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Current Concepts in

Muscle Disease

2005 AANEM COURSE EAANEM 52nd Annual Scientific Meeting

Monterey, California

Anthony A. Amato, MDTimothy M. Miller, MD, PhDMark B. Bromberg, MD, PhD

Gregory T. Carter, MD

American Association ofNeuromuscular &

Electrodiagnostic Medicine

2005 COURSE EAANEM 52nd Annual Scientific Meeting

Monterey, California

Copyright © September 2005American Association of Neuromuscular & Electrodiagnostic Medicine

421 First Avenue SW, Suite 300 EastRochester, MN 55902

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Anthony A. Amato, MDTimothy M. Miller, MD, PhDMark B. Bromberg, MD, PhD


Current Concepts in Muscle Disease

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Faculty

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Anthony A. Amato, MD

Associate Professor

Department of Neurology

Harvard Medical School

Boston, Massachusetts

Dr. Amato is currently the chief of the Division of Neuromuscular Disease,director of the Clinical Neurophysiology Laboratory, and vice-chairman ofthe Department of Neurology at Brigham and Women’s Hospital inBoston. He is an associate professor of neurology at Harvard MedicalSchool. Dr. Amato is a graduate of the University of Cincinnati College ofMedicine. He completed his neurology residency at Wilford Hall MedicalCenter in San Antonio, Texas, and completed his neuromuscular diseasefellowship at the Ohio State University. In addition to co-editing the text-book Electrodiagnostic Medicine, Dr. Amato has authored numerous publi-cations in the field of neuromuscular disease and electrodiagnostic medi-cine. He has been involved in clinical research trials involving patients withamyotrophic lateral sclerosis, peripheral neuropathies, neuromuscularjunction disorders, and myopathies.

Timothy M. Miller, MD, PhD

Clinical Instructor

Neurosciences Department

University of California, San Diego

San Diego, California

Dr. Miller earned his medical degree and doctorate from WashingtonUniversity in Saint Louis, Missouri. He then went on to perform aninternship in internal medicine at the University of California, SanFrancisco, as well as a neurology residency and a neuromuscular fellowshipthere. He is currently a clinical instructor and research fellow at theUniversity of California, San Diego. Dr. Miller is a member of theAmerican Academy of Neurology and the American Association ofNeuromuscular & Electrodiagnostic Medicine. He has won several awards,including the Golseth Young Investigator Award and the NeedlemanAward for Pharmacology Research.

Mark B. Bromberg, MD, PhD

Professor and Vice-chairman

Department of Neurology

University of Utah

Salt Lake City, Utah

Dr. Bromberg began his academic career in basic science research. Hereceived a doctorate in neurophysiology from the Department ofPhysiology at the University of Vermont and conducted research in thesomatosensory and motor systems. Dr. Bromberg attended medical schoolat the University of Michigan and also completed his neurology trainingand neuromuscular/EMG fellowship there. He was on the faculty at theUniversity of Michigan until 1994, when he joined the University of Utah,where he is currently a professor and vice-chairman in the Department ofNeurology. Dr. Bromberg is Director of the Neuromuscular Program andEMG laboratory, and the Muscular Dystrophy Association clinics. Hisresearch interests are in quantitative EMG, including motor unit numberestimation (MUNE) and algorithms for automated motor unit analysis,and in clinical aspects of amyotrophic lateral sclerosis.


Clinical Professor

Department of Rehabilitation Medicine

University of Washington

Tacoma, Washington

Dr. Carter is Clinical Professor of Rehabilitation Medicine at theUniversity of Washington, where he co-directs Muscular DystrophyAssociation (MDA) clinics and attends in the electrodiagnostic lab. He alsoserves as regional medical director of rehabilitation services for theProvidence Health System in Southwest Washington. His clinical researchis investigating the relationships between pain, physical disability, andquality of life in neuromuscular disease (NMD). His pre-clinical researchinvolves studying the role of electromyography and muscle magnetic reso-nance imaging as in vivo measurement tools to follow physiologicalchanges in humans with NMD and transgenic mouse models of musculardystrophy. He has over 100 peer-reviewed publications in these areas. In1994 he won the Best Research Paper Published by a Physiatrist Awardfrom the American Academy of Physical Medicine and Rehabilitation. In1998 he received the Excellence in Research Writing Award from theAssociation of Academic Physiatrists. In 2002, he received the Excellencein Clinical Care Award from the MDA.

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.

Authors had nothing to disclose.

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Contents

Faculty ii

Objectives iii

Course Committee vi

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

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

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

Hereditary and New Myopathies 37Gregory T. Carter, MD

CME Self-Assessment Test 53

Evaluation 57

Future Meeting Recommendations 59

O B J E C T I V E S —As the neuromuscular field continues to advance, the EDX physician not only needs to know the yield of EDX in theevaluation of myopathies, but also needs to understand these diseases as a whole. After attending this course, participants will (1) learn newupdates on channelopathies, periodic paralysis, and congenital myotonia with brief clinical presentations and their diagnosis, (2) under-stand the new classification and diagnosis of inflammatory myopathies as well as the controversies surrounding this topic, (3) learn aboutiatrogenic myopathies and how the EDX physician can help the referring physician, and (4) know the latest discoveries of new congenitalmyopathies and muscular dystrophies.

P R E R E Q U I S I T E —This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physiciansat an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX prin-ciples. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree.

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

CME C R E D I T —The AANEM designates attendance at this course for a maximum of 3.25 hours in category 1 credit towards theAMA Physician’s Recognition Award. This educational event is approved as an Accredited Group Learning Activity under Section 1 of theFramework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal Collegeof Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he/she actually spent in the activity. TheAmerican Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMAPMR category 1 credit. CME for this course is available 9/05 - 9/08.

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

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Thomas Hyatt Brannagan, III, MDNew York, New York

Timothy J. Doherty, MD, PhD, FRCPCLondon, Ontario, Canada

Kimberly S. Kenton, MDMaywood, Illinois

Dale J. Lange, MDNew York, New York

Subhadra Nori, MDBronx, New York

Jeremy M. Shefner, MD, PhDSyracuse, New York

T. Darrell Thomas, MDKnoxville, Tennessee

Bryan Tsao, MDShaker Heights, Ohio

2004-2005 AANEM PRESIDENT

Gary Goldberg, MDPittsburgh, Pennsylvania

2004-2005 AANEM COURSE COMMITTEE

Kathleen D. Kennelly, MD, PhDJacksonville, Florida

INTRODUCTION

Dermatomyositis (DM), polymyositis (PM), and inclusionbody myositis (IBM) are the three major categories of idio-pathic inflammatory myopathy. These inflammatorymyopathies are clinically, histologically, and pathogenicallydistinct (Table 1).1-3,35,36,47,62 Dermatomyositis is not PMwith a rash and IBM is not PM with rimmed vacuoles andinclusions. The annual incidence of these disorders is approx-imately 1 in 100,000.35,97 There are a few reports of DM,PM, and IBM occurring in parents and children and in sib-lings, including identical twins.4,14,34,63,89,133 There may be agenetic predisposition to developing these disorders, possiblysecondary to inherited human leukocyte antigens (HLA)haplotypes. However, the inflammatory myopathies are bestconsidered as acquired diseases.

There are hereditary forms of inclusion body myopathy, butwith rare exceptions. The muscle biopsies in these cases lackinflammation and the clinical phenotype (i.e., age of onset,pattern of weakness) is different from sporadic IBM. On theother hand, inflammatory infiltrate in skeletal muscle is notspecific for the primary autoimmune myositis and can beseen in various forms of muscular dystrophy.

It is important to be able to distinguish the different disor-ders with inflammation on biopsy from one another becauseof important differences in prognosis and response to treat-ment. This entails performing a detailed clinical history andexamination, laboratory evaluation, and muscle biopsies. The

patient’s pattern of weakness is the most important piece ofthe puzzle. The phenotype constitutes more than just the pat-tern of weakness, but also associated clinical features (e.g.,cancer, connective tissue disease, interstitial lung disease),laboratory features (creatine kinase [CK], antinuclear anti-bodies, myositis-specific antibodies), and histological featureson biopsy.

DERMATOMYOSITIS

Clinical Features

Dermatomyositis can present at any age and females areaffected more commonly than males. Most childhood casespresent between 5 and 14 years of age,97 but DM can evendevelop during infancy.26 Although the pathogenesis ofchildhood and adult DM are presumably similar, there areimportant differences in some of the clinical features andassociated disorders. Onset of weakness is typically subacute(over several weeks), although it can develop abruptly (overdays) or insidiously (over months).1,3,21,71,139 The neck flex-ors, pectoral, and pelvic girdle muscles are the earliest andmost severely affected. As a result, patients complain of diffi-culty lifting their arms over their heads, climbing steps, andarising from chairs. Asymptomatic distal extremity weaknessmay occasionally be present. Children are more likely to pres-ent with an insidious onset of muscle weakness and myalgiaswhich are often preceded by fatigue, low grade fevers, and arash. Dysphagia, secondary to inflammation of oropharyngeal

Phenotypes of Myopathies WithInflammation

Anthony A. Amato, MD

Chief, Division of Neuromuscular DiseaseDirector of the Clinical Neurophysiology Laboratory

Brigham and Women’s HospitalAssociate Professor of Neurology

Harvard Medical SchoolBoston, Massachusetts

and esophageal muscles, occurs in approximately 30% ofDM patients.35,71,113,139 A minority of patients can have mas-seter weakness causing chewing difficulties.113 Involvementof the pharyngeal and the tongue muscles may result indysarthria or speech delay in children.113 Sensation is normaland muscle stretch reflexes are preserved until a severe degreeof weakness has developed.

Dermatomyositis is easily recognized and diagnosed becauseof the characteristic rash which may accompany or precedethe onset of muscle weakness.1,71,135 The classic skin manifes-tations include a heliotrope rash (a purplish discoloration ofthe eyelids) often associated with periorbital edema andpapular, erythematous, scaly lesions over the knuckles(Gottron’s papules). In addition, a flat, erythematous, sun-sensitive rash may appear on the face, neck, and anteriorchest (V-sign); on the shoulders and upper back (shawl sign);on the hips (holster’s sign); and on the elbows, knees, andmalleoli (Gottron’s sign). The nail-beds often have dilatedcapillary loops and occasionally appear with thrombi or hem-orrhage.

Calcifications in the subcutaneous tissues occur in 30-70% ofchildren, while this is an uncommon finding in adults.1,31,113

Cutaneous calcinosis tends to develop over pressure points

(buttocks, knees, elbows) and present as painful, hard nod-ules. Ulceration of the overlying skin with extrusion of calcif-ic debris can be seen in severe cases or in patients who havebeen inadequately treated.

Associated Manifestations

Cardiac

While overt clinical symptoms are uncommon, electrocardio-graphic abnormalities including conduction defects andarrhythmias occur frequently in childhood and adultDM.13,39,58,65,71,139 Pericarditis, myocarditis, and congestiveheart failure can occasionally develop.58,71 Echocardiographyand radionucleotide scintigraphy may demonstrate ventricu-lar and septal wall motion abnormalities and reduced ejectionfractions.58

Pulmonary

Interstitial lung disease (ILD) complicates at least 10% ofadult DM and can also occur in childhoodcases.41,52,71,113,115,127 Symptoms of ILD (i.e., dyspnea, non-productive cough) can develop abruptly or insidiously andoften precede the development of the characteristic rash and

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 DiseasesEndomysial 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 fibersEndomysial macrophages, MDC, and PCEM: 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)

muscle weakness. Chest radiographs reveal a diffuse reticu-lonodular pattern with a predilection for involvement at thelung bases. In the more fulminant abrupt-onset cases, a dif-fuse alveolar pattern or “ground-glass” appearance is seen.Pulmonary function tests demonstrate restrictive defects anddecreased diffusion capacity, while hypoxemia is evident onarterial blood gasses. Antibody directed against t-histidyltransfer ribonucleic acid (RNA) synthetase, so-called anti-Jo-1, are present in at least 50% of ILD cases associated withinflammatory myopathies.72,91,136 Patients with significantoropharyngeal and esophageal weakness can develop aspira-tion pneumonia.

Gastrointestinal

Inflammation of the skeletal and smooth muscles of the gas-trointestinal tract can lead to dysphagia and delayed gastricemptying.113 Vasculitis/vasculopathy of the gastrointestinaltract is a serious complication which is much more commonin childhood DM compared to adult DM.113 The vasculitiscan result in mucosal ulceration, perforation, and life-threat-ening hemorrhage.

Joints

Arthralgias with or without arthritis are a frequent presentingfeature. Arthritis is typically symmetric and involves both thelarge and small joints. The arthralgias and myalgias often easewhen the limbs are flexed, which unfortunately leads to thedevelopment of flexion contractures across the major joints.Flexion contractures at the ankles leading to toe-walking is acommon early finding in childhood DM.

Vasculopathy

Besides the skin, muscle, and gastrointestinal system, necro-tizing vasculopathy may affect other tissues including theeyes (retina and conjunctiva), kidneys, and lungs.115,139

Rarely, massive muscle necrosis can lead to myoglobinuriaand acute renal tubular necrosis.

Malignancy

There is an increased incidence of underlying malignancy inadult DM, ranging from 6-45%.21,23,28,71,132,139 The associa-tion with cancer has not been clearly demonstrated in child-hood DM. The rare cases of childhood DM associated withmalignancies had unusual courses.113 Detection of an under-lying neoplasm can precede or occur after the diagnosis ofDM; the majority of malignancies are identified within 2years of the presentation of the myositis. The risk of malig-nancy is similar in males and females and is greater inpatients over the age of 40 years. Some studies have suggest-ed an increased risk of malignancy in patients with cutaneous

vasculitis.18 The severity of the inflammatory myopathy doesnot appear to correlate with the presence or absence of a neo-plasm. Treatment of the underlying malignancy sometimesresults in improvement of muscle strength.

The search for an underlying malignancy should include acomprehensive history and annual physical examinationswith breast and pelvic examinations for women, and testicu-lar and prostate examinations for men. This author obtains acomplete blood count (CBC), routine blood chemistries, uri-nalysis, and stool specimens for occult blood. Chest radi-ograph, pelvic ultrasound, and mammogram are the onlyradiographic studies routinely ordered as well as acolonoscopy for anyone over the age of 50 years or those withgastrointestinal symptoms.

Laboratory Features

Blood Work

Necrosis of muscle fibers results in elevations of serum CK,aldolase, myoglobin, lactate dehydrogenase, aspartate amino-transferase (AST), and alanine aminotransferase (ALT).Serum CK is the most sensitive and specific marker for mus-cle destruction. Serum CK is elevated in more than 90% ofDM patients, and levels can be as high as 50 times the nor-mal value. However, serum CK levels do not correlate withthe severity of weakness and can be normal even in marked-ly weak individuals, particularly in childhood DM.Erythrocyte sedimentation rate (ESR) is usually normal oronly mildly elevated and is not a reliable indicator of diseaseseverity.

Antinuclear antibodies (ANA) can be detected in 24-60% ofDM patients.71,91,136 These antibodies are much more com-mon in patients with overlap syndromes (discussed later).Myositis-specific antibodies (MSAs) deserve special commentbecause it has been suggested that they may prove useful inpredicting response to therapy and prognosis.76,91,100,118,136

The MSAs are associated with specific human leukocyte anti-gen (HLA) haplotypes, and each patient can have only onetype of MSA. However, the MSAs are demonstrated in onlya minority of patients with an inflammatory myopathy andhave not been studied prospectively in regards to their predic-tive value. The pathogenic relationship these antibodies haveto inflammatory myopathies is unknown; they may just rep-resent an epiphenomenon.

