise. 21. Fernando-Roth R, Itabashi H, Louie J, Anderson T, Narahara KA. Amiodarone toxicity: myopathy and neuropathy. Am Heart J 1990;119:1223-1225. REFERENCES 22. Rutkove SB, De Girolami U, Preston DC, Freeman R, Nardin RA, Gouras GK, Johns DR, Raynor EM. Myotonia in colchicine myoneuropathy. Muscle Nerve 1996;19:870-875. 1. Baker SK. Molecular clues into the pathogenesis of statin-mediated 23. Shee CD. Risk factors for hydrocortixone mopathy in acute severe muscle toxicity. Muscle Nerve 2005;31:572-580. asthma. Respir Med 1990;84:229-233. 2. Bromberg MB, Albers JW. Electromyography in idiopathic myositis. 24. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia: Mt Sinai J Med 1988;55:459-464. an apprasial of their efficacy and safety. Eur Heart J 1995;16:5-13. 3. Dropcho EJ, Soong SJ. Steroid-induced weakness in patients with primary brain tumors. Neurology 1991;41:1235-1239. AANEM Course Current Concepts in Muscle Disease 35

25. Sieb J. Myopathies due to drugs, toxins, and nutritional deficiency. 28. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. JAMA 2003;289:1681-1690. New York: McGraw-Hill; 2004. p 1693-1712. 29. Ubogu E, Ruff R, Kaminski H. Endocrine myopathies. In: Engel A, 26. Simpson DM, Bender AN. Human immunodeficiency virus-associ- Franzini-Armstrong C, editors. Myology, 3rd edition. New York: ated myopathy: analysis of 11 patients. Ann Neurol 1988;24:79-84. McGraw-Hill; 2004. p 1713-1738. 27. Simpson DM, Citak KA, Godfrey E, Godbold J, Wolfe DE. 30. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a Myopathies associated with human immunodeficiency virus and review. Muscle Nerve 2002;25:332-347. zidovudine: Can their effects be distinguished? Neurology 31. Wilkinson G. Drug metabolism and variability among patients in 1993;43:971-976. drug response. N Engl J Med 2005;352:2211-2222. 36 AANEM Course 37

Hereditary and New Myopathies

Gregory T. Carter, MD Clinical Professor Department of Rehabilitation Medicine University of Washington School of Medicine Seattle, Washington

INTRODUCTION image muscle have also made it easier to assess muscle structure in a noninvasive fashion. This manuscript provides an The past decade has seen a tremendous expansion in medi- update on myopathic diseases, including hereditary and spo- cine’s understanding of muscle diseases, both hereditary and radic diseases, and emphasizes clinical pearls and latest dis- sporadic. The field of myology has benefited probably more coveries. than any other area of medicine from the enormous increase in the understanding of molecular genetics. Along with this, there have also been vast improvements in enzyme histo- HEREDITARY MUSCLE DISEASES chemistry and electron microscopy (EM), allowing for better definition of structural abnormalities. This has led to the dis- Dystrophinopathies covery of “new diseases,” which are based primarily on better pathophysiological descriptions of old diseases, rather than Duchenne Muscular Dystrophy truly new disorders. Newly named disorders generally reflect the abnormal pathophysiology. Examples include: central Duchenne muscular dystrophy (DMD) is an X-linked disor- and multiminicore diseases, nemaline myopathy, and der caused by an abnormality at the Xp21 gene loci.52,84 The myotubular myopathy. The congenital myopathies can now gene for DMD and Becker muscular dystrophy (BMD) be identified by their abnormal aggregation of proteins, giv- occupies 2.5 million base pairs of DNA on the X-chromo- ing rise to the concept of “protein aggregate myopathies.” some and is approximately 10 times larger than the next largest gene identified to date.2 The gene contains 79 exons Limb girdle, which now includes desminopathies, alpha-B of coding sequence.52,98 Its primary protein product is called crystallinopathies, selenoproteinopathy, myotilinopathy, dystrophin, which is found in the plasma membrane of all actinopathies, and myosinopathies, has expanded from a myogenic cells, certain types of neurons and in small group of 5 myopathies to a group over over 10, and it is still amounts in other cell types.39,74,78,104 Duchenne muscular growing. The recent identification of mutations in respective dystrophy and BMD are thus referred to as dys- genes to the recognition of certain accrued proteins within trophinopathies. Dystrophin-deficiency at the plasma mem- muscle fibers, and the subsequent analysis of their respective brane of muscle fibers disrupts the membrane cytoskeleton genes has resulted in a wealth of genetic data and in reconsid- and leads to the secondary loss of other components of the ering classification and nosologic interpretation of certain muscle cytoskeleton.16,18,25,37,113 The primary consequence of congenital myopathies. Newer and better techniques to the cytoskeleton abnormalities is membrane instability, leading 38 Hereditary and New Myopathies AANEM Course to membrane injury from mechanical stresses, transient The earliest weakness is seen in the neck flexors during pre- breaches of the membrane, and membrane leakage.68,77 school years. Early in the disease course weakness is general- Chronic dystrophic myopathy is characterized by aggressive ized, but predominantly proximal. Pelvic girdle weakness pre- fibrotic replacement of the muscle and eventual failure of dates shoulder girdle weakness by several years. Ankle dorsi- regeneration with muscle fiber death and fiber loss. flexors are weaker than ankle plantar flexors, ankle everters are weaker than ankle inverters, knee extensors are weaker The incidence of DMD has been estimated to be around than knee flexors, hip extensors are weaker than hip flexors, 1:3500 male births.29 Approximately one-third of isolated and hip abductors are weaker than hip adductors.4,5 cases are due to new mutations, which is considerably higher than observed in other X-linked conditions. This high muta- The weakness progresses steadily, but the rate can be variable tion rate might be due to the large size of the gene. during the disease course. Quantitative strength testing shows greater than 40-50% loss of strength by 6 years of While the history of hypotonia and delayed motor milestones age.50,67,99,105 With manual muscle testing, DMD subjects are often reported in retrospect, the parents are often unaware exhibit loss of strength in a fairly linear fashion from ages 5- of any abnormality until the child starts walking. There has 13 and measurements obtained several years apart will show been variability reported in the age of onset of DMD. In 74- fairly steady disease progression. However, a variable course is 80% of instances, the onset is noted before the age of 4 often noted when analyzing individuals over a shorter period years.71 The vast majority of cases are identified by 5-6 years of time.105,116 Investigators have shown a flattening in the of age. The most frequent presenting symptoms are abnormal rate of strength loss curve at approximately ages 14-15.67,105 gait, frequent falls, and difficulty climbing stairs. Difficulty Thus, investigators performing studies involving the natural negotiating stairs is an early feature as is a tendency to fall due history of DMD should be cautious about including subjects to the child tripping or stumbling on a plantar-flexed ankle transitioning to the teenage years because of the flattening of or the knee buckling or giving way due to knee extensor the manual muscle testing strength curve with increasing weakness. There is progressive difficulty getting up from the age.67 This caution is particularly important in studies of floor with presence of a Gowers’ sign. Parents frequently note potential therapeutic agents. Quantitative strength measures the toe walking, which is a compensatory adaptation to knee have been shown to be more sensitive for demonstrating extensor weakness. They also note a lordotic posture of the strength loss than manual muscle testing when strength is lumbar spine, which is a compensatory change due to hip grades 4-5.67 extensor weakness. The average age of wheelchair use in an untreated DMD Duchenne muscular dystrophy