The MSAs include: (1) the cytoplasmic antibodies directedagainst translational proteins (i.e., various t-RNA synthetasesand the anti-signal recognition particle), and (2) those direct-ed against Mi-2 and Mas antigens.91,100,118,136 The most com-mon of the antisynthetases is the anti-Jo-1 antibodies which

AANEM Course Current Concepts in Muscle Disease 3

are associated with ILD and arthritis and are demonstrated inup to 20% of patients with inflammatory myopathy.72,91,136

The other antisynthetases are much less common and areeach found in less than 2-3% of inflammatory myopathypatients. The presence of these anti-Jo-1 antibodies has beenassociated with only a moderate response to treatment and apoor long-term prognosis.76,118 However, it is the associatedILD which is responsible for the less favorable prognosis, notjust the presence of the anti-Jo-1 antibodies. There has notbeen a prospective study demonstrating treatment outcomesof myositis-ILD patients with anti-Jo-1 antibodies comparedto similar patients without these antibodies.

Mi-2 antibodies are seen almost exclusively in DM and canbe found in 15-20% of DM patients. Mi-2 is a 240 kDnuclear protein of unknown function. The anti-Mi-2 anti-bodies are associated with an acute onset, a florid rash, a goodresponse to therapy, and a favorable prognosis.76,91,118,136

However, it is not known whether DM patients with Mi-2antibodies respond differently than DM patients without theantibody.

Electromyography

The characteristic electromyographic (EMG) featuresobserved in myositis patients are: (1) increased insertionaland spontaneous activity with fibrillation potentials, positivesharp waves, and occasionally pseudomyotonic and complexrepetitive discharges, (2) small duration, low amplitude,polyphasic motor unit action potentials (MUAPs), and (3)MUAPs which recruit early but at normal frequencies.1,24

Recruitment may be decreased (fast firing MUAPs) inadvanced disease due to the loss of muscle fibers of entiremotor units. Late in the course of poorly responsive disease,insertional activity may be decreased secondary to fibrosis. Inaddition, large duration polyphasic MUAPs may also be seenlater in the course reflecting chronicity of the disease withmuscle fiber splitting and regeneration rather than a superim-posed neurogenic process. The amount of spontaneous EMGactivity is reflective on ongoing disease activity. Needle EMGcan be helpful in determining which muscle to biopsy inpatients with only mild weakness. In addition, needle EMGmay also be useful in previously responsive myositis patientswho become weaker by differentiating an increase in diseaseactivity from weakness secondary to type 2 muscle fiber atro-phy from disuse or chronic steroid administration. Isolatedtype 2 muscle fiber atrophy is not associated with abnormalspontaneous activity seen during needle EMG.

Muscle Imaging

Magnetic resonance imaging (MRI) can provide informationon the pattern of muscle involvement by looking at the cross-sectional area of axial and limb muscles.51,70,79,114,117

Magnetic resonance imaging may demonstrate signal abnor-malities in affected muscles secondary to inflammation andedema or replacement by fibrotic tissue. Some have advocat-ed MRI as a guide to determine which muscle to biopsy.117

However, this author has found that MRI adds little to agood clinical examination and needle EMG in defining thepattern of muscle involvement and determining which mus-cle to biopsy.

Muscle Biopsy

The pathological process is multifocal and the frequency andseverity of histologic abnormalities can vary within the mus-cle biopsy specimens. The characteristic histologic feature isperifascicular atrophy.1,35,47 However, in this author’s experi-ence this is a late histological feature and is seen in less than50% of cases (particularly less common in adults). The peri-fascicular area contains small degenerating fibers as well asatrophic and nonatrophic fibers with microvacuolation anddisrupted oxidative enzyme staining. Occasionally, wedged-shaped microinfarcts of muscle fascicles are apparent.Scattered necrotic fibers may be present, however, in contrastto PM and IBM, invasion of non-necrotic fibers is notprominent. The inflammatory infiltrate is composed prima-rily of macrophages, B-cells, and CD4+ cells in the per-imysial and perimysial regions.6,46 However, recent studieshave demonstrated that there are many more CD 4+ cells inthe endomysium that previously appreciated and that theseare for the most part plasmacytoid dendritic cells and not T-helper cells.61

The earliest demonstratable histologic abnormality in DM isdeposition of the C5b-9 or membrane attack complex(MAC) on or around small blood vessels.44,83,84 Membraneattack complex precedes inflammation and other structuralabnormalities in the muscle on light microscopy and is spe-cific for DM. Other complement components (C3 and C9),IgM, and less often gamma G immunoglobulin are alsodeposited on or around the walls of intramuscular blood ves-sels.143 The subsequent necrosis of vessels results in a reduc-tion in the capillary density (number of capillaries per area ofmuscle).44 Transforming growth factor b (TGF-b) and itsmessenger RNA are upregulated in regions of severeischemia, which probably accounts for the increased fibrosisin these areas.33 Electron microscopy (EM) reveals smallintramuscular blood vessels (arterioles and capillaries) withendothelial hyperplasia, microvacuoles, and cytoplasmicinclusions; these abnormalities precede other structuralabnormalities on EM.14,38

Pathogenesis

The immunological studies and other histological featuresseen with muscle biopsies suggest that DM is a humorally


mediated microangiopathy. This microangiopathy has beenpostulated to cause ischemic damage and occasionally infarc-tion of muscle fibers. Some authorities suggest that the peri-fascicular atrophy is the result of hypoperfusion to the water-shed region of muscle fascicles. However, many questionsremain regarding this hypothesis and the pathogenic basis ofDM.60,61 It has never been demonstrated that the perifascic-ular region is indeed the watershed area in muscle fibers orthat the perifasicular fibers are more prone to ischemic dam-age. Of note, perifascicular atrophy is not evident in ischemicmuscle damaged from vasculitis. Further, perifascicular atro-phy has not been demonstrated in animal models of smallvessel ischemia. On the contrary, such models demonstrate apredilection for the involvement of more centrofascicularfibers.

Deoxyribonucleic acid (DNA) microarray studies of biopsiedmuscle tissue demonstrate an increased expression of genesinduced by interferon-α/β.59,61 Although this is not specific,it is compatible with the hypothesis of a viral infection trig-gering the autoimmune attack. Interferon-α/β has a well-defined role in antiviral innate immunity, and this has led toadditional consideration of a hypothesis of chronic persistentviral infection as a cause of juvenile DM. However, there areother possibilities. In particular, interferon-a is synthesized byplasmacytoid dendritic cells (PDCs) in response to a serumfactor containing immune complexes of antibody, double-stranded DNA, and RNA viruses. These cells, also called nat-ural interferon producing cells for their ability to secrete mas-sive amounts of IFN-α, can be activated to produce IFN-αby synthetic short palindromic DNA sequences, termed CpGoligodeoxynucleotides. This author and colleagues haverecently demonstrated pyruvate dehydrogenase complex(PDC) in the muscle biopsies of of patients with DM.Pyruvate dehydrogenase complex are CD4+ and comprise alarge component of the inflammatory cell infiltrate in DM.These CD4+ cells were originally thought to be CD4+ T-helper cells, but it was demonstrated that most are CD3- andthus are PDC and not lymphocytes.61 Increased expression ofIFN-α inducible proteins such as myxovirus resistance 1 pro-tein (MxA) has also been demonstrated on blood vessels andmuscle fibers (with a predilection for the perifascicularfibers).61 Interestingly, one postulated function of MxA is toform tubuloreticular inclusions around RNA viruses. Theseinclusions have the same morphology as the tubuloreticularinclusions seen with EM in blood vessels in DM. Usingimmunoelectron microscopy the author and colleagues havedemonstrated MxA within inclusions in vessels in DM muscle

biopsies. Perhaps dysregulated IFN-α production is a centraldriving problem in the pathogenesis of DM.

Prognosis

In the absence of malignancy, prognosis is favorable inpatients with DM. Poor prognostic features are increased age,associated ILD, cardiac disease, and late or previous inade-quate treatment.30,71,76,107,139,146 Five-year survival rates ofadult DM range from 70-93%. The mortality rate in chil-dren is very low.113

INCLUSION BODY MYOSITIS

Clinical Features

Inclusion body myositis is characterized clinically by theinsidious onset of slowly progressive proximal and distalweakness which generally develops after the age of 50years.1,3,35,62,90,126,145 The slow evolution of the diseaseprocess probably accounts in part for the delay in diagnosis,averaging approximately 6 years from the onset of symp-toms.3,90 Males are much more commonly affected thanfemales, in contrast to the female predominance seen in DMand PM. The clinical hallmark of IBM is early weakness andatrophy of the quadriceps, volar forearm muscles (i.e., wristand finger flexors), and the ankle dorsiflexors.3,62,90

Importantly, the manual muscles scores of the finger andwrist flexors are often lower than those of the shoulderabductors and the muscle scores of the knee extensors areoften lower than those of the hip flexors in patients with IBM(Tables 2 and 3 and Figures 1 and 2).1 The opposite relation-ship between muscles scores are present in DM and PM.

In addition, muscle involvement in IBM is often asymmetric,in contrast to the symmetrical involvement in DM and PM.The presence of slowly progressive, asymmetric, quadricepsand wrist/finger flexor weakness in a patient over 50 years ofage strongly suggests the diagnosis of IBM.3

Dysphagia occurs in up to 40% of patients and can be debil-itating requiring cricopharyneal myotomy.37,90,141 Likewise,mild facial weakness can be detected on examination in atleast 33% of IBM patients, however, this weakness is clinical-ly insignificant.3,90 Extraocular muscles are spared. Althoughmost patients have no sensory symptoms, evidence for a gen-eralized peripheral neuropathy can be detected in up to 30%


of patients on clinical examination and electrophysiologicaltesting.3 Muscle stretch reflexes are normal or slightlydecreased. In particular, the patellar reflexes are lost early.


Unlike DM and PM, IBM is not associated with myocarditisor ILD; nor is there an increased risk of malignancy.28

Autoimmune disorders such as systemic lupus erythematosus(SLE), Sjögren’s syndrome, scleroderma, thrombocytopenia,and sarcoidosis have been reported in up to 15% of IBMpatients.85,90 Diabetes mellitus was reported in 20% ofpatients in one large series.90

Laboratory Features

Blood Work

Serum CK is normal or only mildly elevated (less than 10-fold above normal).3,62,90 Autoantibodies are usually absentexcept for the occasional patients with concurrent connectivetissue disease, although some series have reported positiveANAs in approximately 20% of their IBM patients.85,91

There is a significant incidence of the HLA DR3 phenotype(*0301/0302) in IBM.55

Needle Electromyography and Nerve Conduction Studies

Increased spontaneous and insertional activity, smallpolyphasic MUAPs, and early recruitment are usually evidentduring the needle EMG examination.3,90 In addition, largepolyphasic MUAPs can also be demonstrated in one-third ofpatients.42,77,90,92 However, large polyphasic MUAPs can alsobe seen in DM, PM, and other muscle disorders (i.e., muscu-lar dystrophies) and probably reflects chronicity of the diseaseprocess rather than a neurogenic etiology. Nevertheless, nerveconduction studies reveal evidence of a mild axonal sensoryneuropathy in up to 30% of patients.3

Muscle Imaging

Radiological studies demonstrate atrophy and signal abnor-malities in affected muscle groups.51,128

Muscle Biopsy

The characteristic light microscopic findings are endomysialinflammation, small groups of atrophic fibers, eosinophiliccytoplasmic inclusions, and muscle fibers with one or morerimmed vacuoles lined with granular material.3,62,90 Amyloid


Table 2 Clinical features of inflammatory myopathies


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

DM = dermatomyosits; IBM = inclusion body myositis; PM = polymyositis

Table 3 Pattern of weakness in the inflammatory myopathies

deposition is evident on Congo red staining using polarizedlight or fluorescence techniques.9,99 The number of vacuolat-ed and amyloid-positive fibers may increase with time inindividual patients.17 An increased number of ragged redfibers and cytochrome oxidase (COX)-negative fibers are alsoevident in IBM compared to DM and PM patients and age-matched control subjects.120 Electron microscopy demon-strates 15-21 nm cytoplasmic and intranuclear tubulofila-ments, although a minimum of three vacuolated fibers mayneed to be scrutinized to confirm their presence.90 Vacuolatedfibers also contain cytoplasmic clusters of 6-10 nm amyloid-like fibrils.9,62 Because of sampling error, repeat muscle biop-sies may be required to identify the rimmed vacuoles andabnormal tubulofilament or amyloid accumulation in orderto histologically confirm the diagnosis of IBM.3 This sam-pling error probably accounts for IBM being misdiagnosed asPM or “inflammatory myopathy with COX-negative musclefibers.”20,88

Similar to PM, the inflammation in IBM is predominantlyendomysial and composed of macrophages and CD8+ cyto-toxic/suppressor T-lymphocytes which invade non-necroticfibers.46 Major histocompatibilty complex class 1 antigens areexpressed on necrotic and non-necrotic muscle fibers.43

Investigations of the T-cell receptor repertoire demonstratean oligoclonal pattern of gene rearrangement, although thereis heterogeneity in the CDR3 domain.94,110 These findingssuggest that the T-cell response is not directed against a mus-cle-specific antigen, although the response could be triggeredby a superantigen. Recently, others have found persistentclonal restriction of T-cell receptors in infiltrating lympho-cytes on repeated muscle biopsies in some patients suggestingthat there is a continuous antigen driven attack against themuscle fibers.5 Gene expression studies in muscle demon-strated up-regulation of immunoglobulin genes.59 Thisauthor and colleagues have found large numbers ofendomysial plasma cells sometimes surround muscle fibers.


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

PM = polymyositis; IBM = inclusion body myositis

Myelodendritic cells that in part function to present antigensto both T-cells and B-cells are abundant in the endomysiumas well.

Pathogenesis

The pathogenesis of IBM is unknown. Whether IBM is a pri-mary inflammatory myopathy like DM and PM, or a myopa-thy in which the inflammatory response plays a secondaryrole is the subject of intense research.62 The histological andimmunological studies previously described provides evi-dence that IBM may be an autoimmune disorder mediatedby cytotoxic T-cells. The autoinvasive T-cells in IBM containperforin granules. Upon release of these granules, pores formon the muscle membrane, resulting in osmolysis.57 Pruitt andcolleagues reported the frequency of invaded fibers wasgreater than either necrotic or amyloidogenic fibers suggest-ing that the inflammatory response plays a more importantrole than the accumulation of vacuoles or amyloidogenic fil-aments in the pathogenesis of IBM.119 Although antibodieshave not been demonstrated binding to muscle fibers, it isclear that the humoral wing of the immune system is alsoupregulated, as evidenced by the plasma cell infiltrate.

The lack of significant clinical response with variousimmunosuppressive therapies alone or in combination arguesagainst IBM being a primary autoimmune disorder. Eightpatients were treated with IBM for 6-24 months withimmunosuppressive medications. Their response to treat-ment was evaluated and their pre- and post-treatment musclebiopsies were analyzed.17 None of the patients improved instrength or function despite lower serum CK levels andreduced inflammation on the post-treatment muscle biop-sies. Interestingly, the amount of vacuolated muscle fibersand fibers with amyloid deposition were increased in the fol-low-up biopsies suggesting that inflammation may play a sec-ondary role in the pathogenesis of IBM, while the accumula-tion of vacuoles and amyloid may have a more significantrole.

Another line of evidence which suggests that IBM could be adegenerative disorder of muscle rather than an autoimmuneinflammatory myopathy is the accumulation of “Alzheimer-characteristic proteins” in vacuolated muscle fibers.62

Abnormal accumulation of B-amyloid, C- and N-terminalepitopes of B-amyloid precursor protein (B-APP), prion pro-tein (PrPc), apolipoprotein E, α1-antichymotrypsin, ubiqui-tin, hyper-phosphorylated tau protein and neurofilamentheavy chain similar to that observed in the brains ofAlzheimer’s patients is evident within IBM vacuolatedfibers.7-12 Interestingly, a study of 14 IBM patients reporteda significant increase in the apolipoprotein E ε4 frequency as

observed in Alzheimer patients.56 However, other studies ofIBM patients reported no significant increase in apolipopro-tein E ε4 allele frequency.12,64 Askanas and colleagues havealso described increased acetylcholine receptor, PrPc, and B-APP mRNAs in IBM vacuolated fibers.62,125 Thus, increasedprion and B-amyloid deposition in these muscle fibers prob-ably result, in-part, from increased transcription of the PrPc

and B-APP genes. Muscle fibers transfected in vitro with B-APP cDNA using a recombinant-deficient adenovirus vectorresults in Congo red positive, vacuolated fibers withtubulofilaments, and abnormal mitochondria typical of thatobserved in IBM.

Interestingly, B-amyloid and prion proteins can induce apop-tosis of neurons invitro. In this regard, regenerating anddegenerating muscle fibers express Fas and Fas ligand, a pro-apoptotic complex.19,53 However, there is no evidence thatapoptosis plays a role in muscle fiber destruction in IBM.75

Perhaps as in PM, the demonstrated increased co-expressionof the anti-apoptotic protein, Bcl-2, in muscle fibers protectsagainst the potential apoptotic effect of Fas/Fas ligand.19

Although intriguing, the pathogenic relationship of the“Alzheimer-characteristic proteins” in IBM to the pathogen-esis of the myopathy is not clear. The accumulation of theseproteins in IBM vacuolated muscle fibers may be an epiphe-nomena rather than the primary pathogenic defect of IBM.

Besides the accumulation of rimmed vacuoles and tubulofil-aments, mitochondrial abnormalities as indicated by raggedred fibers and mitochondrial DNA mutations are more fre-quent in IBM patients than in the other inflammatorymyopathies.62,111,120 However, these mitochondrial abnor-malities are believed to be secondary changes and not the pri-mary cause of the myopathy. In addition, increasedimmunoreactivity for nitrotyrosine and both the inducibleand nuclear forms of nitric oxide synthase (NOS) have beendemonstrated in vacuolated muscle fibers.144 These findingssuggest that nitric oxide-induced oxidative stress may play arole in muscle fiber destruction in IBM. αB crystalin expres-sion, a member of the heat-shock protein family, is increasedin normal as well as abnormal appearing IBM muscle fiberssuggesting that there is a pathologic stressor acting upstreamfrom to the development of structural abnormalities includ-ing the accumulation of Alzheimer-like proteins, NOSexpression, and mitochondrial abnormalities.15

A viral etiology has also been speculated in the pathogenesisof IBM. Chronic persistent mumps was previously hypothe-sized based on immunostaining of inclusions by anti-mumpsantibodies.29 This was subsequently rejected after in-situhybridization and polymerase chain reaction studies failed toconfirm mumps infection.78,86,109 Interestingly, histologic


abnormalities on muscle biopsy similar to IBM have beenseen in patients with retroviral infections and post-polio syn-drome.

Prognosis

Most IBM patients are older and life expectancy does notappear to be significantly altered. Progressing slowly, IBMdoes not respond well to immunosuppressive medications.Most patients remain ambulatory, although they frequentlyrequire or at least benefit from a cane or a wheelchair for longdistances. However, some patients become severely incapaci-tated and require a wheelchair or become bed-ridden within10-15 years.90

Many patients with steroid-resistant or “refractory” PM even-tually are diagnosed with IBM. Importantly, there arepatients who clinically resemble IBM, but in whom a defini-tive diagnosis cannot be confirmed with muscle biopsy.3

These patients are diagnosed with “possible” or “probable”IBM.3,62

POLYMYOSITIS

Background

What had been described in the literature as “polymyositis” ismost likely a heterogenious group of disorders.2,36,140 Despitewhat one might suspect from reading the literature, PM is theleast common of the major idiopathic inflammatorymyopathies. There are definitely cases of PM, but it is impor-tant to realize that many cases of so-called PM in the litera-ture are in fact IBM, dystrophies with inflammation, andperhaps even DM. The reasons for the erroneous diagnosisare multiple.

Misdiagnosed Dermatomyositis?

Most published papers regarding epidemiology and treat-ment of PM have used Bohan and Peter’s criteria for PM andDM (Table 4).21,22 These criteria were fine in 1975, but asone can see a muscle biopsy is not required for the diagnosisof PM and DM, and the only feature distinguish the PMfrom DM is the presence of a rash in DM. Further, the biop-sy abnormalities as listed are nonspecific (except for perifasci-cular atrophy—a finding specific for DM, but not seen inPM) and do not help in distinguishing PM from DM or anymyopathy with necrosis, including muscular dystrophies.Importantly, the histological criteria do not take into accountthe advances in histopathology, particularly in regard toimmunohistochemistry. It is now appreciated that DM is ahumerally mediated microangiopathy, while PM is an HLA-

restricted, antigen-specific, cell-mediated immune responsedirected against muscle fibers.

This author believes there is a clinical spectrum of dermato-myositis with respect to muscle and skin involvement (Figure3).

Most patients with classic dermatomyositis have a combina-tion of skin and muscle involvement. It is appreciated bymany authorities that some patients have the characteristicrash but never develop weakness—so called myopathic der-matomyositis or dermatomyositis sine myositis.48,134 Whatabout the converse? Are there patients with dermatomyositissine dermatitis? Traditionally, such patients have been diag-nosed as having PM based on Bohan and Peter’s criteria.However, if one looks carefully at the muscle biopsies, thefeatures are more similar to DM than PM.

In this regard, some have tried to classify the myositis on thebasis of so-called MSAs.91,100,118,136 These studies suggestedthat antibodies such as anti- signal recognition particle (SRP)were specific for PM or that anti-Jo-1 antibodies could beseen in either PM or DM. However, no details regarding thehistopathology was ever mentioned in these early papers andthe diagnosis of DM apparently was made only because thecharacteristic rash was not present or at least not appreciated.In studies that have made the diagnosis of PM or DM based


Table 4 Bohan and Peter’s criterial for PM and DM

1. Symmetrical Weakness of the limb girdle muscles and anteripr neckflexors, progressiving over weeks to months, with or withoutdysphagia or respiratory muscle involvement.

2. Muscle biosy evidence of necrosis of myofibers, phagocytosis,regeneration with basophils, large vesicular sarcolemmal nuceli.Anlsoprominent nucleoli, atrophy in a perifasciuclar distribution,variaqbtion in fiber size and an inflammatory exudate, oftenperivascular.

3. Elevation in serum skeletal muscle enzymes, particularly the CK andoften aldolase AST, ALT, and LDH.

4. Needle EMG triad of short, small polyphasic motor units, fibrillationpotentials, positive sharp waves, insertial irritability, and complexrepetitive discharges.

Three out of four of the above features are needed for a diagnosis of PM.The diagnosis of DM is made if the patient also has characteristic rash.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatinekinase; DM = dermatomyositis; EMG = electromyography; LDH = lactate dehydro-genase; PM = polymyositis.

upon currently accepted histological criteria, myositis associ-ated with anti-SRP and anti-Jo-1 antibodies all had histolog-ical features of a humorally mediated microangiopathy simi-lar to DM.59-61,101,105 No patient has been reported with his-tolopathological abnormalities of PM.

Misdiagnosed Inclusion Body Myositis

Bohan and Peter’s criteria do not take into account the exis-tence of IBM. This myopathy was not well-appreciated untilthe late 1980s and early 1990s, particularly in regard to itbeing the most common inflammatory myopathy in patientsover 50 years of age. Further, although more physicans areaware of IBM now, they still do not realize that because ofsampling error, any given biopsy may lack definitive histolog-ical criteria for IBM.3 Thus, many patients with IBM areerroneously diagnosed as PM.

One group of investigators has tried to define a distinct sub-group of PM on the basis of the presence of COX-negativefibers on muscle biopsy and a modest response to methotrex-ate in a small number of patients.20,88 The clinical features ofthis subgroup are male predominance, age over 50 years,prominent quadriceps weakness, mildly elevated serum CKlevels, and poor response to corticosteroid treatment. As illus-trated above, these are the characteristic features of IBM,which are believed to be the most likely diagnosis of this“subgroup” of patients.2,62

Misdiagnosed Muscular Dystrophies

Occasionally, prominent endomysial inflammatory cell infil-trates are evident on biopsies of patients with different forms

of muscular dystrophy (i.e., congenital, facioscapulohumeral,limb-girdle, and the dysferlinopathies). Myositis with perina-tal onset was first described in Japan.81,82,108,112 Subsequently,there have been several reports in the western hemisphere ofinfantile myositis or congenital inflammatory myopa-thy.123,131,137 The myopathy is characterized by the antenatalor perinatal presentation of hypotonia and generalized weak-ness and the presence of inflammation on muscle biopsy.Serum CK is usually elevated and needle EMG is myopath-ic. However, careful review of the clinical features in thesereported patients are suggestive of a congenital muscular dys-trophy (i.e., Fukayama-type, Walker-Warburg syndrome, orthe occidental type) in most. Only one case where the patienthad perifascicular atrophy and immunoglobulin and comple-ment deposition on the biopsy characteristic of DM, and thepatient improved with steroids was strongly suggestive of aprimary myositis.123 Most of the reported children did notsignificantly improve with corticosteroids. In addition, thebiopsies had dystrophic features in addition to the inflamma-tory infiltrates. Finally, there have been several reports ofpatients with the occidental type of congenital muscular dys-trophy with hypomyelination whose muscle biopsy showedprominent inflammation and merosin (alpha-2 laminin)deficiency.98,103,116 It is suspected that the majority of infantswith inflammation seen on muscle biopsy have a form ofcongenital muscular dystrophy rather than a primary myosi-tis.

Inflammation on biopsies is not specific for the congentialmuscular dystrophies, but is also evident in dys-trophinopathies, facioscapulohumeral dystrophy, dysfer-linopathy, and other forms of limb-girdle muscular dystro-phy.54,96,106,124,129 This author has seen many patients withmuscular dystrophy misdiagnosed as PM and subjected tolong-term complications associated with immunosuppressivetherapy. There are clinical features that may help distinguishdystrophy with inflammation from a primary inflammatorymyopathy. Scapular winging, prominent facial weakness, andasymmetrical involvement is common in facioscapulohumer-al muscular dystrophy (FSHD), but is not in PM. Patientswho have severe proximal weakness (i.e., Medical ResearchCouncil grade 3 or less) but normal strength distally (wristsand ankles) would be more likely to have a form of a limb gir-dle muscular dystrophy (LGMD) as opposed to PM.Dysferlinopathies can manifest with a LGMD pattern ofweakness, early gastrocnemius weakness and atrophy, tibalisanterior weakness, or any combination of the above andmarkedy elevated serum CK levels.

Muscle biopsy features can also be helpful in distinguishing adystrophy from PM. Although endomysial inflammatory cellinfiltration and necrotic fibers can be seen in dystrophies,unlike PM there should be no invasion of non-necrotic muscle


Figure 3 Clinical spectrum of dematonyositis

Amyopathic DM Classic DM Adermatopathic DM

Modified from Sontheimer RD. Current Op Rheum 1999;11:465-482.

DM = dermatomyositis

fibers by the mononuclear inflammatory cells. Also, depositionof MAC may be seen on the sarcolemma of scattered non-necrotic fibers in FSHD, LGMD, and dysferlinopathies, butnot in PM, DM, or IBM.22,135 Further, there is oftenincreased endomysial connective tissue in the dystrophiesprior to the muscle end-stage.

Necrotizing Myopathy

The idiopathic necrotizing myopathy are often diagnosed asPM by Bohan and Peter’s criteria.25,45,87,142 Nevertheless, thepathogenic basis appears to be quite distinct from PM and inother reported cases more closely resembles humorally medi-ated microangiopathy. As in DM, deposition of MAC onsmall blood vessels and depletion of capillaries can be seen.However, these patients do not have a characteristic rash,biopsy shows no perifascicular atrophy, perivascular inflam-mation is sparse, and tubuloreticular inclusions in endotheli-um are not commonly seen on EM. So-called pipestem cap-illaries may be evident on routine histochemistry and EM.45

Necrotizing myopathy should lead to a search for an under-lying connective tissue disease (usually scleroderma or mixedconnective tissue disease) and cancer. Muscular dystrophiesand toxic myopathies (e.g., statin myopathies) also need to beexcluded. However, many cases of necrotizing myopathy areidiopathic.

For the various reasons previously listed, it is impossible todetermine from the literature the true incidence of PM, asso-ciated laboratory abnormalities, medical conditions (e.g,CTD, ILD, myocarditis, cancer) that may accompany it, andprognosis. Prospective trials using currently histopathologicalcriteria for PM are needed to address this issue.

Clinical Features

Polymyositis generally presents in patients over the age of 20years and is more prevalent in females.3,21,23,71,97,139 Diagnosisis often delayed compared to DM, because there is no associ-ated rash which serves as a “red-flag” to patients and theirphysicians. Patients present with neck flexor and symmetricproximal arm and leg weakness, which typically develops overseveral weeks or months. Distal muscles may also becomeinvolved but are not as weak as the more proximal muscles.Muscle pain and tenderness are frequently noted. Dysphagiareportedly occurs in approximately one-third of patients sec-ondary to oropharyngeal and esophageal involvement. Mildfacial weakness occasionally may be demonstrated on exami-nation. Sensation is normal and muscle stretch reflexes areusually preserved.


The cardiac and pulmonary complications of PM are report-edly similar to those previously described for DM. Myositiswith secondary congestive heart failure or conduction abnor-malities occur in up to one-third of patients, but againhistopathologic confirmation of true PM is lacking in mostof these studies.13,39,58,65,68,71,80,139 Anti-SRP antibodies havebeen associated with myocarditis and had been noted to bespecific for PM.91,100,118,136 However, in studies in whichdetailed immunohistochemistries were performed, the biop-sies were not suggestive of PM but rather resembled DM.101

Also, ILD has been reported to occur in at least 10% of PMpatients with at least half having Jo-1 antibod-ies.41,52,91,100,118,127,136,139 However, as has been noted, thesestudies did not define PM histologically, and subsequentbiopsy specimens from patients with Jo-1 antibodies demon-strated features again more similar to DM then PM.

Polyarthritis has been reported in as many as 45% of PMpatients at the time of diagnosis.139 The risk of malignancywith PM is lower than that seen in DM, but it may be slight-ly higher than expected in the general population.23,28,139 Butagain, the diagnosis of PM in these studies was not based onhistopathology so if there actually is an increased risk ofmalignancy in PM, it is unclear.

Laboratory Features

Blood Work

Serum CK level is elevated 5 to 50 fold in the majority of PMcases. Serum CK can be useful in monitoring response totherapy, but only in conjunction with the physical examina-tion. The serum CK level does not correlate with the degreeof weakness. Erythrocyte sedimentation rate (ESR) is normalin at least half the patients and does not correlate with diseaseactivity or severity.22

Positive ANAs are reportedly present in 16-40% of PMpatients.71,91,139 Again the exact relationship of ANAs andCTD in patients with histologically defined PM is unclear.