is occasionally identified pre- population is 10 years, with a range of 7-13 years.14,15,67 symptomatically in situations where a creatine kinase (CK) Timed motor performance is a useful predictor of time when value is obtained with a markedly elevated value or when ambulation will be lost without provision of long-leg braces. malignant hyperthermia occurs during general anesthesia for One large natural history study showed that all DMD sub- an unrelated surgical indication. Early identification also jects who took 9 seconds or longer to ambulate 30 feet lost occurs when the diagnosis is pursued in a male with an affect- ambulation within 2 years.67 All DMD subjects who took 12 ed older sibling. seconds or longer to ambulate 30 feet lost ambulation within 1 year.67 Ambulation past the age of 14 should raise the Pain in the muscles, especially the calves, is a common symp- suspicion of a milder form of muscular dystrophy (MD) such tom. Enlargement of muscles, particularly the calves, is com- as BMD or limb girdle muscular dystrophy (LGMD). monly seen. Recently, children aged 8-11 years with DMD Ambulation beyond 16 years was previously used as exclu- have been noted to exhibit an unusual clinical examination sionary criteria for DMD.13 Immobilization for any reason sign that results from selective hypertrophy and wasting in can lead to a marked and often precipitous decline in muscle different muscles in the same region.90 When viewing these power and ambulatory ability. A fall with resultant fracture patients from behind with their arms abducted to 90° and leading to immobilization and loss of ambulatory ability is elbows flexed to 90°, DMD patients demonstrate a linear or not an uncommon occurrence. oval depression (due to wasting) of the posterior axillary fold with hypertrophied or preserved muscles on its two borders Significant joint contractures have been found in nearly all (i.e., infraspinatus inferomedially and deltoid superolaterally) DMD children older than age 13.67,120,121 The most common as if there were a valley between the two mounts. contractures include ankle plantar flexion and inversion, knee flexion, hip flexion, iliotibial band, elbow flexion, and The tongue is also frequently enlarged. An associated wide- wrist flexion contractures.67 Shortening of two joint muscles arch to the mandible and maxilla with separation of the teeth occurs particularly in the iliotibial band and gastrocnemius.67 is frequently seen, presumably secondary to the macroglossia. Significant contractures have been shown to be rare in DMD AANEM Course Current Concepts in Muscle Disease 39 before age 9 for all joints. There is no association between and early pulmonary function measurements.85 Those with- muscle imbalance around a specific joint (defined as grade 1 out significant kyphosis or hyperlordosis and a peak absolute or greater difference in flexor and extensor strength) and the forced vital capacity (FVC) greater than 2000 mL tend not to frequency or severity of contractures involving the hip, knee, show severe progressive scoliosis. ankle, wrist, and elbow in DMD.67 No cause-and-effect relationship has been established The presence of lower extremity contractures in DMD has between the onset of wheelchair reliance and occurrence of been shown to be strongly related to onset of wheelchair scoliosis.41,67 Wheelchair reliance and scoliosis are both an reliance.67,107 Lower extremity contractures were rare while age-related phenomenon. The causal relationship between DMD subjects were still upright, but developed soon after loss of ambulatory status and scoliosis is doubtful, given the they began using a wheelchair for most of the day. The occur- substantial time interval between the two variables in most rence of elbow flexion contractures also appears to be direct- subjects (scoliosis usually develops after 3-4 years in a wheel- ly related to prolonged static positioning of the limb, and chair). Both wheelchair reliance and spinal deformity can be these contractures develop soon after wheelchair reliance as significantly related to other factors (e.g., age, adolescent well. There is a relationship between wheelchair reliance and growth spurt, increase in weakness of trunk musculature, and hip and knee flexion contractures.106 Mild contractures of the other unidentified factors) and appear to represent coinci- iliotibial bands, hip flexor muscles, and heel cords occur in dental signs of disease progression. most DMD patients by 6 years of age.45 Limitations of knee, elbow, and wrist extension occurs about 2 years later, howev- Absolute FVC volumes increase in patients with DMD dur- er, these early observed contractures were relatively mild.45 ing the first decade and plateau during the early part of the Given the tremendous replacement of muscle by fibrotic tis- second decade.40,67 A linear decline in percent predicted FVC sue in DMD subjects, it is not surprising that a muscle of less is apparent between 10-20 years of age in DMD.67 Rideau than antigravity extension strength, statically positioned in reported that the FVC was predictive of the risk of rapid sco- flexion in a wheelchair, would develop a flexion contracture. liosis progression.95 In the most severe DMD cases, maximal The lack of lower extremity weight bearing likely contributes FVC reached a plateau of less than 1200 mL. This was asso- to the rapid acceleration in the severity of these contractures ciated with the loss of ability to walk before age 10 and severe after transition to wheelchair. Ankle plantar flexion contrac- progressive scoliosis. Maximum FVCs plateau between 1200 tures are likely not a significant cause of wheelchair reliance, mL and 1700 mL. Spinal deformity was present consistently as few subjects exhibit plantar flexion contractures of 15 in these cases but varied in intensity. The least severe DMD before their transition to a wheelchair.67 Natural history data cases reached plateaus in FVC of greater than 1700 ml. suggest that weakness is the major cause of loss of ambulation Similarly, McDonald and colleagues also found that those in DMD, rather than contracture formation.19,67 patients with higher peak FVC (> 2500 mL) had a milder disease progression, losing 4% predicted FVC per year.67 The The reported prevalence of scoliosis in DMD varies from 33- peak predicted FVC less than 1700 mL lost 9.6% predicted 100%.60,61,67,94 This marked variability is primarily because FVC per year.67 The peak obtained absolute values of FVC of retrospective selection for scoliosis, the inclusion or exclu- that usually occur early in the second decade is an important sion of functional curves, and dissimilar age groups. The prognostic indicator for severity of spinal deformity, as well prevalence of scoliosis is strongly related to age. Fifty percent as of the severity of restrictive pulmonary compromise due to of DMD patients acquire scoliosis between ages 12-15, cor- muscular weakness. responding to the adolescent growth spurt. At least 90% of older DMD subjects with no specific treatment for scoliosis Reduced maximal static airway pressures (both maximal have clinical spinal deformity. This is consistent with Oda’s inspiratory pressure and maximal expiratory pressure) are the report that 15% of older DMD patients show mild nonpro- earliest indicators of restrictive pulmonary compromise in gressive curves (usually 10-30o).85 The rate of progression of DMD.3,10 Impaired values are usually noted between 5-10 the primary or single untreated lateral curve is reported to years of age. Vital capacity typically increases concomitant range from 11o to 42o per year, depending on the age span with growth between 5-10 years of age with the percent of studied. Johnson and Yarnell reported an association between predicted FVC remaining relatively stable and close to 100% the side of curvature, convexity, and hand dominance.47 predicted. Duchenne muscular dystrophy patients typically McDonald’s study, on the other hand, showed no correlation show a linear decline in percent predicted FVC between 10- between side of primary convexity and handedness.67 Oda 20 years of age. An FVC falling below 40% of predicted can and colleagues reported that the likelihood of severe progres- contraindicate surgical spinal arthrodesis, irrespective of scoli- sive spinal deformity could be predicted by the type of curve otic severity, because of increased perioperative morbidity.43,94 40 Hereditary and New Myopathies AANEM Course