Electromyography and Muscle Imaging

Electromyography is usually abnormal in PM with increasedinsertional and spontaneous activity, small polyphasicMUAPs, and early recruitment.1,24 Muscle imaging studiescan suggest areas of inflammation in affected muscles.51,117


Muscle Biopsy

The histologic features of PM are distinct from DM. Thepredominate histologic features in PM are variability in fibersize, scattered necrotic and regenerating fibers, andendomysial inflammation with invasion of non-necroticmuscle fibers.1 All of the invaded and some of the noninvad-ed muscle fibers may express major histocompatibility com-plex class 1 antigen which is not normally present in the sar-colemma of muscle fibers.43 The endomysial inflammatorycells consist primarily of activated CD8+ (cytotoxic), alpha,beta T-cells, and macrophages.6,46,47 A single case of PM withCD4- CD8- gamma/delta T-cell inflammation has beenreported in detail.74 Investigations of the T-cell receptor(TCR) repertoire of endomysial T-cells in PM demonstratean oligoclonal pattern of gene rearrangements and a restrict-ed motif in the CD3R region of the TCR suggesting theimmune response is antigen-specific.94 Finally, in contrast toDM, there is no evidence of immune deposits (MAC, com-plement, or immunoglobulins) on the microvasculature inPM. Gene expression studies in muscle demonstrated upreg-ulation of immunoglobulin genes.59 It has been demonsratedthat large numbers of endomysial plasma cells sometimes sur-round muscle fibers. Myelodendritic cells that in part func-tion to present antigens to both T-cells and B-cells are abun-dant in the endomysium as well.

Pathogenesis

The histologic and immunologic features seen by the musclebiopsy suggest that PM is the result of a HLA-restricted, anti-gen-specific, cell-mediated immune response directed againstmuscle fibers. The trigger of this autoimmune attack is notknown. A viral etiology has been speculated, but there is noconclusive evidence supporting this theory.1,86 Most class 1molecules on the surface of cells express endogenous self-pep-tides. Viral antigens and genomes have not been identified inthe muscle fibers suggesting that the immune response maybe directed against endogenous self-antigens rather thanprocessed viral antigens. Nonetheless, viral infection couldindirectly trigger an autoimmune response secondary tocross-reactivity with specific muscle antigens, altering theexpression of self-antigens on muscle fibers, or by the loss ofphysiologic self-tolerance.47 Interestingly, PM can develop asa complication of human immunodeficiency virus (HIV)and human T-lymphocyte virus 1 (HTLV-1) infections.35,47

In these cases, the myositis appears to be the result of suchindirect triggering of the immune response against musclefibers.

The cytotoxic T cells appear to induce cell death via the per-forin pathway. The autoinvasive T-cells in PM contain per-

forin granules, which are orientated to the surface of the mus-cle fibers.57 When released by exocytosis, these granulesinduce pore formations on the sarcolemma and result inosmolysis of muscle fibers. Although regenerating and degen-erating muscle fibers express Fas and Fas ligand (a pro-apop-totic complex),19,53 there is no evidence that apoptosis playsa role in muscle fiber destruction. The increased expression ofBcl-2, an anti-apoptotic protein may protect against thepotential apoptotic effect of Fas/Fas ligand.

Prognosis

The majority of patients with PM respond favorably toimmunosuppressive therapies, but usually require life-longtreatment.1,3,30,69,71,73,76,146 Some retrospective studies suggestthat PM does not respond to immunosuppressive agents aswell as DM. However, interpretation of the results of theseretrospective series is difficult as the diagnosis of PM was usu-ally made on the basis of Bohan and Peter’s criteria ratherthan more current criteria based on strict clinical and histo-logical criteria.

OVERLAP SYNDROMES

The overlap syndromes apply to a group of disorders inwhich DM or PM is associated with another well-definedCTD such as scleroderma, mixed connective tissue disease,Sjögren’s syndrome, systemic lupus erythematosus, andrheumatoid arthritis. Whether or not PM is associated withCTD is not clear as the histology in such patients was notdescribed—just that they did not have an obvious DM rash.

Scleroderma

Proximal muscle weakness is common in scleroderma, how-ever, most of the patients have normal serum CKs and nor-mal needle EMG findings. Muscle biopsies may demonstratemild variability in fiber size with atrophy of type 2 musclefibers and perimysial fibrosis. However, active myositis hasbeen reported in 5-17% of patients with scleroderma and canoccur in either of its two major forms—progressive systemicsclerosis or calcinosis cutis, Raynaud’s phenomenon,esophageal dysfunction, sclerodactyly and telangiectasia(CREST) syndrome.49,95,121,138 Scleroderma-myositispatients have increased serum CK levels, and irritable andmyopathic EMGs.

Anticentromere antibodies are seen in the majority ofpatients with CREST syndrome, while anti-Scl-70 antibod-ies are common in patients with progressive systemic sclero-sis. In addition, approximately 25% of North American


patients with scleroderma-myositis have anti-PM-Scl (alsocalled anti-PM-1) antibodies. Anti-PM-Scl is not specific forthis disorder, because only 50% of patients with this anti-body have the scleroderma-myositis overlap syndrome. InJapan, the scleroderma-myositis syndrome is associated withanti-Ku antibodies, rather than anti-PM-Scl antibodies. InNorth America, anti-Ku antibodies are not associated withmyositis, but can be demonstrated in some patients with sys-temic lupus erythematosus.

Sjögren’s Syndrome

Sjögren’s syndrome is characterized by dryness of the eyes andmouth (sicca syndrome) and other mucosal membranes.Muscle pain and weakness are common in Sjögren’s syn-drome, however, actual myositis is rare. Weakness is usuallydue to disuse atrophy secondary to arthritis and pain.Nonetheless, there are reports of both DM and PM associat-ed with Sjögren’s syndrome.40,122,136 About 90% of patientshave ANAs directed against ribonucleoproteins, specificallySS-A (Ro) and less commonly SS-B (La) antibodies.122,134

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune dis-order affecting multiple organ systems. Weakness is notunusual in SLE, but is most often the result of disuse atrophy.Inflammatory myositis is uncommon in SLE. However, someseries have reported that up to 8% of DM and PM patientshave SLE.50,136

The majority of patients with SLE have positive ANA titerswhich are directed against native DNA (highly specific forSLE) and ribonuclear proteins (RNP). The anti-RNP anti-bodies are present in less than half of SLE patients andinclude anti-SS-A and anti-SS-B (also present in Sjögren’ssyndrome), anti-U1 RNP (also present in mixed connectivetissue disease), and anti-Sm (specific for SLE).

Rheumatoid Arthritis

Rheumatoid arthritis (RA) has been reported in up to 13%of patients with DM and PM, although the incidence ofinflammatory myopathy in patients with RA is much less.136

The most common etiology of weakness in RA is type 2 mus-cle fiber atrophy from chronic steroids or disuse secondary toarthralgias.

Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) has clinical featuresof scleroderma, SLE, RA, and myositis.130 Dermatomyositisis more common than PM, although both have beendescribed in association with MCTD.93,130,136 High titers of

anti-U1 RNP antibodies are common in MCTD, these anti-bodies but can also be detected in SLE.

FOCAL MYOSITIS

Clinical features

Focal myositis is a rare disorder which can develop in infan-cy to late adult life.27,32,66,67,102,104 It presents as a solitary,painful, and rapidly expanding skeletal muscle mass whichoften mimics a malignant soft tissue tumor. The legs are themost common site of involvement but it can also affect theupper extremities, abdomen, head, and neck. There are rarecases of focal myositis generalizing to more typicalpolymyositis.67 The disorder needs to be distinguished fromsarcoidosis, Bechet’s syndrome, muscle infarction secondaryto diabetes or vasculitis, and soft tissue tumors. The lesionsmay resolve spontaneously or with corticosteroid treatment.

Laboratory Features

Serum CK and ESR are usually normal. Magnetic resonsanceimaging and CT imaging demonstrate edema within theaffected muscle groups.27,102,104

Histopathology

Mononuclear inflammatory cells composed of CD4+ andCD8+ T-lymphocytes and macrophages are present in theendomysium.27 Necrosis and phagocytosis of necrotic fibersis apparent. Nonspecific myopathic features such as fiber sizevariablity, split fibers, increased centronuclei, and endomysialfibrosis are also described. One report noted that MHC class1 antigens were not expressed on muscle fibers, in contrast topolymyositis where these antigens are typically abnormallyexpressed on the fibers.

Pathogenesis

The etiology is unknown. Immunological studies suggest thedisorder is distinct from PM and not the result of a cell-medi-ated attack directed against a muscle specific antigen.27

SUMMARY

Dermatomyositis, PM, and IBM are clinically, histologically,and pathogenically distinct categories of idiopathic inflam-matory myopathy. Features of DM and PM can overlap withthose of other autoimmune connective tissue diseases. Othertypes of inflammatory myopathy are much less common butare clinically and histologically distinguishable.Dermatomyositis is a humorally-mediated microangiopathy,


while PM is a T-cell mediated disorder directed against mus-cle fibers. The pathogenesis of IBM is unknown.Dermatomyositis and PM are responsive to immunosuppres-sive therapy, in contrast to IBM which is generally refractoryto therapy.16 Prospective, double-blind, placebo-controlledtrials are necessary to determine prognostic features and thebest treatment options for the different disorders.

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INTRODUCTION

Selecting which charged molecule and how much of thatcharged molecule should be allowed to enter or exit a cell orits subcompartments is a critical task accomplished throughnumerous ion channels. Proper regulation of ions may beparticularly important for nerve and muscle given thedemands of electrical excitability. Indeed, dysfunction ofthese channels (“channelopathy”) has been linked to a widevariety of inherited diseases of the nervous system and mus-cle,8,10,20,22 including periodic paralysis, myotonia congenita,episodic ataxia, familial hemiplegic migraine, and episodicataxia (Table 1). Presumably, sporadic disorders with similarphenotypes may also be related to ion channel function,though this remains less well established. The majority of thismanuscript will focus on the genetic syndromes since thoseare the best characterized.

One strikingly common feature of the diverse group of disor-ders secondary to mutations in ion channels is the paroxys-mal nature of the symptoms. Many patients are normal inbetween attacks. Although some triggers of attacks such ascertain foods or temperature have been well defined bypatients, how exactly these trigger symptoms and why thedisease is episodic remain a mystery. Many of the chan-nelopathies start in infancy or childhood and worsen in ado-lescence or young adult life. Some improve in the middle tolate adult years. A common set of medications is effective intreating these disorders. Carbonic anyhdrase inhibitorsimprove attack frequency and severity in periodic paralysis,episodic ataxia, and migraine headache.

Disorders secondary to mutations in skeletal muscle ionchannels are among the best characterized channelopathiesand will be the focus in this manuscript. Recognizing the typ-ical presentation of these disorders avoids the risks and costsof further diagnostic testing and has clear implications fortreatment. The skeletal muscle channelopathies includehypokalemic periodic paralysis (HOPP), hyperkalemic peri-odic paralysis (HYPP), Andersen-Tawil syndrome, paramy-otonia congenita (PC), Becker’s myotonia congenita (MC),and Thomsen’s MC. Malignant hyperthermia and congenitalmyasthenic syndromes may also be linked to dysfunction ofmuscle ion channels.

MUSCLE PHYSIOLOGY AND ION CHANNELS

Nerve input to skeletal muscle depolarizes the outer musclemembrane, which in turn triggers an action potential that ispropagated through the muscle membrane. The actionpotential begins by an inward sodium current mediated bythe rapid opening of voltage-gated sodium channels.Inactivation of sodium channels as well as outward flow ofpotassium through potassium channels leads to repolariza-tion of the membrane. Repolarization is also dependent onhigh chloride conductance. Propagation of the action poten-tial through the muscle membrane causes release of the of cal-cium ions from the sarcoplasmic reticulum. This burst of cal-cium triggers muscle contraction.

Abnormal sodium channel inactivation in vitro first implicat-ed sodium channels as a possible cause for HYPP. Subsequent

19

Skeletal Muscle Channelopathies

Timothy M. Miller, MD, PhD

Clinical InstructorNeurosciences Department

University of CaliforniaSan Diego, California

genetic studies and functional analysis proved this hypothesiscorrect5,18,19 and helped establish the group of channelopathydiseases. The specific gene defects associated with the disor-ders are listed in Table 1. Sodium channel dysfunction is alsoresponsible for PC and a small subset of HOPP. The majori-ty of HOPP is caused by mutations in calcium channels. Aninwardly rectifying potassium channel has been linked toAndersen-Tawil syndrome.

Myotonia congenita is caused by mutations in the CLCN1gene, the major skeletal muscle chloride channel.9 Thesemutations shift the membrane potential to the depolarizingrange. The sustained depolarization allows a new prematureaction potential, which results in skeletal muscle hyperex-citability.4,6,7,24,25 On needle electromyography (EMG) this isrepresented by myotonic runs. Patients with MC experiencemuscle hyperexcitability as stiffness and weakness.

CLINICAL PRESENTATIONS

Periodic Paralyses

Periodic paralyses are a group of dominantly inherited disor-ders characterized by episodic weakness of skeletal muscleswithout effects on the central nervous system or respiratoryfunction.

Patients with inherited periodic paralysis typically present inchildhood with episodic weakness. In general, those withHYPP present at an earlier age (infancy) than those withHOPP (pre-teen). Onset of symptoms after age 20 is strik-ingly unusual for the inherited form of the disease.15 Theattacks of weakness range from mild to full tetraplegia, last-ing from several minutes to 24 hours. The frequency ofattacks is highly variable, with some patients only having afew attacks per year, while others experience attacks daily. Ingeneral, attacks for HOPP occur infrequently (1 per week ormonth), but when they do occur, they are severe and thepatient is unable to get out of bed for hours to a full day.Attacks in HOPP often occur upon first awakening. ForHYPP or PC the attacks may occur daily, lasting only sever-al minutes and causing some disability, but still allowing thepatient to move. The large variability in frequency, severity,and duration has made this generalization difficult to formal-ly quantify. Some of this variability among patients may berelated to behavioral modification, in that attacks are oftenprovoked. Rest after exercise is a common precipitant to anattack for all periodic paralyses. Diet also influences attacks,but with different effects. Missing meals commonly provokesan attack in HYPP whereas eating a large carbohydrate mealprovokes attacks in HOPP. Certain foods may also provokeattacks. Anesthesia is a well-known precipitant for paralyticattacks. For patients with PC, the attacks of episodic weak-ness are usually much less prominent than the myotonia.Some HOPP and HYPP patients describe cold as a precipi-tant. For PC, worsening with cold exposure is a nearly uni-versal phenomenon, often associated with significant weak-ness as well as increased myotonia. The myotonia in HYPPand PC is “paradoxical” in that it is worsened by activityrather than improved with activity. In MC, the myotonia

20 Skeletal Muscle Channelopathies AANEM Course

Table 1 Human channelopathies

Skeletal Muscle Channelopathies

Disorder Gene Channel

Paramyotonia congenita SCN4A Sodium channel

Potassium aggravated myotonia SCN4A Sodium channel

Hyperkalemic periodic paralysis SCN4A Sodium channel

Hypokalemic periodic paralysis CACNA1S Calcium channel

Andersen-Tawil syndrome KCNJ2 Potassium channel

Myotonia congenita CLCN1 Chloride channel

Congenital myasthenic CHRNA Acetylcholine receptorsyndrome

CHRNB Acetylcholine receptor

CHRNE Acetylcholine receptor

Other Neurological Diseases

Spinocerebellar ataxia type 6 CACNA1A Calcium channel

Familial hemiplegic migraine CACNA1A Calcium channel

ATP1A2 Sodium-potassium transporter

Episodic ataxia with myokymia KCNA1 Potassium channel

Episodic ataxia with nystagmus CACNA1A Calcium channel

Hereditary hyperekplexia GLRA1 Glycine receptor

Cardiac Disease

Long QT syndrome

Type 1 KVLQT1 Potassium channel

Type 2 HERG Potassium channel

Type 3 SCN5A Sodium channel

Type 4 ANK2 Ankyrin B

Type 5 minK Potassium channel

Type 7 KCNJ2 Potassium channel

QT = quick time.

improves with continued activity, termed the “warm-up”phenomenon.

Neurological examination between attacks in youngerpatients with periodic paralysis may be entirely normal, withthe exception of myotonia in patients with HYPP or PC. Asnoted earlier, the myotonia is paradoxical. In older patientswith periodic paralysis, a surprising number of patients willhave evidence of proximal weakness,2,12,13,15 which in some issevere.

Laboratory testing has found that potassium does indeedhelp distinguish HYPP and HOPP especially if potassium istested during one of the attacks. Hyperkalemic periodicparalysis or PC has normal or slightly elevated potassium.Hypokalemic periodic paralysis patients have low potassiumduring the attacks. Needle EMG is strikingly differentbetween HYPP and HOPP or PC. Electrical myotonia iscommon in HYPP and PC and almost never found inHOPP. On muscle biopsy, a vacuolar myopathy is the mostcommon finding.

As will be discussed in more detail, the exercise test shows adecrement in HOPP, HYPP, and PC. In general, HOPP andHYPP do not show an objective cold effect; PC patients dohave an objective cold effect. In occasional patients with PCor HYPP, there may be some overlap in the exercise test andobjective cold effect. Administration of potassium will pro-voke attacks in HYPP, although this test is not routinely per-formed. Similarly driving potassium into cells by givinginsulin and glucose simultaneously may provoke an attack inHOPP, although this is also not routinely performed.

Genetic testing for periodic paralysis is performed by somespecialized laboratories. The easiest way to find suchresources may be by logging on to http://www.genetests.org/.Most laboratories will only test for the common mutations.Typically HOPP shows mutations in the calcium channelgene CACNA1S, most commonly R528H and R1239H,although disease-causing sodium channels and potassiumchannel mutations are recognized. There are some differencesbetween the various mutations, e.g., HOPP secondary tosodium channels is often less responsive to acetazolamidetherapy. Two mutations in the sodium channel SCN4A gene,T704M and M1592V, account for the majority of HYPP.Mutations in the sodium channel are also responsible for PC;residues R1448C and T1313M are the most commonlyaffected.

Treatment with carbonic anhydrase inhibitors decreasedattack severity and frequency in both HYPP and HOPP. Theefficacy of dichlorphenamide was demonstrated in one clini-

cal trial.27 Acetazolamide is also commonly used. During anacute attack for HOPP, replacing potassium often helpsrestore strength. Education regarding typical triggers in thedisease may help prevent attacks, although in the inheritedforms of the disease, the triggers are usually well-known tothe patients.

Andersen-Tawil Syndrome

Andersen-Tawil syndrome is associated with the triad of car-diac arrhythmias, dysmorphic features, and periodic paraly-sis. The episodic weakness may be similar to periodic paraly-sis. There is no myotonia. The distinguishing features are theother manifestations of the disease including dysmorphismssuch as clinodactyly, syndactyly, hypertelorism, and low setears. The dysmorphisms may be subtle and not easily recog-nized. The part of the disease that causes the most concern isthe cardiac abnormalities, which sometimes cause malignantventricular arrhythmias. It is the cardiac problems with thisdisorder that strongly argues for checking an electrocardio-gram (EKG) in all patients suspected to have periodic paral-ysis, especially since the dysmorphic features may be verysubtle. The EKG findings in Andersen-Tawil syndrome mayinclude prolonged quick time interval (common early sign),bigeminy, and ventricular tachycardia. Some patients requirecardioverter defibrillators. Andersen-Tawil syndrome iscaused by a mutation in potassium channel KCNJ2.17

Potassium-Aggravated Myotonia

Potassium administration “aggravates” or brings on myotoniain patients with potassium-aggravated myotonia. They alsoexperience random, episodic myotonia without any associat-ed weakness. The myotonia is not sensitive to cold and ismost prominent about 20 minutes after exercise. Like HYPPand PC, the disorder is linked to sodium channel dysfunc-tion.21

Inherited Periodic Paralysis of Uncertain Etiology

There is a group of patients that have some of the features ofperiodic paralysis, but no demonstrable mutation in sodium,calcium, or potassium ion channels.15 Some of these patientsalso have a convincing family history. In general, patientswithout evidence of ion channel mutations are older at dis-ease onset. In addition, these patients rarely describe diet as aprecipitant for an attack, a common trigger for those withmutations. Finally, patients with mutations often show vac-uolar myopathy on muscle biopsy. Patients without muta-tions often have nonspecific, abnormal muscle biopsies.Despite the less typical features, these patients also respond tocarbonic anhydrase treatment. All of these patients with less


typical features and especially those without a family historyneed to have a thorough investigation of secondary (metabol-ic) causes of periodic paralysis.

Metabolic Periodic Paralysis

The most common metabolic derangement associated withHOPP is thyrotoxicity. At first presumed to only effectAsians, it is now recognized among a large number of ethnicgroups. Despite the fact that thyrotoxicosis is more commonamong women, thyrotoxic periodic paralysis is much morecommon among men (20:1 ratio). The second to fourthdecade is the typical age presentation for thyrotoxic periodicparalysis. The genetic contribution and how the thyrotoxici-ty triggers the HOPP remains unknown. The attacks in thisdisorder are commonly provoked by rest after exercise or alarge carbohydrate meal, and are associated with signs ofhyperthyroidism and a low serum potassium. Returning thepatient to a euthymic state treats the disorder. Potassiumreplacement aids recovery of strength, but should be moni-tored closely, especially if given intravenously, as reboundhyperkalemia may occur.26 All patients with suspected peri-odic paralysis should be checked for thyroid disease.

Chronic potassium wasting, e.g., with diuretics or because ofrenal tubular acidosis, can also cause periodic paralysis. Inpatients without a family history of the disease and no evi-dence of the thyroid disease, especially in older patients, a fullsearch for chronic potassium wasting should be sought.

Myotonia Congenita

Myotonia congenita presents in infancy to childhood. Bothforms of MC, Thomsen’s MC, and Becker’s MC present withnearly identical phenotypes. They are distinguished by theirmode of inheritance. Thomsen’s MC is dominant whileBecker’s MC is recessive. Some physicians have noted thatBecker’s MC tends to present somewhat later (age 4-12) thanThomsen’s MC (infancy) and that Becker’s MC patients havemore severe symptoms.22 While the attacks of myotonia areoften described as being associated with mild weakness, stiff-ness (myotonia) is the predominant symptom. The myotoniain MC differs clinically from that found in PC or HYPP. InHYPP or PC, the myotonia worsens with continued activity.In MC, myotonia improves with continued activity and thisso called, “warm-up” phenomenon is characteristic. Attacksof myotonia may be provoked by rest after exercise or cold, aswith the periodic paralyses. However, triggers for the myoto-nia are usually a less prominent feature of the disease thanwith the periodic paralyses. As with periodic paralyses, thereare patients with a positive family history and some featuresof the disease who do not have demonstrable mutations in

ion channels. There are often less typical features in thesepatients and myotonia is less prominent on needle EMG.

On examination, patients often have preserved strength withhypertrophied muscles that seem at odds with their physicallimitation. Masseter muscle hypertrophy may produce acharacteristic facial appearance. Percussion myotonia may bereadily demonstrated. Myotonia improves with repeatedmovement.

General laboratory findings are normal, except creatine phos-phokinase may be slightly elevated. Needle EMG showsprominent, widespread myotonia.

A subset of patients with MC may have a decrement on theexercise test.1,11 There is no objective cold effect, althoughelectrical myotonia may increase with cooling. Mutations inchloride channels are responsible for MC. Why the variousmutations cause either dominant or recessive disease remainsa mystery. In fact, the same mutation may cause recessive(Becker’s) or dominant (Thomsen’s) disease. There are fewlaboratories performing routine genetic testing for MC. Thewebsite http://www.genetests.org/ may be the best resourceto find current testing.

Many patients with MC do not need or seek treatment fortheir myotonia. However, for others the symptoms are dis-abling. Although there are no approved medications for thetreatement of MC, the myotonic symptoms are best treatedwith mexilitene, an orally absorbed lidocaine derivative thatfunctions as a use-dependent sodium channel blocker.Quinine, procainamide, phenytoin, and carbamazepine havealso been used with some success.

SPECIALIZED TESTING

Exercise Test

The exercise test and provocative cold test are two straightfor-ward examinations that can be performed in any electrodiag-nostic (EDX) laboratory. A protocol for the exercise test andprovocative cold test are provided in Tables 2 and 3. Theexercise test, as first described by Phil McManis14 shows adecrement of the compound muscle action potential(CMAP) when the CMAP is tested over time following 5minutes of sustained exercise. The test is positive in bothHOPP, HYPP, and in PC. A positive test is defined as agreater than 40% drop in CMAP. Both metabolic and famil-ial cases are likely to be positive. The decrease in patients withPC differs qualitatively from HOPP and HYPP. In PC, fol-lowing exercise, there is a rapid fall in the amplitude followed


by a slow increase back to baseline over the next 60-90 min-utes. In HOPP and HYPP, the amplitude may be mildly lowat rest, increase slightly, and then fall by greater than 40%over the next 15-30 minutes. Some cases of MC also show adecrement on the exercise test as well, but this is not consis-tent. The response to the exercise test is summarized in Figure1.

Provocative Cold Test

Patients with PC often describe weakness and stiffness pro-voked by cold. This may be a direct effect on the muscles andcan be reproduced in the EDX laboratory.16,23 A protocol forthe provocative cold test is provided in Table 3 and a positivetest is defined as an objective cold effect with a decrease inCMAP amplitude greater than 75%. The most specializedpiece of equipment not standard to many EDX laboratoriesis a basic, long thermometer that can be submerged in water.The “old style” with a column of fluid works best. TheCMAP is recorded before and after cooling the hand in abucket of cool (15˚ C) water. Patients with PC may initiallyshow increased myotonia with mild cooling, but will then

show decreased electrical activity during needle EMG and aremarkable decrease in CMAP amplitude. Patients with MCwill show an increase in myotonia with cooling, but theCMAP amplitude will not be effected. Typically HOPP andHYPP do not show any changes with cooling. However,some “overlap” cases of HYPP do show an objective coldeffect.

Differential Diagnosis

Table 4 summarizes the clinical features of MC and Table 5summarizes the clinical findings in MC. With these tables inmind, often the correct diagnosis can be reached byhistory/physical and relatively few diagnostic tests. Figure 2outlines one approach to patients with episodic weakness.

The approach to patients with suspected MC is often lesschallenging than periodic paralysis. In clinical practice, itmay make little difference whether the patient is labeled ashaving Thomsen’s MC versus Becker’s MC, though someauthors have argued that Becker’s is more severe thanThomsen’s. The first important step is to establish that there


Table 2 Exercise test

1. Rule out compressive or other lesion affecting nerve to bestudied

2. Record CMAP of EDB, APB, or ADM

3. Be sure that recording electrode is secured well

4. Exercise patient by sustained contraction of muscle for 5 minutesRest breaks of a few seconds are allowed for patient

5. Following exercise, Record CMAP every 1 minute for 5 minutes

6. After first 5 minutes, record CMAP every 5 minutes for 30 to 60minutes

7. Test is positive if CMAP area decreased greater than 40%

8. Note that CMAP may increase slightly in the first few minutes

9. See Figure 1 and text for interpretation

ADM = adductor digiti minimi; APB = abductor pollicis brevis; CMAP = compoundmuscle action potential; EDB = extensor digitorum brevis.

Table 3 Provocative cold test

1. Rule out compressive or other lesion of nerve to be studied

2. Record CMAP from APB, ADM or if needed EDB

Hand muscles preferable

3. Use indelible marker to mark exactly where the recordingelectrode is placed

It is useful to draw a box/circle around the entire electrode

4. Remove electrodes

5. Place patient’s hand (or foot) in a basin with water cooled toapproximately 15˚ C

This should be monitored closely with a thermometer. Muchcolder than 15˚ C is uncomfortable (and possibly harmful)and much warmer than 15˚ C may be produce a falsenegative result

6. Ask patient to self regulate the temperature by occasionallyadding 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 = compoundmuscle action potential; EDB = extensor digitorum brevis.


Figure 1 Exercise test.

Changes in compound muscle action potential (CMAP) in response to 5minutes of exercise. The amplitude increases minimally in normalsubjects with a return to baseline over 5 minutes. In paramyotoniacongenita, there is a precipitous decline in CMAP amplitude with a slowreturn towards baseline. In periodic paralysis, there is an initial increasein CMAP amplitude followed by a slow decline over 15 to 30 minutes.Lambert-Eaton syndrome shows a low amplitude at rest and a prominent(usually > 200%), nonsustained increase in amplitude followingexercise.

Modified from a chapter by P. McManis in: Neuromuscular function and disease:basic, clinical, and electrodiagnostic aspects, ed. Brown, Bolton, Aminoff, 2002.3

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, myotoniaexamination findings

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 Coldcarbohydrates

Salt Potassium-richfoods

Myotonia No Yes Always

Weakness Yes Yes Yes

Potassium level Low Normal to NormalHigh

Response to Relieves acute Causes No effectpotassium paralysis weakness

Objective cold effect None None Causes weakness

Muscle biopsy Vacuolar Vacuolar Variablemyopathy myopathy

HOPP = hypokalemic periodic paralysis; HYPP = hyperkalemic periodic paralysis;PC = paramyotonia congenital.

Table 5 is reproduced from Miller and colleagues, Neurology 2004;63(9):1647-165515 with permission from Lippincott Williams & Wilkins.


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 presentsduring 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.

is indeed myotonia, both clinically and by needle EMG. Thenext step is to exclude other myotonic disorders, such asmyotonic dystrophy.

CONCLUSION

Current management of patients with periodic paralysis andMC depends on an accurate clinical diagnosis, one in whichthe EDX consultant often plays an important role. Furtherstudies of ion channel mutations and their functional conse-quences may lead to a better understanding of skeletal mus-cle channelopathies and other episodic neurological disor-ders, as well as guide future therapies.

REFERENCES

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2. Bradley WG, Taylor R, Rice DR, Hausmanowa-Petruzewicz I,Adelman LS, Jenkison M, Jedrzejowska H, Drac H, PendleburyWW. Progressive myopathy in hyperkalemic periodic paralysis. ArchNeurol 1990;47:1013-1017.

3. Brown WF, Bolton CF, Aminoff MJ. Neuromuscular function anddisease : basic, clinical, and electrodiagnostic aspects. Philadelphia:Saunders; 2002.

4. Fahlke C. Molecular mechanisms of ion conduction in ClC-typechloride channels: lessons from disease-causing mutations. KidneyInt 2000;57:780-786.

5. Fontaine B, Khurana TS, Hoffman EP, Bruns GA, Haines JL,Trofatter JA, Hanson MP, Rich J, McFarlane H, Yasek DM.Hyperkalemic periodic paralysis and the adult muscle sodium chan-nel alpha-subunit gene. Science 1990;250:1000-1002.

6. Fontaine B. Periodic paralysis, myotonia congenita, and sarcolemmalion channels: a success of the candidate gene approach.Neuromuscular Disorders 1993;3:101-107.

7. Heine R, George AL Jr, Pika U, Deymeer F, Rudel R, Lehmann-Horn F. Proof of a non-functional muscle chloride channel in reces-sive myotonia congenita (Becker) by detection of a 4 base pair dele-tion. Hum Mol Genet 1994;3:1123-1128.

8. Jurkat-Rott K, Lerche H, Lehmann-Horn F. Skeletal muscle chan-nelopathies. J Neurol 2002;249:1493-1502.

9. Koch MC, Steinmeyer K, Lorenz C, Ricker K, Wolf F, Otto M, ZollB, Lehmann-Horn F, Grzeschik KH, Jentsch TJ. The skeletal musclechloride channel in dominant and recessive human myotonia.Science 1992;257:797-800.