Patients who need surgical intervention for scoliosis or other sudden death.111 Yanagisawa and colleagues reported an age- deformities should have surgery before the vital capacity related increase in the prevalence of cardiac arrhythmias drops below 40% of predicted.94 detected by ambulatory 24-hour ECG recordings.127 They also noted an association between ventricular arrhythmias Respiratory failure in DMD is insidious in its onset and and sudden death in DMD. Clinically evident cardiomyopa- results from a number of factors, including: (1) respiratory thy is usually first noted after age 10 and is apparent in near- muscle weakness and fatigue; (2) alteration in respiratory sys- ly all patients over age 18.81 Development of cardiomyopathy tem mechanics; and (3) impairment of the central control of is a predictor of poor prognosis.67 Echocardiography has been respiration. Noninvasive forms of both positive and negative used extensively to follow the development of cardiomyopa- pressure ventilatory support are increasingly being offered to thy and predict prognosis in patients with DMD. The onset DMD patients. of systolic dysfunction noted by echocardiography is associated with a poor prognosis.67 The myocardial impairment The dystrophin protein is present in both the myocardium remains clinically silent until late in the course of the disease, and the cardiac Purkinje fibers.1,81 Abnormalities of the heart possibly caused by the absence of exertional dyspnea, second- may be detected by clinical examination, electrocardiogram ary to lack of physical activity. Death has been attributed to (ECG), echocardiography, and Holter monitoring. Cardiac congestive heart failure in as many as 40-50% of patients examination is notable for the point of maximal impulse pal- with DMD by some investigators.67,81 Regular cardiac evalu- pable at the left sternal border due to the marked reduction ations with an ECG, echocardiography, and Holter monitor in anteroposterior chest dimension common in DMD. A should be employed in teenagers with preclinical cardiomy- loud pulmonic component of the second heart sound sug- opathy. gests pulmonary hypertension in patients with restrictive pulmonary compromise. Nearly all patients over the age of 13 The dystrophin isoform is present in the brain.84,86,109 The demonstrate abnormalities of the ECG.22,36,67 Q-waves in the role of dystrophin in the central nervous system (CNS) is not lateral leads are the first abnormalities to appear, followed by known but it has been theorized to play a role in neuronal elevated ST-segments and poor R-wave progression, metabolic transport across the cell membrane.38 Previous increased R/S ratio, and resting tachycardia and conduction studies on intellectual function on children with DMD have defects. Electrocardiogram abnormalities have been demon- generally revealed decreased intelligence quotient (IQ) scores strated to be predictive for death from the cardiomyopathy when these children are compared with both control and with the major determinants including: R-wave in lead V1 normative groups.67,109 A mean score for the DMD popula- less than 0.6 mV; R-wave in lead V5 less than 1.1 mV; R- tion of 1.0-1.5 standard deviations (SD) below population wave in lead V6 less than 1.0 mV; abnormal T-waves in leads norms has been reported. There has generally been a consid- II, III, AVF, V5, and V6; cardiac conduction disturbances; erable consistency in the degree of impairment across meas- premature ventricular contraction; and sinus tachycar- ures reflecting a rather mild global deficit. Some studies have dia.58,59,89 Sinus tachycardia can be due to low stroke volume demonstrated relative deficits in verbal IQ.109 In a longitudi- from the progressive cardiomyopathy, or in some cases can be nal assessment of cognitive function, McDonald and col- sudden in onset and labile, suggesting an autonomic distur- leagues found IQ measure in DMD to be stable over time.67 bance or direct involvement of the sinus node by the dys- On neuropsychological testing, a large proportion of DMD trophic process.73 subjects fell within the “mildly impaired” or “impaired” range according to normative data.67 These findings likely reflect a Autopsy studies and thallium-201 single proton emission mild global deficit rather than focal nervous system impair- computed tomography imaging show left ventricular lateral ment. and posterior wall defects that might explain the lateral Q- waves and the increased R/S ratio in V1 seen on ECG.76,80,126 Substantial anthropometric alterations have been described Localized posterior wall fibrosis is peculiar to DMD and is in DMD. Short stature and slow linear growth with onset not seen in other types of MD. Pulmonary hypertension shortly after birth have been reported.28,70,92 Accurate meas- leading to right ventricular enlargement is also known to urement of linear height is extremely difficult in this popula- cause prominent R-waves in V1 and has been demonstrated tion. Arm span measurements can be used as an alternative in patients with DMD.129 measure of linear growth; but this measurement can be difficult as elbow flexion contractures of greater than 30o are fre- Ventricular ectopy is a known complication of the cardiomy- quently present in patients older than age 13. Forearm seg- opathy in DMD which likely explains the observed cases of ment length has been proposed as an alternative linear meas- AANEM Course Current Concepts in Muscle Disease 41 urement in DMD patients with proximal upper extremity point mutations that cannot be detected by these methods. contractures and radius length can be followed for those with Since the gene is so large and complex, it is currently not fea- wrist and finger contractures.92 sible to routinely test for the other types of smaller mutations. Approximately 55% of DMD patients and 70% of Obesity is a substantial problem in DMD, subsequent to the BMD patients show deletion mutations of the gene on cur- loss of independent ambulation.20,27,108 Weight control dur- rently available tests.21 A positive DNA test result (presence ing early adolescence facilitates ease of care, in particular ease of a deletion) is diagnostic of a dystrophinopathy (DMD or of transfers during later adolescence. BMD). There are no false-positives if the test is performed appropriately.21 Longitudinal weight measurements in DMD confirm significant rates of weight loss in subjects ages 17-21.27,64 This is Differential diagnosis between DMD and BMD is best per- likely caused by relative nutritional compromise during the formed by family history of clinical phenotype. If the patient later stages when boys with DMD have higher protein and is still ambulating at 16-20 years of age and has a deletion energy intake requirements because of hypercatabolic protein mutation, then the correct diagnosis is BMD. Some labora- metabolism.37 Protein and calorie requirements can often be tories will report “the reading frame.” This information can 160% that predicted for able-bodied populations during the differentiate between a DMD and BMD diagnosis in approx- later stages of DMD.112 Restrictive lung disease becomes imately 90% of deletion-positive cases.65,66 Mutations at the more problematic during this time, and this can also influ- Xp21 locus, which maintain the translational reading frame ence caloric intake and requirements. Self-feeding often (in-frame mutations), result in an abnormal but partially dys- becomes impossible during this period because of biceps functional dystrophin, whereas in DMD the mutations shift weakness. Some subjects with DMD also develop signs and the reading