10. Kullmann DM, Hanna MG. Neurological disorders caused by inher-ited ion-channel mutations. Lancet Neurol 2002;1:157-166.

11. Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A,Gonnaud PM, Ochsner F, Soichot P, Chan V, Monnier G. Exercisetest in muscle channelopathies and other muscle disorders. MuscleNerve 2000;23:1089-1094.

12. Links T, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ.Permanent muscle weakness in familial hypokalaemic periodic paral-ysis. Clinical, radiological and pathological aspects. Brain1990;113:1873-1889.

13. Links TP, Smit AJ, Molenaar WM, Zwarts MJ, Oosterhuis HJ.Familial hypokalemic periodic paralysis. Clinical, diagnostic and ther-apeutic aspects. J Neurol Sci 1994;122:33-43.

14. McManis PG, Lambert EH, Daube JR. The exercise test in periodicparalysis. Muscle Nerve 1986;9:704-710.

15. Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR,Tawil R, McManis P, Griggs RC, Angelini C, Servidei S, Petajan J,Dalakas MC, Ranum LP, Fu YH, Ptacek LJ. Correlating phenotypeand genotype in the periodic paralyses. Neurology 2004;63:1647-1655.

16. Nielsen VK, Friis ML, Johnsen T. Electromyographic distinctionbetween paramyotonia congenita and myotonia congenita: effect ofcold. Neurology 1982;32:827-832.

17. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S,Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R,Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A,Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, PtacekLJ. Mutations in Kir2.1 cause the developmental and episodic electri-cal phenotypes of Andersen’s syndrome. Cell 2001;105:511-519.

18. Ptacek L, George AL Jr, Griggs RC, Tawil R, Kallen RG, Barchi RL,Robertson M, Leppert MF. Identification of a mutation in the genecausing hyperkalemic periodic paralysis. Cell 1991;67:1021-1027.

19. Ptacek L, Tyler F, Trimmer JS, Agnew WS, Leppert M. Analysis in alarge hyperkalemic periodic paralysis pedigree supports tight linkageto a sodium channel locus. Am J Hum Genet 1991;49:378-382.

20. Ptacek LJ, Fu YH. Channels and disease: past, present, and future.Arch Neurol 2004;61:1665-1668.

21. Ptacek LJ, Tawil R, Griggs RC, Storvick D, Leppert M. Linkage ofatypical myotonia congenita to a sodium channel locus. Neurology1992;42:431-433.

22. Renner DR, Ptacek LJ. Periodic paralyses and nondystrophic myoto-nias. Adv Neurol 2002;88:235-252.

23. Ricker K, Hertel G, Langscheid K, Stodieck G. Myotonia not aggra-vated by cooling. Force and relaxation of the adductor pollicis in nor-mal subjects and in myotonia as compared to paramyotonia. J Neurol1977;216:9-20.

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INTRODUCTION

Toxic and metabolic myopathies are considered to be rare dis-orders. Or are they? Their incidence is not known, and giventhe large number of available drugs, the frequency ofpolypharmacy and its effect on drug metabolism, and othervariables such as genetic differences in metabolism, it is like-ly that the incidence is much higher than suspected. Sincetoxic and metabolic myopathies are potentially treatable, it isimportant to recognize them at an early stage. Some of thechallenges in assessing a patient for such a myopathy relate tothe many possible variables that could cause the myopathy.For example, there are known toxins, toxins that rarely causemuscle disease, and some that are possible toxins in certainsituations. Similarly, there are known metabolic states thatcause muscle disease, some that rarely do, and others thatappear on lists of metabolic disorders with little firm clinicaldata. Clinically, the definitions of symptoms supporting tox-icity vary among incidence reports, and there are patientswho present with clear weakness, some with ill-definedfatigue or muscle pain, and some who have normal strengthbut an elevated serum creatine kinase (CK) level discoveredon a random blood test panel and who are also taking a list-ed drug. Given these factors, assessment of potential toxinsand metabolic states must always be considered in the differ-ential diagnosis of any muscle disorder.

This manuscript will focus on toxins and metabolic states inskeletal muscle (and will exclude primary cardiomyopathies).The list of possible agents will be narrowed to those thatcould be encountered in the outpatient clinic and inpatientconsultation service. It will consider primary causes but notsecondary causes such as drugs that induce coma resulting inmuscle compression. Primary genetic disorders will not bediscussed. Tables 1 and 2 include lists of toxins and metabol-ic states, respectively, for reference. Toxic myopathies havebeen tabulated by a mixed list of headings, including thosebased on muscle biopsy findings (necrotic, inflammatory),on organelle involvement (mitochrondrial), on class of drug(lipid-lowering agents), and a variety of other headings. It isdifficult to improve upon this disparate scheme. For most,the mechanism of toxicity is unknown, and general descrip-tions have to suffice.

DEFINITIONS OF MUSCLE DISEASE

The spectrum of symptoms used to support a toxic and meta-bolic myopathy is broad and influences the interpretation ofthe literature. Examples of definitions are: “myopathy” as anymuscle complaint; “myositis” as symptoms plus an elevatedCK; and “rhabdomyositis” when the CK is greater than10,000 IU/L and the creatinine level is elevated.19

27

Toxic Drug-induced Myopathies

Mark B. Bromberg, MD, PhD

Department of NeurologyUniversity of Utah

Salt Lake City, Utah

VULNERABILITY OF MUSCLE

Skeletal muscle is susceptible to a variety of toxic and meta-bolic insults. Direct pressure and vascular insufficiency areobvious examples, but will not be considered. Muscle is acomplex structure. Macroscopically, muscles are made up ofinnumerable fibers that run the length of the whole muscle.Microscopically, muscle fiber cytoplasm (sarcoplasma) is con-tained and separated from extracellular and vascular environ-ments by a bi-lipid membrane (sarcolemma). The membraneis composed of a variety of lipids, including cholesterols.Further, the sarcolemma is not a simple tubular structure, buthas an extensive network of invaginations of the membraneinto the middle of the fiber (transverse tubules), and the over-all square area of the sarcolemma is tremendous. Within thesarcoplasma are the contractile proteins actin and myosin.There is an extensive endoplasmic reticulum that participatesin the release of calcium required for contractile function.There is also an important series of proteins that may be vul-nerable in toxic and metabolic myopathies. These includeproteins that link actin to the basal lamina, and include dys-trophin and the sarcoglycan complex, and other protein com-plexes that are involved in muscle function.

Energy requirements of muscle are high, and muscles at restconsume approximately 35% of total energy, and with vigor-ous activity a much greater percentage. The internal ionicenvironment of muscle is tightly regulated, particularly for

28 Toxic Drug-Induced Myopathies AANEM Course

Table 1 List of drugs implicated in muscle disease.

Necrotizing

Cholesterol-lowering agents

HMG-CoA reductase inhibitors

Atorvastatin

Fluvastatin

Lovastatin

Pravistatin

Rosuvastatin

Simvastatin

Fibric acid derivatives

Gemfibrozil

Probucol

Clofibrate

Epsion-aminocaproic acid

Immunophilins

Cyclosporine

Tacrolimus

Propofol

Ethanol

Amphiphilic

Chloroquine

Hydroxychloropuine

Aminodarone

Antimicrotubular

Colchicine

Vincristine

Drug-induced mitochondrial myopathy

Zidovudine

Other HIV-related antiretrovirals

Hypokalimic

Diuretics

Laxatives

Impaired protein sythensis

Emedine (Ipecac syrup)

Unknown mechanism

Critical illness

Omeprazole

Cyclosporine

HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A.

Table 2 List of metabolic abnormalities implicated in muscledisease.

Glucocorticoid Diseases

Excess

Cushing disease

Corticosteroid drugs

Deficiency

Adrenal insufficiency

Thyroid Disease

Excess

Thyrotoxicosis

Thyrotoxic periodic paralysis

Deficiency

Hypothyroidism

Growth Hormone

Acromeglay

calcium, and its regulation has a major role in the contractionprocess. Adenosine triphosphate (ATP) is the source of ener-gy for these regulatory processes. Energy is supplied by threemetabolic pathways. The first, immediate availability ATP,comes from the combining of phosphocreatine with adeno-sine diphosphate (ADP). This reaction is rapid but is used upwithin minutes with intense exercise. The second most avail-able source is anerobic metabolism from glycogen through itsconversion to glucose, and on to pyruvate. The energy fromglycogen via anerobic metabolism is limited for two reasons;(1) glycogen stores in muscle are modest, and can be con-sumed within 2 hours of active exercise; (2) only a net twoATP molecules are generated from each molecule of glucose.Aerobic metabolism results in a greater yield of ATP. Pyruvicacid, through the tricyclic acid cycle, generates 36 ATP mol-ecules. The third metabolic pathway is the metabolism oftriglycerides which can yield up to 129 ATP moleculesthrough the electron transport system.

Another issue is that the enzymes responsible for anerobicmetabolism are located in the sarcoplasm, while those for aer-obic metabolism are located in mitochondria. Mitochondriaare complex in that there are transport proteins that are nec-essary for the shuttling of molecules back and forth across theinner and outer membranes. Evidence for the key roles thatmitochondrial production of energy play in contraction arethe large number of mitochondria in muscle and their loca-tion close to contractile proteins. Thus, there are many stepswhere disturbances of muscle metabolism could lead to mus-cle dysfunction.

CLINICAL AND LABORATORY FEATURES

There are a number of clinical and laboratory symptoms andfindings that suggest a toxic or metabolic disorder of muscle.Unfortunately, none are specific, and some toxic or metabol-ic disorders are largely silent. The symptom list includes mus-cle pain, soreness, swelling, fatigability, and weakness. Thelaboratory findings are an elevated serum CK, myoglobin-uria, needle electromyography (EMG) abnormalities, andpathologic changes in biopsied muscle tissue. Muscle pain orsoreness is not specific, making it challenging to determinewhether they represent a metabolic or toxic disorder whensymptoms are unaccompanied by true weakness, elevatedCK, and EMG abnormalities. Similarly, nonspecific fatigabil-ity without other clinical features is challenging, and disor-ders of the neuromuscular junction (myasthenia gravis andLambert-Eaton syndrome) must be excluded. Nonspecificsymptoms are also part of the chronic fatigue syndrome,

which further increases the diagnostic difficulties. Muscleweakness is usually assessed by brief testing in the clinic basedon the Medical Research Council (MRC) scale that has awide range for normal (grade 5), and factors for gender, age,physical build, and degree of conditioning must be included,or mild degrees of weakness can be missed. The time courseof symptoms varies from acute (rare) to subacute over sever-al months (most common), to insidious over years (leastcommon).

Among laboratory tests, serum CK is felt to be a good mark-er for sarcolemmal disruption. However, values vary betweengenders and among ethnic groups.6 Serum CK is occasional-ly high (>10 x upper limb of normal [ULN]) to extraordinar-ily high (1000+ x ULN) in acute cases, and may be mildlyelevated (2 x ULN) in asymptomatic individuals who areimplicated because they are taking a listed drug. The signifi-cance of incidental mild elevations (approximately 2 x ULN)is not clear.20 Needle EMG is a sensitive tool for assessingstructural (architectural) alterations of muscle fibers.Abnormal spontaneous activity (positive sharp waves and fib-rillation potentials) and complex motor unit action potentials(polyphasic and polyturn) with rapid recruitment are find-ings supporting a myopathic process (Figure 1).2 However,in less severe cases, and with abnormalities of energy metab-olism, such changes do not occur and the EMG may be nor-mal. Muscle biopsy findings are helpful in several ways. It isthe most sensitive tool for making a diagnosis of a myopathybecause subtle morphologic changes can be detected, and his-tochemical stains can directly measure enzymatic activity andidentify specific abnormalities (Figure 2). However, in caseswith mild symptoms, the biopsy may be normal or minimal-ly abnormal with only nonspecific findings.

DIAGNOSIS

A diagnostic algorithm is advantageous, but there are fewclear nodal points (Figure 3). In general, the history andphysical examination determines whether there is weaknessand its pattern (proximal for a myopathy, proximal and dis-tal for a neuromyopathy), an electrodiagnostic (EDX) studyto determine if there is a defect in neuromuscular junctiontransmission or altered muscle fiber architecture (necroticand inflammatory myopathies), and a serum CK level.Assessment for myoglobinuria and renal failure are requiredin severe cases. A muscle biopsy can define the type of pathol-ogy (necrotic, inflammatory, mitochondrial, myosin dissolu-tion). Laboratory studies for underlying metabolic causes andcontributing factors (renal and hepatic failure, thyroid dys-


function) are appropriate. Finally, careful consideration forpossible interactions of multiple drugs, including ones notspecifically listed, should be considered for their effect ondrug metabolism.

TREATMENT

Treatment is relatively straightforward for most toxicmyopathies—removal of the toxic drug and treatment of themetabolic abnormalities. Associated metabolic consequences,such as rhabdomyolisis and renal failure, must be appropri-ately managed.30 Muscle has a high capacity to regenerate,and recovery of strength will take time.

RISK FACTORS FOR TOXIC AND METABOLIC MYOPATHIES

The overall incidence of muscle toxicity from prescriptiondrugs is low. This has been assessed for cholesterol-lowering

agents with myalgias reported in 2-7%, weakness or elevatedCK in 0.1-1%, and severe myopathy in 0.08%.28 There areassociated factors that may increase the risk in subpopula-tions of patients, and many risk factors are interrelated (Table3). For example with lipid-lowering agents, advanced age isassociated with other diseases that may raise lipid levels andlead to a greater need for such agents. Further, there may beneeds for additional medications to treat concurrent age-related diseases, resulting in polypharmacy. Multiple drugsalso increase the chances of affecting the cytochrome P-450(CYP) enzyme system, the major detoxification pathway formany drugs. Advanced age and other diseases may reducerenal and hepatic function, altering metabolism.

The CYP system is responsible for oxidative metabolism of alarge percentage of drugs (Table 4). However, drugs mayeither induce or inhibit CYP enzymes.31 Inhibition occursfrom other drugs, and also with natural foods (grapefruitjuice). Further, there are genetic differences in the CYP sys-tem in greater than 1% of the population due of polymor-phisms or variant alleles that can increase or reduce drug oxi-dation.

CHOLESTEROL-LOWERING AGENTS

HMG-CoA Reductase Inhibitors

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)reductase is the rate-limiting step in the synthesis of choles-terol, and catalyzes the formation of mevalonic acid. Thereare another dozen enzymatic steps from mevalonic acid tocholesterol. While it was initially thought that drugs inhibit-


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

Figure 2 Left: Vacuolar changes. Right: Ragged red fiberssupporting mitochondrial changes.

ing HMG-CoA reductase could contribute to decreased sar-colemmal cholesterol content leading to destabilization andeventual destruction of the membrane, there are newer datato implicate a more complex pathology involving steps alongthe way.1

Clinical features vary from asymptomatic elevations in serumCK to myalgias to weakness.28 The drug cervistatin is anexample of a drug that produced a much higher incidence ofrhabdomyolysis leading to mortality and morbidity in thesetting of renal failure, and was subsequently taken off themarket. Needle EMG in weak patients shows abnormalitiesconsistent with muscle fiber damage, but is usually normal in


Table 3 Factors and their effects on drug metabolism that maylead to myotoxicity.

Factors Effect

Advanced age Concomitant diseases

Polypharmacy Increases or decreases P-450 metabolism

Hepatic insufficiency Reduced metabolism

Renal insufficiency Reduced elimination

P-450 enzyme system Increased or decreased drug metabolism

Diet P-450 inhibition by grapefruit juice

Symptoms suggestive of muscle disease:

Myalgias

Cramps

Fatigue

Weakness

Review medications:

Discontinue or reduce dose of suspected medications

If symptoms mild and CK mildly elevated:

Follow patient

If symptoms marked and CK high:

Muscle biopsy

Initial laboratory studies:

Serum CK

TSH

Creatinine

EMG

If CK > 10,000:

Check for myoglobinuria

If creatinine high:

Fluids

Treat thyroid disease

Figure 3 Algorithm for evaluation and treatment of toxic andmetabolic myopathies.

CK = creatine kinase; EMG = electromyography; TSH = thyroid stimulating hormone.

Table 4 List of common drugs and their effect on the CYP3Afamily of cytochrome P-450 enzyme system (modified fromWilkinson G.).

SUBSTRATES INHIBITORS INDUCERS

Calcium-channel Calcium-channel Rifamycinsblockers blockers

Diltiazem Diltiazem Rifampin

Nifedipine Verapamil

Verapamil

Immunosuppressant Axole antifungal Anticonvulsant agents agents agents

Cyclosporine Ketoconazole Carbamazepine

Tacrolimus Phenobarbital

Phenytoin

Benzodiazepines Microlide antibiotics

Alprazolam Clarithomycin

Midazolam Erythromycin

Triazolam

Statins

Atorvastatin

Lovastatin

Anti-HIV agents Anti-HIV agents Anti-HIV agents

Indinavir Delavirdine Efavirenz

Nelfinavir Indinavir Nevarapine

Ritonavit Ritonavit

Saquinavir Saquinavir

Miscellaneous Miscellaneous Miscellaneous

Sildenafil Mifepristone St John’s wort

Grapefruit juice

HIV = human immunodeficiency virus

asymptomatic patients with only elevated CK levels. Musclebiopsy shows fiber necrosis and regeneration, and subsar-colemmal accumulation of autophagic lysosomes in electronmicrographic examination. In general, symptoms and signsreverse with removal of the drug.

FIBRIC ACID DERIVATIVES

In fibric acid derivatives, the mechanism is not known, but ispostulated to destabilize muscle fiber membrane leading todegeneration.24 The clinical, needle EMG, and biopsy fea-tures vary as they do with HMG-CoA reductase inhibitors.

IMMUNOPHILINS

Cyclosporine and tacrolimus are immunosuppressive agentsused particularly for organ transplant patients. Cyclosporinemay cause myalgias and weakness.7 Rhabodmyolysis has beendescribed with concurrent use of cholesterol-lowering agents(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-tulated to destabilize the membrane in a similar manner aswith cholesterol-lowering agents, thus explaining theincreased risk with the combination of drugs.

PROPOFOL

Propofol is used in intensive care settings for sedation of ven-tilated patients and treating status epilepticus. There arereports of rhabodmyolysis and myoglobinuria primarily inchildren.8 Given the intensive care setting, concomitant fac-tors such as acute quadriplegic myopathy must be consid-ered.

AMIODARONE

Amiodarone is unique in that it can cause a neuropathy andmyopathy (neuromyopathy).5,17 Thus there may be distalweakness from the neuropathy and proximal weakness fromthe myopathy. Accordingly, nerve conduction studies areconsistent with an axonal neuropathy, but in cases with acuteonset there may be initial demyelinating features similar tothose recorded in Guillain-Barré syndrome. Needle EMGwill show abnormal spontaneous activity and motor unitswill likely have a myopathic pattern in proximal muscles anda neuropathic pattern (high amplitude potentials with

reduced recruitment) in distal muscles. Serum CK levels areelevated. Muscle biopsy shows autophagic vacuoles.Pathogenesis is attributed to drug interaction with the mus-cle fiber membrane.

ANTIMICROTUBULAR MYOPATHIES

Colchicine

Colchicine can cause a neuromyopathy and symptoms devel-op usually after long-term use. Renal insufficiency is a pro-moting factor.13 Weakness develops slowly, and the neuropa-thy is mild. Nerve conduction studies show distal slowingand reduced sensory and motor responses. Needle EMGshows a proximal myopathic and distal neuropathic pattern,and may include myotonic discharges.22 Serum CK levelsvary from mildly to markedly elevated. Muscle pathologyshows a vacuolar pattern. Disruption of microtubular trans-port of lysosomes is felt to be the underlying pathologicprocess.

DRUG-INDUCED MITOCHONDRIAL MYOPATHIES

Anti-human Immunodeficiency Virus Drugs

Zidovudine is an antiretroviral drug used for human immun-odeficiency virus (HIV) infections, and causes myalgias in20-50% of patients and proximal weakness with or withoutan elevation of serum CK in patients at all stages of HIVinfection.26 The muscle biopsy is significant for ragged redfibers and cytochrome oxidase-negative fibers. Other findingsare fiber necrosis, cytoplasmic bodies, nemaline rods, andmicrovaculoated fibers. A clinical challenge in diagnosingantiretrovial-induced myopathy is that HIV itself can causean inflammatory myopathy, a necrotizing myopathy withoutinflammation, and type 2 muscle fiber atrophy from a wast-ing syndrome. Drug-induced myopathy from anti-retroviraldrugs is slowly progressive, and should be differentiated fromthe acute rhabdomyolysis characterized by myalgias, weak-ness, and high CK levels (>1500) secondary to antiretroviraldrug toxicity. Needle EMG will show similar myopathic pat-terns for all myopathies in HIV, and thus will be unable todifferentiate these diagnoses. Accordingly, a muscle biopsy isimportant to help determine which or whether there are sev-eral superimposed pathologic processes.27 The source ofpathology is thought to result from a mitochondrial cytopa-thy, and electron microscopy shows such abnormalities.Azidothymidine acts as a false substitute for viral reverse tran-scriptase not only for cellular deoxyribonucleic acid (DNA)


polymerse but also for mitochondrial DNA polymerase,which is felt to account for mitochondrial abnormalities onbiopsy.

EMATINE

Ematine is extracted from the ipecac root and has been usedas an amebicide and emetic. Its greatest potential for toxicityis misuse for weight control in people with eating disorders.Overuse over a few days can cause in marked weakness ofskeletal and cardiac muscle.18 Serum CK levels are mildly ele-vated and the needle EMG is mildly abnormal. Muscle biop-sy shows necrosis, moth-eaten fiber perimeter, and partialclearing of oxidative enzymes in a targetoid pattern. Electronmicroscopy shows degeneration of contractile proteins.Ematine interferes with protein synthesis, although themechanism for the changes in muscle is not clear.

CRITICAL ILLNESS MYOPATHY

Quadriplegia can occur in the setting of critical illness froma variety of causes, including a myopathy. There are a num-ber of terms used, including acute quadriplegic myopathy,acute illness myopathy, critical illness myopathy, and myopa-thy associated with myosin destruction. Another factor is anaxonal neuropathy that may present as a similar clinical pic-ture of weakness, and critical illness neuropathy may co-existwith critical illness myopathy. Given the complexity of criti-cally ill patients, several factors have emerged, and includeuse of high-dose intravenous corticosteroids with or withoutnondepolarizing neuromuscular blocking drugs, althoughthe use of these drugs is not required for the development ofcritical illness myopathy11 Weakness develops over days, andfailure to wean from the ventilator is a major clinical issue.Serum CK levels are normal or mildly elevated. Needle EMGmay show abnormal spontaneous activity, but assessment ofmotor units is hampered by the patient’s inability to recruitmotor units. The electrophysiologic technique of direct mus-cle stimulation may be helpful in separating critical illnessmyopathy from neuropathy.21 In this technique, musclefibers are directly activated by an intramuscular stimulatingneedle electrode and compared to the response to stimulationof the nerve. With critical illness neuropathy, the response todirect muscle stimulation should be of good amplitude andthat to stimulation of the nerve of low amplitude, while withcritical illness myopathy, the response to stimulation of eithersite should be the same. Muscle biopsy shows atrophy of type2 fibers as well as loss of ATPase staining in type 1 and 2fibers. By electron microscopy there is loss of myosin.14 Themechanism is not known, but calcium-activated proteasesmay be enhanced and thus contribute to myosin breakdown.

Diverse factors related to sepsis may also contribute to break-down.

ALCOHOL MYOPATHY

Ethanol can cause a variety of myopathic conditions, includ-ing: (1) acute necrotizing myopathy; (2) acute hypokalemicmyopathy; (3) chronic myopathy; and (4) asymptomaticmyopathy.15,25 The acute necrotizing form occurs in the set-ting of high ethanol consumption usually associated with abinge, and includes marked muscle pain, tenderness to palpa-tion, swelling, marked weakness and elevated CK levels.Muscle pathology shows fiber necrosis. Acute hypokalemicmyopathy has similar clinical features to other types ofhypokalemic myopathy, and is associated with serum potassi-um levels between 1.4 and 2.1 meq/L. Biopsy findings in theacute phase show vacuoles. Chronic alcoholic myopathy hasan insidious onset and affects primarily leg muscles. Biopsyfindings are not specific and include atrophy, necrosis, andregenerating fibers. An asymptomatic alcoholic myopathyloosely designates a condition with elevated serum CK levels.The mechanism of ethanol toxicity is not known, and is com-plicated because many such patients are malnourished andhave vitamin deficiencies.

THYROTOXIC MYOPATHY

The incidence of weakness in patients with thyrotoxicosis ishigh. Serum CK is normal. Needle EMG shows no abnormalspontaneous activity, but motor unit recruitment may beincreased and motor units complex. Muscle biopsy findingsare variable, and may include inflammatory changes.9 Thereis a small increased association between thyroid disease andmyasthenia gravis. Thyroid hormones have many metabolicinfluences affecting a number of aspects of muscle func-tions—specific mechanisms causing weakness are not clearlyknown.

THYROTOXIC PERIODIC PARALYSIS

Episodic weakness that is clinically similar to that of familialhypokalemic periodic paralysis occurs in association withthyrotoxicity, most commonly, but not exclusively, in Asianpopulations.29 Attacks are associated with ingestion of carbo-hydrate-rich meals and weakness may be profound. Serumpotassium values range from 1.1 to 3.4 mmol/L, and phos-phate values are frequently low.16 Thyrotoxic periodic paral-ysis is usually a sporadic condition and resolves with treat-ment of hypokalemia, and does not recur with treatment ofthe thyroid disorder.


HYPOTHYROID MYOPATHY

When the symptoms of myopathy are expanded to includefatigability, pain, stiffness, cramps, and weakness the inci-dence of myopathy can be up to 80%.4 Serum CK may ormay not be elevated.

CORTICOSTEROID MYOPATHY

The incidence of weakness due to the use of corticosteroids isdifficult to access, in part because corticosteroids are fre-quently given for disorders that themselves cause weakness,and the balance of positive and negative effects is usually toimproved strength, thus masking a negative drug effect onstrength. A reasonable estimate of 10% comes from patientswith brain tumors treated with corticosteroids or those withasthma.3,23 It appears that fluorinated corticosteroids (dex-amethasone) are more likely than prednisone to cause weak-ness. Weakness is not highly correlated with corticosteroidpeak or accumulative dose. Serum CK levels are usually nor-mal, as is the EMG. Muscle biopsy is remarkable primarilyfor type 2 fiber atrophy. Corticosteroids have a number ofroles in muscle metabolism, and when in excess, their effecton protein catabolism is likely a major factor.29

GROWTH HORMONE MYOPATHY

Acromegaly is associated with a myopathy in 50% ofpatients.12 Weakness is mild and serum CK values are normalor mildly elevated. Myopathic EMG findings were mild.Muscle biopsy findings are type 2 atrophy.

SUMMARY

The challenge in assessing for toxic and metabolicmyopathies is not to miss them. This is difficult because ofthe ill-defined symptoms, the vulnerability of muscle toinsults, and the growing frequency of polypharmacy. It isalways wise to discontinue a suspicious medication, or tosubstitute with a different type of medication. Finally, whenthere are doubts, a muscle biopsy is clinically wise.

REFERENCES

1. Baker SK. Molecular clues into the pathogenesis of statin-mediatedmuscle toxicity. Muscle Nerve 2005;31:572-580.

2. Bromberg MB, Albers JW. Electromyography in idiopathic myositis.Mt Sinai J Med 1988;55:459-464.

3. Dropcho EJ, Soong SJ. Steroid-induced weakness in patients withprimary brain tumors. Neurology 1991;41:1235-1239.

4. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH.Neuromuscular findings in thyroid dysfunction: a prospective clinicaland electrodiagnostic study. J Neurol Neurosurg Psychiatry2000;68:750-755.

5. Gledhill R, Van Der Merwe C, Greyling M, Van Niekerk M. Race-gender differences in serum creatin kinase activity: a study amongSouth Africans. J Neurol Neurosurg Psychiatry 1988;51:301-304.

6. Grezard O, Lebranchu Y, Birmele B, Sharobeem R, Nivet H, BagrosP. Cyclosporin-induced muscular toxicity. Lancet 1990;335:177.

7. Hanna J, Ramundo M. Rhabdomyolysis and hypoxia associated withprolonged propofol infusion in children. Neurology 1998;50:301-303.

8. Hardiman O, Molloy F, Brett F, Farrell M. Inflammatory myopathyin thyrotoxicosis. Neurology 1997;48:339-341.

9. Hibi S, Misawa A, Tamai M, Tsunamoto K, Todo S, Sawada T,Imashuku S. Severe rhabodmyolysis associated with tacrolimus.Lancet 1995;346:702.

10. Hirano M, Ott BR, Raps EC, Minetti C, Lennihan L, Libbey NP,Bonilla E, Hays AP. Acute quadriplegic myopathy: a complication oftreatment with steroids, nondepolarizing blocking agents, or both.Neurology 1992;42:2082-2087.

11. Khaleeli AA, Levy RD, Edwards RH, McPhail G, Mills KR, RoundJM, Betteridge DJ. The neuromuscular features of acromegaly: a clin-ical and pathologic study. J Neurol Neurosurg Psychiatry1984;47:1009-1015.

12. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, PeperM. Colchicine myopathy and neuropathy. N Engl J Med1987;316:1562-1568.

13. Lacomis D, Giuliani MJ, Van Cott A, Kramer DJ. Acute myopathyof intensive care: clinical, electromyographic, and pathologic aspects.Ann Neurol 1996;40:645-654.

14. Lafair JS, Myerson RM. Alcoholic myopathy: with special referenceto significance of creatine phosphokinase. Arch Intern Med1968;122:417-422.

15. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic fea-tures of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med1999;159:601-606.

16. Martinez-Arizala A, Sobol S, McCarty G, Nichols B, Rakita L.Amiodarone neuropathy. Neurology 1983;33:643-645.

17. Palmer EP, Guay AT. Reversible myopathy secondary to abuse ofipecac in patients with major eating disorders. N Engl J Med1985;313:1457-1459.

18. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, CleemanJI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use andsafety of statins. Circulation 2002;106:1024-1028.

19. Reijneveld JC, Notermans NC, Lissen WH, Wokke JH. Benignprognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000;23:575-579.

20. Rich MM, Bird SJ, Raps EC, McCluskey LF, Teener JW. Direct mus-cle stimulation in acute quadriplegic myopathy. Muscle Nerve1997;20:665-673.

21. Fernando-Roth R, Itabashi H, Louie J, Anderson T, Narahara KA.Amiodarone toxicity: myopathy and neuropathy. Am Heart J1990;119:1223-1225.

22. Rutkove SB, De Girolami U, Preston DC, Freeman R, Nardin RA,Gouras GK, Johns DR, Raynor EM. Myotonia in colchicinemyoneuropathy. Muscle Nerve 1996;19:870-875.

23. Shee CD. Risk factors for hydrocortixone mopathy in acute severeasthma. Respir Med 1990;84:229-233.

24. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia:an apprasial of their efficacy and safety. Eur Heart J 1995;16:5-13.