frame (out-of-frame mutations) so that virtually symptoms of upper gastrointestinal dysfunction.8,43 no dystrophin is produced.21 The reading frame interpretation is most accurate for deletions in the center of the gene Becker Muscular Dystrophy (exons 40-60) and is least accurate for deletions in the beginning of the gene (exons 1-20). Becker muscular dystrophy is a form of MD with a similar pattern of muscle weakness seen in DMD. It also has X- Absent dystrophin or levels less than 3% of normal generally linked inheritance, but with later onset and a much slower are considered diagnostic of DMD, however, 5% of such rate of progression than DMD. It was first described by patients have BMD phenotypes. The dystrophin in BMD Becker and Kiener in 1955.6,96 The disorder has the same typically has an abnormally small molecular weight (<427 gene location as the DMD gene (Xp21) and is allelic. Using kDa). A minority of patients have dystrophin of larger than immunoblotting or immunostaining of muscle biopsy speci- normal molecular weight (>427 kDa), or normal molecular mens, the presence of altered molecular weight or decreased weight. Most BMD patients with larger or smaller molecular abundance of dystrophin suggests a BMD phenotype.2 Some weight dystrophin also have decreased quantities of the pro- subjects have 20-80% dystrophin levels of the normal quan- tein.65,66 All BMD patients with normal molecular weight tity of dystrophin while other subjects may have reduced or dystrophin have decreased quantities, usually less than 30% increased molecular weight dystrophin.2 Becker muscular normal. Smaller size dystrophin typically is caused by dele- dystrophy has a lower incidence than DMD, with prevalence tion mutations, and larger size dystrophin by duplication rates for BMD ranging from 12-27 per million and a recent mutations. A further refinement is the use of antibodies spe- estimated overall prevalence of 24 per million.30,32,66 cific to the carboxy-terminal (C-terminal) region of dystrophin. Using such antibodies, immuno-histochemistry The demonstration of a deletion in the Xp21 gene with reveals that the C-terminal region is almost always absent in c deoxyribonucleic acid (DNA) probes is useful in the diag- DMD but invariably present in BMD.2 nostic evaluation of dystrophin deficient myopathies.21 In the gene deletion test, small blood samples are used as a source of Studies have shown significant overlap in the observed age of patient DNA, and the dystrophin (DMD, BMD) gene is onset between DMD and BMD.66 Determination of the tested to determine whether it is intact or not. This is per- quantity and molecular weight of dystrophin has substantial- formed by polymerase chain reaction (PCR) or Southern ly improved the early differentiation among BMD, “outlier” blotting, and the methods determine whether all segments of DMD, and the more common and rapidly progressive DMD the gene are present. If any segment is missing, the findings phenotype. However, Bushby and colleagues found no clear indicate the presence of a “deletion mutation.” Not all DMD correlation between abundance of dystrophin and clinical and BMD patients have deletion mutations. Many have course within the BMD group.13 42 Hereditary and New Myopathies AANEM Course

The series of Bushby and Gardner-Medwin included 67 Spinal deformity is not nearly as common or severe in BMD BMD subjects and supported the presence of two major pat- as it is in DMD. Spinal instrumentation is rarely required by terns of progression in BMD—a “typical” slowly progressive BMD patients.66 course and a more “severe” and rapidly progressive course.12 All of the “severe” BMD cases showed difficulty climbing Compromised pulmonary function is also much less prob- stairs by age 20, whereas none of the “typical” BMD cases lematic in BMD.7,66 The percent predicted FVC does not had difficulty climbing stairs before age 20. Abnormal ECGs appear substantially reduced until the third to fourth were seen in 27% of typical BMD subjects and 88% of sub- decade.66 The percent predicted maximal expiratory pressure jects with more severe phenotype. Bushby and Gardner- appears relatively more reduced at younger ages than the per- Medwin found BMD subjects to have a mean age of onset of cent predicted maximal inspiratory pressure, a finding seen in 12 years in the typical group and 7.7 years in the severe DMD and other neuromuscular diseases.7 This might be due group.12 Some patients with BMD present with major mus- to more relative involvement of the intercostals and abdomi- cle cramps as an isolated symptom.9 nal musculature, with relative sparing of contractile function in the diaphragm of BMD. Predicted maximal expiratory The most useful clinical criterion to distinguish BMD from pressure can be a useful quantitative measure of impairment DMD is the continued ability of the patient to walk into late and perhaps disease progression early in the course of BMD. teenage years. Those with BMD will typically remain ambulatory beyond 16 years. Some patients become wheelchair The pattern of occasional life-threatening cardiac involve- reliant in their late teens or 20s, whereas others continue ment in otherwise mild and slowly progressive BMD has walking into their 40s and 50s, or later. Outlier DMD cases been reported.82,100,128 A significant percentage of BMD cases generally stop ambulating between 13-16 years of age.66,67 develop cardiac abnormalities. The rate of progression of cardiac failure can be more rapid than the progression of skele- As in DMD, preclinical cases are often identified by the find- tal myopathy.111,128 In fact, successful cardiac transplantation ing of a grossly elevated CK value. There is also considerable has been increasingly reported in BMD subjects with cardiac overlap in CK values between DMD and BMD cases at the failure.21,26 Approximately 75% of BMD patients have been time of presentation, and CK values cannot be used to differ- found to exhibit ECG abnormalities.66 The abnormal find- entiate DMD from BMD. ings most commonly reported include abnormal Q-waves, right ventricular hypertrophy, left ventricular hypertrophy, Patients with BMD have a distribution of weakness that is right bundle branch block, and nonspecific T-wave abnor- similar to those with DMD.66 Proximal lower limb muscles malities. Unlike DMD, resting sinus tachycardia has not are involved earlier in the disease course. Gradual involve- been a frequent finding. Echocardiography has shown left ment of the pectoral girdle and upper limb musculature ventricular dilation in 37%, whereas 63% have subnormal occurs 10-20 years from onset of disease. Extensors have been systolic function because of global hypokinesia.23,48 The car- noted to be weaker than flexors.66 The muscle groups, which diac compromise can be disproportionately severe, relative to are the most severely involved early in the course of disease the degree of restrictive lung disease in some BMD subjects. includes the hip extensors, knee extensors, and neck flexors.66 The evidence for significant myocardial involvement in BMD is sufficient to warrant screening of all of these patients Calf enlargement is a nonspecific finding in BMD, as is the at regular intervals using ECG and echocardiography. The presence of a Gowers’ sign. Over time, the gait becomes sim- slowly progressive nature of this dystrophic myopathy, which ilar to other neuromuscular disease conditions with proximal is compatible with many years of functional mobility and weakness. Patients often ambulate with a lumbar lordosis, longevity, makes these patients suitable candidates for cardiac forefoot floor contact, decreased stance phase knee flexion, transplantation if end-stage cardiac failure occurs.91 and a modified Trendelenburg or gluteus medius lurch, often described as a waddle. Some cases with BMD present with an isolated cardiomyopathy with no clinical manifestation of skeletal muscle involve- Early development of contractures does not appear to be a ment.55 The diagnosis can be established by demonstration of feature of BMD.45,66 As with DMD, nonambulatory BMD a deletion in the Xp21 gene or by muscle biopsy. Isolated subjects may develop equinus contractures, knee flexion con- cases of cardiomyopathy in children, particularly those with tractures and hip flexion contractures. Subjects with BMD family histories indicative of X-linked inheritance, should be are more likely to develop flexion contractures subsequent to screened for BMD with an initial serum CK estimation and wheelchair reliance. molecular genetic studies of the Xp21 gene. AANEM Course Current Concepts in Muscle Disease 43

Cognitive testing in BMD subjects has shown large variabil- Myotonia is a state of delayed relaxation or sustained contrac- ity in IQ scores and neuropsychological test measures. Mildly tion of skeletal muscle that is easily identified in children reduced intellectual performance has been noted in a subset with MMD. Grip myotonia can be demonstrated by delayed of BMD patients, however, the degree of impairment is not opening of the hand with difficulty extending the fingers fol- as severe as noted in DMD.66 lowing tight grip. Percussion myotonia can be elicited by striking the thenar eminence with a reflex hammer, produc- Other atypical clinical presentations include a complaint of ing adduction and flexion of the thumb with slow return. cramps on exercise in individuals with no muscle weakness.32 Needle electromyography (EMG) shows myotonic dis- Patients with focal wasting of the quadriceps who have previ- charges, which are spontaneous waxing and waning spikes ously been diagnosed with quadriceps myopathy have recent- that produce a characteristic “dive bomber” sound.53 ly been diagnosed with BMD. This is based on molecular genetic testing and/or dystrophin analysis on muscle biop- Myotonic muscular dystrophy is one of the few dystrophic sy.66 myopathies with greater distal weakness than proximal weakness.62 Although neck flexors, shoulder girdle musculature, Myotonic Disorders and pelvic girdle musculature can become significantly involved over decades, the weakness is initially most predom- Myotonic Muscular Dystrophy inant in the ankle dorsiflexors, ankle everters and inverters, and hand muscles.44 Significant muscle wasting can occur Myotonic muscular dystrophy (MMD) is an autosomal dom- over time. In MMD patients with infantile onset, a congeni- inant multisystem MD with an incidence of 1 per 8000.29,44 tal clubfoot or talipes equinovarus frequently occurs. In adult The disorder affects skeletal muscle, smooth muscle, onset MMD, contractures at the wrist, ankle, and elbows are myocardium, brain, and ocular structures. Associated find- relatively uncommon and mild.44,45 Patients with congenital ings include frontal pattern baldness and gonadal atrophy (in onset MMD may develop spinal deformity requiring surgical males), cataracts, and cardiac dysrhythmias. Insulin insensi- spinal arthrodesis.41 tivity can be present. The gene has been localized to the region of the DM protein kinase gene at 19q13.3.42,93 Patients Abnormalities on ECG and echocardiography are demon- demonstrate expansion of an unstable cytosine thymine gua- strated in approximately 70-75% of patients with nine trinucleotide repeat within the region. Normal individ- MMD.44,59,75 Prolongation of the pulse rate-interval, abnor- uals generally have less than 37 repeats that are transmitted mal axis, and infranodal conduction abnormalities are all from generation to generation. Myotonic muscular dystro- suggestive of conduction system disease which might explain phy patients may have 50 to several thousand CTG repeats the occurrence of sudden death which occurs in less than 5% with remarkable instability. The age of onset is inversely cor- of MMD patients.59 Ventricular tachycardia can also con- related by the repeat links.42 Mild, late onset MMD usually tribute to the syncope and sudden death associated with is associated with 50-150 repeats, classic adolescent or young MMD. Some patients have required implantation of cardiac adult onset MMD shows 100-1000 repeats and congenital pacemakers. Q-waves have been reported on screening ECGs MMD patients show greater than 1000 repeats.21,42,93 The in MMD patients and this abnormality might reflect expanded CTG repeat further expands as it is transmitted to myocardial fibrosis.44,59 Any MMD patient with dyspnea, successive generations, providing a molecular basis for chest pain, syncope, or other cardiac symptoms should “genetic anticipation.” Both maternal-to-child and paternal- receive thorough cardiac evaluation. to-child transmission occurs. However, it can be more severe if transmitted from the mother with repeat size in offspring Subjects with MMD have a very high incidence of restrictive exceeding 1000 CTG repeats or more. Affected fathers sel- lung disease.44,117 Involvement of respiratory muscles is a dom transmit alleles larger than 1000 copies to offspring due major cause of respiratory distress and mortality in affected to a lack of sperm containing such alleles, presumably due to infants with MMD. Swallowing difficulties that produce the poor motility of sperm containing alleles of that size, aspiration of material into the trachea and bronchial tree, although this has not been proven. along with weakened respiratory muscles and a weak cough have been reported as factors that may result in pulmonary Several characteristic facial features of MMD may be seen on complications in MMD patients. Care should be taken dur- inspection. The adult with long-standing MMD often has ing general anesthesia in MMD due to risk of cardiac characteristic facial features. The long thin face with tempo- arrhythmias and malignant hyperthermia. ral and masseter wasting is drawn and has been described by some as lugubrious or “hatchet face.” Adults of both sexes Constipation is a fairly common complaint in congenital often exhibit frontal balding. MMD, owing to smooth muscle involvement. Myotonic 44 Hereditary and New Myopathies AANEM Course muscular dystrophy patients should also be screened for dia- involvement of hands and muscles of the face. Myotonic betes mellitus as there is an increased incidence of insulin episodes usually subside within a matter of hours but are sig- insensitivity. nificantly aggravated by cold temperatures. This is usually not a severe disease and these patients have a good overall Those with congenital MMD usually show significantly prognosis and normal life expectancy.21,65 reduced IQ, often in the mentally retarded range.44 In adult onset MMD, there is evidence for a generally lower intelli- Schwartz-Jampel Syndrome gence of a mild degree (full-scale IQs have been reported to be in the 86-92 range).44 However, there is a wide range of Schwartz-Jampel syndrome is an autosomal recessive disorder IQ values found in this population with many subjects scor- with myotonia, dwarfism, diffuse bone disease, narrow palpe- ing in the above-average range. Cognitive functioning also bral fissures, blepharospasm, micrognathia, and flattened appears to be directly related to the size of the CTG expan- faces.56,110 Limitation of joint movement can be present sion at the MMD gene locus. along with skeletal abnormalities, including short neck and kyphosis. Muscles are typically hypertrophic and clinically There is a newly discovered form of MMD, known as type II stiff. The symptoms are not progressive and the overall prog- MMD (MMD2 or DM2). It has also been referred to as nosis is good. proximal myotonic myopathy.41,91 MMD2 is now known to be caused by a mutation on chromosome 3 and is thought to Electrodiagnostic studies show continuous electrical activity be clinically less severe than either typical MMD or congen- with electrical silence being difficult to obtain. There is rela- ital MMD, and may be associated with insulin insensitivity, tively little waxing and waning in either amplitude or fre- diabetes, and low testosterone levels in males. quency of complex repetitive discharges. Abnormal sodium channel kinetics in the sarcolemma of muscle has been Myotonia Congenita demonstrated.56 Some therapeutic benefit has been reported with procainamide HCL and carbamezapine.110 Myotonia congenita (MC) (Thomsen’s disease) is inherited as an autosomal dominant condition. It is a condition in which Limb Girdle Muscular Dystrophies the patient has myotonia but not weakness. Symptoms may be present from birth, but usually develop later. The myoto- Advances in molecular biology have shown that LGMD is a nia can manifest as difficulty in releasing objects or difficulty heterogeneous group of dystrophic myopathies, usually with walking or climbing stairs. Prolonged rest or inactivity exac- a childhood or adolescent onset (although there are late onset erbates the myotonia. Myotonia may be aggravated by cold. forms), no sex linkage, and a distribution and pattern of Patients may demonstrate grip myotonia or lid lag following weakness similar to DMD but with a much slower rate of upward gaze or squint, and diplopia following sustained con- progression.69 There are at least 15 different subtypes of jugate movement of the eyes in one direction. The other LGMD, most of which have been linked to abnormalities of common feature of MC is muscle hypertrophy. Patients can the dystrophin-associated glycoproteins (DAG), especially have a “Herculean” appearance.34,65 alpha sarcoglycan (adhalin), a 50kD DAG and gamma sarcoglycan.63 The 50 DAG protein has been linked to the 17q12- A recessive form of MC (Becker form) also exists with later q21.33 locus and children with this have been referred to as onset, more marked myotonia, more striking hypertrophy of severe, childhood-onset, autosomal recessive muscular dys- muscles and associated weakness of muscles. The dominant trophy (SCARMD), which is also classified as LGMD form seems more prone to aggravation of the myotonia by 2D.63,88 Other families with SCARMD have been linked to cold.65 chromosome 13q12 and individuals with LGMD 2C may show a primary deficiency of gamma sarcoglycan and a sec- The diagnosis is essentially made clinically with confirmation ondary deficiency of alpha sarcoglycan.61 Limb girdle muscu- of classical myotonic discharges on electrodiagnostic exami- lar dystrophy 2E patients (chromosome 4q12) show a pri- nation. Muscle biopsy is essentially normal, apart from mary deficiency in beta sarcoglycan and LGMD 2F patients hypertrophy of fibers and an absence of type II-B fibers.32,35 (chromosome 5q33-q34) show a primary deficiency of delta sarcoglycan.33,61 Most of the primary sarcoglycan abnormali- Paramyotonia Congenita ties lead to secondary deficiencies of alpha sarcoglycan. All the DAGs are reduced in DMD patients because the C-ter- Paramyotonia congenita (PC) is an autosomal dominant minal portion of dystrophin binds to the dystrophin-associ- myotonic condition characterized by generalized hypertro- ated proteins and maintains their integrity.2,97 A less severe phy, mild involvement of proximal muscles, and more severe autosomal recessive dystrophic myopathy (LGMD 2A) has AANEM Course Current Concepts in Muscle Disease 45 been linked to chromosome 15q1-q21.1, the gene for the of left ventricular hypertrophy, increased R/S ratio in V1, and protein Calpain III.21,118 Diagnosis of SCARMD or LGMD abnormal Q-waves. Intellectual function in SCARMD has subtypes is confirmed by muscle biopsy.59 generally been found to be normal.69

Dystrophin analysis is generally normal in subjects with Facioscapulohumeral Muscular Dystrophy LGMD.21 Of the seven recessive loci identified to date, four are sarcoglycan genes.21,65 These four proteins make up the Facioscapulohumeral muscular dystrophy (FSHD) is a slow- sarcoglycan complex, which is believed to interact directly ly progressive dystrophic myopathy with predominant with the 43kD DAG and with dystrophin.21,86 Dystrophin- involvement of facial and shoulder girdle musculature. The associated glycoproteins probably provide connections condition is autosomal dominant with linkage to the chro- between the extracellular matrix (the protein merosin) and mosome 4q35 locus.118,119,124 Prevalence has been difficult to the intracellular membrane cytoskeleton (attached to dys- ascertain because of undiagnosed mild cases, but has been trophin).21,61,65,86 An abnormality of the dystrophin-glyco- estimated at 10-20 per million.29,51 protein complex, resulting from primary deficiencies of one or more of the dystrophin-associated glycoproteins results in Facial weakness is an important clinical feature of FSHD. a disruption in the linkage between the intracellular sar- The initial weakness affects the facial muscles, especially the colemmal cytoskeleton and the extracellular matrix. orbicularis oculi, zygomaticus, and orbicularis oris. These Disruption of the membrane cytoskeleton is common to the patients often have difficulty with eye closure, but not ptosis. pathophysiology of most MDs, the dystrophinopathies. Subjects with FSHD often have an expressionless appearance and exhibit difficulty whistling, pursing the lips, drinking Patients with SCARMD can exhibit calf hypertrophy and a through a straw, or smiling. Even in the early stages, forced Gowers’ sign. Loss of ambulation generally occurs between closure of the eyelids can be easily overcome by the examin- 10-20 years but occasionally after 20 years of age. In one er. Masseter, temporalis, extraocular, and pharyngeal muscles series, several differences between DMD and SCARMD were characteristically are spared in FSHD. noted.69 In contrast to DMD, the limb extensors were not weaker than limb flexors. In particular, ankle dorsiflexors Patients with FSHD show characteristic patterns of muscle were similar in strength to ankle plantar flexors, knee exten- atrophy and scapular displacement. Involvement of the latis- sors showed similar strength compared with knee flexors and simus dorsi, trapezius, rhomboids, and serratus anterior hip extensors and hip flexors showed similar strength values. results in a characteristic appearance of the shoulders, with The severity and rate of progression often varies between and the scapula positioned more laterally and superiorly, giving within the families of SCARMD patients. Contractures the shoulders a forward-sloped appearance. The upper border appear to be much less prevalent and severe in SCARMD of the scapula rises into the trapezius, falsely giving it a hyper- compared with DMD. The prevalence of joint contractures trophied appearance. From the posterior view, the medial in SCARMD subjects was found to be similar to that border of the scapula may exhibit profound posterior and lat- observed in BMD subjects in one series.45 eral winging. The involvement of shoulder girdle musculature in FSHD can be quite asymmetric. Spinal deformity appears to be less problematic in SCARMD than DMD. Less than 50% of SCARMD subjects were The typical onset is in adolescence or early adult life. Initially, found to have curves of mild-to-moderate severity, ranging patients show predominant involvement of facial and shoul- from 5-30°.67 The prevalence and severity of spinal deformi- der girdle musculature. Scapular stabilizers, shoulder abduc- ty in SCARMD appears to be similar to that observed in tors, and shoulder external rotators may be significantly BMD. affected, but at times the deltoids are surprisingly spared if tested with the scapulae stabilized. Both the biceps and tri- Restrictive pulmonary insufficiency occurs in SCARMD but ceps may be more affected than the deltoids. Over time, is not as severe as that seen in DMD. The prevalence of severe ankle dorsiflexion weakness often becomes significant in restrictive lung disease in SCARMD is similar to that addition to pelvic girdle weakness. Late in the disease course, observed in BMD.7,69 patients can show marked wrist extension weakness. Some authors have found asymmetric weakness in the dominant Few studies have systematically evaluated the cardiac mani- upper extremity.46,51 festations of SCARMD and other limb girdle dystrophies. In one series, the prevalence of abnormal ECG findings in A sensory neural hearing deficit was originally observed in SCARMD was 62%.69 Electrocardiogram abnormalities Coates syndrome (early onset FSHD). These individuals include evidence of infranodal conduction defects, evidence have a myopathy that presents in infancy. The disease pro- 46 Hereditary and New Myopathies AANEM Course gression is fairly rapid with most individuals becoming associated intellectual involvement in this dystrophic myopa- wheelchair reliant by the late second or third decade.87 These thy. individuals also have a progressive exudative telangiectasia of the retina. Early recognition and photocoagulation of the Changes seen with muscle biopsy are relatively slight, with abnormal retinal vessels can often prevent loss of vision. the most consistent finding being the presence of isolated Several audiometry studies have demonstrated hearing small atrophic fibers. Other fibers may be hypertrophied. deficits in many late onset FSHD patients in addition to Serum CK levels are normal in the majority of patients. those with Coates syndrome, suggesting that impaired hear- Molecular genetic testing for the FSHD gene is now available ing function is more common than expected in FSHD.72,119 for diagnostic confirmation. All patients with FSHD should have screening audiometry and ophthalmologic evaluation. Emery-Dreifuss Muscular Dystrophy

Contractures are relatively uncommon in FSHD. In the most Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked comprehensive study to date, 22 subjects had range of recessive progressive dystrophic myopathy with a gene locus motion (ROM) testing of major upper and lower extremity identified at Xq28.30,31,122 The muscle protein that is defi- joints.51 Clinically significant loss of ROM (defined as a cient in EDMD has been termed as “Emerin.” The condition reduction in ROM greater than 20°) was present in two sub- usually presents in adolescence or early adult life, and many jects (9%) at the wrist and in one subject (5%) at the hip, clinical features can be seen in early childhood. Patients can knee, and ankle. This subject had been wheelchair-reliant for present with a selective scapulohumeral peroneal distribution 15 years at the time of ROM testing. Although active motion weakness with striking wasting of the biceps, accentuated by is severely restricted, subjects with FSHD typically maintain sparing of the deltoids and forearm muscles. However, this is full passive ROM. clinically differentiated from FSHD by the lack of facial involvement. Ankle dorsiflexors often are weaker than ankle Spinal deformity is common with 80% of FSHD subjects plantar flexors. Significant atrophy usually is present in the exhibiting hyperlordosis, alone or in combination with scol- upper arms and legs due to focal wasting of the calf muscles iosis. Rarely, severe and progressive hyperlordosis is associat- and biceps. ed with FSHD. The patient with severe hyperlordosis might utilize their lordotic posturing to compensate for hip exten- An associated cardiomyopathy usually presents with arrhyth- sor weakness. Scoliosis alone accounts for only 20% of spinal mia and may lead to sudden death in early adult life.30,123 The deformity in FSHD41 and patients with scoliosis typically cardiomyopathy can progress to four-chamber dilated car- have mild and nonprogressive curves. diomyopathy with complete heart block and ventricular arrhythmias.123 Atrial arrhythmia usually appears prior to Mild restrictive lung disease has been reported in nearly one- complete heart block. Reported features include first degree half of FSHD patients.7,17,51 Expiratory musculature appears heart block, followed by Wenckebach phenomenon and then to be more affected than inspiratory muscles in FSHD.17 A complete atrial ventricular dissociation and atrial fibrillation recent Dutch study identified 10 FSHD patients on noctur- or flutter with progressive slowing of the rate.123 Syncope or nal ventilatory support at home, representing approximately near-syncope commonly occurs later in the second decade or 1% of the Dutch FSHD population.125 Severe muscle dis- early in the third decade.123 Evidence of cardiac arrhythmia, ease, wheelchair dependency, and kyphoscoliosis appeared to sometimes only present at night, might be detected on 24- be risk factors for respiratory failure.125 hour Holter monitoring. The provision of a cardiac pacemak- er to the patient with arrhythmia may be life-saving and can The presence of cardiac abnormalities in FSHD is still debat- considerably improve life expectancy. ed. While diverse ECG abnormalities have been noted, one study showed no abnormalities on ECG, chest radiography, Some patients with EDMD may show evidence of nocturnal Holter monitoring, and echocardiography.23 Nuclear scan- hypoventilation as a result of restrictive expansion of the ning with thallium-201 has demonstrated diffuse defects chest in association with the rigid spine, and partly due to consistent with diffuse fibrosis.23 Abnormalities in systolic involvement of the diaphragm.30 time intervals on echocardiography and elevations in atrial natriuretic peptide are consistent with subclinical cardiomy- Creatine kinase can be moderately elevated, with a value opathy.23,51 Cardiac complications in FSHD are rare and between 2 and 5 times the upper limit of normal. Needle patients in general have normal longevity. There is usually no EMG usually shows a myopathic pattern. Muscle biopsy AANEM Course Current Concepts in Muscle Disease 47 shows a myopathic process with variation in fiber size, clus- dilatation in low density of the white matter. Walker- ters of atrophic fibers, mild proliferation of connective tissue, Warburg syndrome is described as CMD with mental retar- and some focal necrosis of fibers. dation and consistent CNS abnormalities on imaging (type II lissencephaly, abnormally thick cortex, decreased interdigita- A clinical hallmark of EDMD is the early presence of con- tions between white matter and cortex and cerebellar malfor- tractures of the elbow flexors with limitation of full elbow mation). Ocular abnormalities and cleft lip or palate may also extension. Heel cord tightness might be present early in the be present. disorder, concomitant with ankle dorsiflexion and toe walking. Unlike DMD, the toe walking in EDMD usually is sec- Cases with more pure CMD without CNS involvement have ondary to ankle dorsiflexion weakness and not a compensa- been identified. The main clinical features are muscle weak- tory strategy to stabilize the knee due to proximal limb weakness and hypotonia, congenital contractures, histological ness. Tightness of the cervical and lumbar spinal extensor changes of a dystrophic nature—often with extensive con- muscles, resulting in limitation of neck and trunk flexion, nective tissue or adipose proliferation—but no substantial with the inability to flex the chin to the sternum and to touch evidence of necrosis or regeneration, normal to moderately the toes, also has been reported in EDMD. elevated CK, normal intellect, and brain imaging which may be either normal or show changes in the white matter on CT A dominantly inherited disorder with a similar phenotype or MRI imaging. One form results from merosin deficiency, has been reported, but the gene locus is unknown. Some an extracellular protein important for maintenance of sar- reported cases of “rigid spine syndrome,” a form of congeni- colemmal membrane stability in the muscle fiber.115 The loci tal MD (CMD), may be EDMD cases in view of the marked for merosin deficient CMD has been linked to chromosome predominance of males with this disorder and the associated 6q.21 A further subtype of congenital muscular dystrophy contractures reported at the elbows and ankles.30 without CNS involvement and normal merosin has been reported, but the genetic locus has not been established. Congenital Muscular Dystrophy Patients with CMD often exhibit early contractures, includ- The term “congenital muscular dystrophy” has been widely ing equinovarus deformities, knee flexion contractures, hip used for a group of infants presenting with hypotonia, mus- flexion contractures, and tightness of the wrist flexors and cle weakness at birth or within the first few months of life, long finger flexors. The contractures can become more severe congenital contractures, and a dystrophic pattern on muscle over time with prolonged static positioning and lack of ade- biopsy. The dystrophic changes noted on biopsy separate this quate ROM and splinting/positioning. group of disorders from the congenital myopathies. The condition tends to remain relatively static. However, some subjects show slow progression, whereas others gain develop- THE CONGENITAL MYOPATHIES mental milestones and achieve the ability to walk. The term congenital myopathy is used to describe a group of There are several syndromes of CMD with CNS abnormali- heterogeneous disorders usually presenting with infantile ty. Fukuyama CMD is associated with mental retardation, hypotonia due to genetic defects causing primary myopathies structural brain malformations evident on magnetic reso- with the absence of any structural abnormality of the CNS or nance imaging (MRI) imaging and a dystrophic myopathy. peripheral nerves. The specific diagnosis of each entity is The gene loci has recently been identified to be at 9q31- made on the basis of specific histological and electron micro- 33.35,114 scopic changes found on muscle biopsy. While patients can be hypotonic during early infancy, they later develop muscle Muscle-eye-brain disease describes a syndrome comprising weakness that is generally nonprogressive and static. The CMD, mental retardation, and ocular abnormality. Infants weakness is predominantly proximal, symmetric, and in a present with congenital hypotonia, muscle weakness, elevat- limb girdle distribution. ed CK, myopathic EMG, and a dystrophic changes on muscle biopsy.101,102,103 Ophthalmologic findings include severe The serum CK values are frequently normal and the needle visual impairment with uncontrolled eye movements associ- EMG findings may be normal or may show mild, nonspecif- ated with severe myopia. Patients often deteriorate around 5 ic changes, usually of a myopathic nature (small amplitude years of age with progressive occurrence of spasticity. polyphonic potentials). The only congenital myopathy con- Computerized tomography scans have shown ventricular sistently associated with needle EMG abnormalities is 48 Hereditary and New Myopathies AANEM Course myotubular (centronuclear) myopathy.24,53 In this disorder, kyphoscoliosis, pigeon chest, pes cavus feet, high arched the needle EMG shows myopathic motor unit action poten- palate, and an unusually long face has been noted. tials with frequent complex repetitive discharges and diffuse Cardiomyopathy has been described in both severe neonatal fibrillation potentials.68 These myopathies can be considered and milder forms of the disease. primarily structural in nature. Patients do not actively lose muscle fibers. Autosomal dominant inheritance has been described in a few instances with the gene localized to chromosome 1, q21- Central Core Myopathy q23.54 The locus of the more common autosomal recessive forms have not yet been located. This is an autosomal dominant disorder with autosomal dominant gene locus at 19q13.1, the same gene locus as the Myotubular Myopathy (Centronuclear Myopathy) malignant hyperthermia gene.49 Indeed, these patients have a high incidence of malignant hyperthermia with inhalation Patients with non-X-linked myotubular myopathy have mus- anesthetic agents. Muscle fiber histology shows amorphous- cle biopsies showing a striking resemblance to the myotubes looking central areas within the muscle that may be devoid of of fetal muscle. Patients typically present with early hypoto- enzyme activity. Electron microscopy shows the virtual nia, delay in motor milestones, generalized weakness of both absence of mitochondria and sarcoplasmic reticulum in the proximal and distal musculature. They also present with pto- core region, and a marked reduction in the interfibrillary sis with weakness of the external ocular muscles as well as space and an irregular zig-zag pattern (streaming) of the Z- weakness of the axial musculature. Nocturnal hypoventila- lines.86 There is a predominance of high oxidative, low gly- tion has been described.57 The gene locus has not been iden- colytic type I fibers and a relative paucity of type II fibers, tified to date, but most known non-X-linked forms appear to resulting in a relative deficiency of glycolytic enzymes. show autosomal dominant inheritance.

Patients generally demonstrate mild and relatively nonpro- Severe X-linked (Congenital) Myotubular Myopathy gressive muscle weakness, either proximal or generalized, presenting in either early infancy or later. Mild facial weakness Cases with neonatal onset and severe respiratory insufficien- can be seen. Patients often achieve gross motor milestones cy have been identified with an X-linked recessive mode of rather late, such as walking, and have difficulty climbing inheritance. The gene for this disorder has been located to stairs. They may show a Gowers’ sign. The disorder typically Xq28.21 Muscle biopsy shows characteristic fetal-appearing remains fairly static over the years. A frequent occurrence of myotubes. congenital dislocation of the hip is observed. Patients present with severe generalized hypotonia, associated Central core myopathy and familial malignant hyperthermia muscle weakness, swallowing difficulty, and respiratory insuf- appear to be allelic as the ryanodine receptor chain implicat- ficiency. They often become ventilator-dependent at birth. If ed in malignant hyperthermia has the same locus.21,86 they are able to be weaned from the ventilator, subsequent death due to pulmonary complications is not uncommon. Nemaline Myopathy Aspiration pneumonias are common. Additional clinical features include congenital contractures, facial weakness, and Nemaline myopathy, also referred to as rod body myopathy, weakness of the external ocular muscles. Needle EMG shows represents a varied group of disorders with different modes of many fibrillations and positive sharp waves.53 inheritance, but the most typical form is autosomal recessive. While the rods can be easily overlooked using routine hema- Minicore Disease (Multi-Core Disease) toxylin-eosin staining, they can readily be demonstrated with the Gomori trichrome stain. The rods are readily demonstrat- Minicore disease is a relatively rare congenital myopathy with ed with an EM. They are thought to be abnormal depositions muscle biopsies showing multiple small randomly distributed of Z-band material of a protein nature and possibly alpha- areas in the muscle with focal decrease in mitochondrial actinin.54 oxidative enzyme activity and focal myofibrillar degenerative change. Characteristic changes are present on EM. There is a A severe form of the disease may present in the neonatal peri- predominance of type I fiber involvement.11 od with very severe weakness, respiratory insufficiency, and often a fatal outcome. Most cases present with a mild, non- Clinically, patients present with hypotonia, delays in gross progressive myopathy with hypotonia and proximal weak- motor development and nonprogressive symmetric weakness ness. In more severe cases, swallowing difficulty can be pres- of the trunk and proximal limb musculature. There may be ent in the neonatal period. Skeletal abnormalities, such as mild facial weakness and there is also associated diaphragmat- AANEM Course Current Concepts in Muscle Disease 49 ic weakness, placing patients at risk for nocturnal hypoventi- REFERENCES lation. Subtle ultrastructural changes allow this condition to be distinguished from central core disease. Inheritance is 1. Akita H, Matsuoka S, Juroda Y. Predictive electrocardiographic score autosomal recessive, but the gene location is not yet known. for evaluating prognosis in patients with Duchenne muscular dystrophy. Tokushima J Exp Med 1995;40:55-67. 2. 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