25. Sieb J. Myopathies due to drugs, toxins, and nutritional deficiency.In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition.New York: McGraw-Hill; 2004. p 1693-1712.

26. Simpson DM, Bender AN. Human immunodeficiency virus-associ-ated myopathy: analysis of 11 patients. Ann Neurol 1988;24:79-84.

27. Simpson DM, Citak KA, Godfrey E, Godbold J, Wolfe DE.Myopathies associated with human immunodeficiency virus andzidovudine: Can their effects be distinguished? Neurology1993;43:971-976.

28. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy.JAMA 2003;289:1681-1690.

29. Ubogu E, Ruff R, Kaminski H. Endocrine myopathies. In: Engel A,Franzini-Armstrong C, editors. Myology, 3rd edition. New York:McGraw-Hill; 2004. p 1713-1738.

30. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: areview. Muscle Nerve 2002;25:332-347.

31. Wilkinson G. Drug metabolism and variability among patients indrug response. N Engl J Med 2005;352:2211-2222.


36 AANEM Course

INTRODUCTION

The past decade has seen a tremendous expansion in medi-cine’s understanding of muscle diseases, both hereditary andsporadic. The field of myology has benefited probably morethan any other area of medicine from the enormous increasein the understanding of molecular genetics. Along with this,there have also been vast improvements in enzyme histo-chemistry and electron microscopy (EM), allowing for betterdefinition of structural abnormalities. This has led to the dis-covery of “new diseases,” which are based primarily on betterpathophysiological descriptions of old diseases, rather thantruly new disorders. Newly named disorders generally reflectthe abnormal pathophysiology. Examples include: centraland multiminicore diseases, nemaline myopathy, andmyotubular myopathy. The congenital myopathies can nowbe identified by their abnormal aggregation of proteins, giv-ing rise to the concept of “protein aggregate myopathies.”

Limb girdle, which now includes desminopathies, alpha-Bcrystallinopathies, selenoproteinopathy, myotilinopathy,actinopathies, and myosinopathies, has expanded from agroup of 5 myopathies to a group over over 10, and it is stillgrowing. The recent identification of mutations in respectivegenes to the recognition of certain accrued proteins withinmuscle fibers, and the subsequent analysis of their respectivegenes has resulted in a wealth of genetic data and in reconsid-ering classification and nosologic interpretation of certaincongenital myopathies. Newer and better techniques to

image muscle have also made it easier to assess muscle struc-ture in a noninvasive fashion. This manuscript provides anupdate on myopathic diseases, including hereditary and spo-radic diseases, and emphasizes clinical pearls and latest dis-coveries.

HEREDITARY MUSCLE DISEASES

Dystrophinopathies

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked disor-der caused by an abnormality at the Xp21 gene loci.52,84 Thegene for DMD and Becker muscular dystrophy (BMD)occupies 2.5 million base pairs of DNA on the X-chromo-some and is approximately 10 times larger than the nextlargest gene identified to date.2 The gene contains 79 exonsof coding sequence.52,98 Its primary protein product is calleddystrophin, which is found in the plasma membrane of allmyogenic cells, certain types of neurons and in smallamounts in other cell types.39,74,78,104 Duchenne musculardystrophy and BMD are thus referred to as dys-trophinopathies. Dystrophin-deficiency at the plasma mem-brane of muscle fibers disrupts the membrane cytoskeletonand leads to the secondary loss of other components of themuscle cytoskeleton.16,18,25,37,113 The primary consequence ofthe cytoskeleton abnormalities is membrane instability, leading

37

Hereditary and New Myopathies


Clinical ProfessorDepartment of Rehabilitation Medicine

University of Washington School of MedicineSeattle, Washington

to membrane injury from mechanical stresses, transientbreaches of the membrane, and membrane leakage.68,77

Chronic dystrophic myopathy is characterized by aggressivefibrotic replacement of the muscle and eventual failure ofregeneration with muscle fiber death and fiber loss.

The incidence of DMD has been estimated to be around1:3500 male births.29 Approximately one-third of isolatedcases are due to new mutations, which is considerably higherthan observed in other X-linked conditions. This high muta-tion rate might be due to the large size of the gene.

While the history of hypotonia and delayed motor milestonesare often reported in retrospect, the parents are often unawareof any abnormality until the child starts walking. There hasbeen variability reported in the age of onset of DMD. In 74-80% of instances, the onset is noted before the age of 4years.71 The vast majority of cases are identified by 5-6 yearsof age. The most frequent presenting symptoms are abnormalgait, frequent falls, and difficulty climbing stairs. Difficultynegotiating stairs is an early feature as is a tendency to fall dueto the child tripping or stumbling on a plantar-flexed ankleor the knee buckling or giving way due to knee extensorweakness. There is progressive difficulty getting up from thefloor with presence of a Gowers’ sign. Parents frequently notethe toe walking, which is a compensatory adaptation to kneeextensor weakness. They also note a lordotic posture of thelumbar spine, which is a compensatory change due to hipextensor weakness.

Duchenne muscular dystrophy is occasionally identified pre-symptomatically in situations where a creatine kinase (CK)value is obtained with a markedly elevated value or whenmalignant hyperthermia occurs during general anesthesia foran unrelated surgical indication. Early identification alsooccurs when the diagnosis is pursued in a male with an affect-ed older sibling.

Pain in the muscles, especially the calves, is a common symp-tom. Enlargement of muscles, particularly the calves, is com-monly seen. Recently, children aged 8-11 years with DMDhave been noted to exhibit an unusual clinical examinationsign that results from selective hypertrophy and wasting indifferent muscles in the same region.90 When viewing thesepatients from behind with their arms abducted to 90° andelbows flexed to 90°, DMD patients demonstrate a linear oroval depression (due to wasting) of the posterior axillary foldwith hypertrophied or preserved muscles on its two borders(i.e., infraspinatus inferomedially and deltoid superolaterally)as if there were a valley between the two mounts.

The tongue is also frequently enlarged. An associated wide-arch to the mandible and maxilla with separation of the teethis frequently seen, presumably secondary to the macroglossia.

The earliest weakness is seen in the neck flexors during pre-school years. Early in the disease course weakness is general-ized, but predominantly proximal. Pelvic girdle weakness pre-dates shoulder girdle weakness by several years. Ankle dorsi-flexors are weaker than ankle plantar flexors, ankle evertersare weaker than ankle inverters, knee extensors are weakerthan knee flexors, hip extensors are weaker than hip flexors,and hip abductors are weaker than hip adductors.4,5

The weakness progresses steadily, but the rate can be variableduring the disease course. Quantitative strength testingshows greater than 40-50% loss of strength by 6 years ofage.50,67,99,105 With manual muscle testing, DMD subjectsexhibit loss of strength in a fairly linear fashion from ages 5-13 and measurements obtained several years apart will showfairly steady disease progression. However, a variable course isoften noted when analyzing individuals over a shorter periodof time.105,116 Investigators have shown a flattening in therate of strength loss curve at approximately ages 14-15.67,105

Thus, investigators performing studies involving the naturalhistory of DMD should be cautious about including subjectstransitioning to the teenage years because of the flattening ofthe manual muscle testing strength curve with increasingage.67 This caution is particularly important in studies ofpotential therapeutic agents. Quantitative strength measureshave been shown to be more sensitive for demonstratingstrength loss than manual muscle testing when strength isgrades 4-5.67

The average age of wheelchair use in an untreated DMDpopulation is 10 years, with a range of 7-13 years.14,15,67

Timed motor performance is a useful predictor of time whenambulation will be lost without provision of long-leg braces.One large natural history study showed that all DMD sub-jects who took 9 seconds or longer to ambulate 30 feet lostambulation within 2 years.67 All DMD subjects who took 12seconds or longer to ambulate 30 feet lost ambulation with-in 1 year.67 Ambulation past the age of 14 should raise thesuspicion of a milder form of muscular dystrophy (MD) suchas BMD or limb girdle muscular dystrophy (LGMD).Ambulation beyond 16 years was previously used as exclu-sionary criteria for DMD.13 Immobilization for any reasoncan lead to a marked and often precipitous decline in musclepower and ambulatory ability. A fall with resultant fractureleading to immobilization and loss of ambulatory ability isnot an uncommon occurrence.

Significant joint contractures have been found in nearly allDMD children older than age 13.67,120,121 The most commoncontractures include ankle plantar flexion and inversion,knee flexion, hip flexion, iliotibial band, elbow flexion, andwrist flexion contractures.67 Shortening of two joint musclesoccurs particularly in the iliotibial band and gastrocnemius.67

Significant contractures have been shown to be rare in DMD

38 Hereditary and New Myopathies AANEM Course

before age 9 for all joints. There is no association betweenmuscle imbalance around a specific joint (defined as grade 1or greater difference in flexor and extensor strength) and thefrequency or severity of contractures involving the hip, knee,ankle, wrist, and elbow in DMD.67

The presence of lower extremity contractures in DMD hasbeen shown to be strongly related to onset of wheelchairreliance.67,107 Lower extremity contractures were rare whileDMD subjects were still upright, but developed soon afterthey began using a wheelchair for most of the day. The occur-rence of elbow flexion contractures also appears to be direct-ly related to prolonged static positioning of the limb, andthese contractures develop soon after wheelchair reliance aswell. There is a relationship between wheelchair reliance andhip and knee flexion contractures.106 Mild contractures of theiliotibial bands, hip flexor muscles, and heel cords occur inmost DMD patients by 6 years of age.45 Limitations of knee,elbow, and wrist extension occurs about 2 years later, howev-er, these early observed contractures were relatively mild.45

Given the tremendous replacement of muscle by fibrotic tis-sue in DMD subjects, it is not surprising that a muscle of lessthan antigravity extension strength, statically positioned inflexion in a wheelchair, would develop a flexion contracture.The lack of lower extremity weight bearing likely contributesto the rapid acceleration in the severity of these contracturesafter transition to wheelchair. Ankle plantar flexion contrac-tures are likely not a significant cause of wheelchair reliance,as few subjects exhibit plantar flexion contractures of 15before their transition to a wheelchair.67 Natural history datasuggest that weakness is the major cause of loss of ambulationin DMD, rather than contracture formation.19,67

The reported prevalence of scoliosis in DMD varies from 33-100%.60,61,67,94 This marked variability is primarily becauseof retrospective selection for scoliosis, the inclusion or exclu-sion of functional curves, and dissimilar age groups. Theprevalence of scoliosis is strongly related to age. Fifty percentof DMD patients acquire scoliosis between ages 12-15, cor-responding to the adolescent growth spurt. At least 90% ofolder DMD subjects with no specific treatment for scoliosishave clinical spinal deformity. This is consistent with Oda’sreport that 15% of older DMD patients show mild nonpro-gressive curves (usually 10-30o).85 The rate of progression ofthe primary or single untreated lateral curve is reported torange from 11o to 42o per year, depending on the age spanstudied. Johnson and Yarnell reported an association betweenthe side of curvature, convexity, and hand dominance.47

McDonald’s study, on the other hand, showed no correlationbetween side of primary convexity and handedness.67 Odaand colleagues reported that the likelihood of severe progres-sive spinal deformity could be predicted by the type of curve

and early pulmonary function measurements.85 Those with-out significant kyphosis or hyperlordosis and a peak absoluteforced vital capacity (FVC) greater than 2000 mL tend not toshow severe progressive scoliosis.

No cause-and-effect relationship has been establishedbetween the onset of wheelchair reliance and occurrence ofscoliosis.41,67 Wheelchair reliance and scoliosis are both anage-related phenomenon. The causal relationship betweenloss of ambulatory status and scoliosis is doubtful, given thesubstantial time interval between the two variables in mostsubjects (scoliosis usually develops after 3-4 years in a wheel-chair). Both wheelchair reliance and spinal deformity can besignificantly related to other factors (e.g., age, adolescentgrowth spurt, increase in weakness of trunk musculature, andother unidentified factors) and appear to represent coinci-dental signs of disease progression.

Absolute FVC volumes increase in patients with DMD dur-ing the first decade and plateau during the early part of thesecond decade.40,67 A linear decline in percent predicted FVCis apparent between 10-20 years of age in DMD.67 Rideaureported that the FVC was predictive of the risk of rapid sco-liosis progression.95 In the most severe DMD cases, maximalFVC reached a plateau of less than 1200 mL. This was asso-ciated with the loss of ability to walk before age 10 and severeprogressive scoliosis. Maximum FVCs plateau between 1200mL and 1700 mL. Spinal deformity was present consistentlyin these cases but varied in intensity. The least severe DMDcases reached plateaus in FVC of greater than 1700 ml.Similarly, McDonald and colleagues also found that thosepatients with higher peak FVC (> 2500 mL) had a milderdisease progression, losing 4% predicted FVC per year.67 Thepeak predicted FVC less than 1700 mL lost 9.6% predictedFVC per year.67 The peak obtained absolute values of FVCthat usually occur early in the second decade is an importantprognostic indicator for severity of spinal deformity, as wellas of the severity of restrictive pulmonary compromise due tomuscular weakness.

Reduced maximal static airway pressures (both maximalinspiratory pressure and maximal expiratory pressure) are theearliest indicators of restrictive pulmonary compromise inDMD.3,10 Impaired values are usually noted between 5-10years of age. Vital capacity typically increases concomitantwith growth between 5-10 years of age with the percent ofpredicted FVC remaining relatively stable and close to 100%predicted. Duchenne muscular dystrophy patients typicallyshow a linear decline in percent predicted FVC between 10-20 years of age. An FVC falling below 40% of predicted cancontraindicate surgical spinal arthrodesis, irrespective of scoli-otic severity, because of increased perioperative morbidity.43,94


Patients who need surgical intervention for scoliosis or otherdeformities should have surgery before the vital capacitydrops below 40% of predicted.94

Respiratory failure in DMD is insidious in its onset andresults from a number of factors, including: (1) respiratorymuscle weakness and fatigue; (2) alteration in respiratory sys-tem mechanics; and (3) impairment of the central control ofrespiration. Noninvasive forms of both positive and negativepressure ventilatory support are increasingly being offered toDMD patients.

The dystrophin protein is present in both the myocardiumand the cardiac Purkinje fibers.1,81 Abnormalities of the heartmay be detected by clinical examination, electrocardiogram(ECG), echocardiography, and Holter monitoring. Cardiacexamination is notable for the point of maximal impulse pal-pable at the left sternal border due to the marked reductionin anteroposterior chest dimension common in DMD. Aloud pulmonic component of the second heart sound sug-gests pulmonary hypertension in patients with restrictive pul-monary compromise. Nearly all patients over the age of 13demonstrate abnormalities of the ECG.22,36,67 Q-waves in thelateral leads are the first abnormalities to appear, followed byelevated ST-segments and poor R-wave progression,increased R/S ratio, and resting tachycardia and conductiondefects. Electrocardiogram abnormalities have been demon-strated to be predictive for death from the cardiomyopathywith the major determinants including: R-wave in lead V1less than 0.6 mV; R-wave in lead V5 less than 1.1 mV; R-wave in lead V6 less than 1.0 mV; abnormal T-waves in leadsII, III, AVF, V5, and V6; cardiac conduction disturbances;premature ventricular contraction; and sinus tachycar-dia.58,59,89 Sinus tachycardia can be due to low stroke volumefrom the progressive cardiomyopathy, or in some cases can besudden in onset and labile, suggesting an autonomic distur-bance or direct involvement of the sinus node by the dys-trophic process.73

Autopsy studies and thallium-201 single proton emissioncomputed tomography imaging show left ventricular lateraland posterior wall defects that might explain the lateral Q-waves and the increased R/S ratio in V1 seen on ECG.76,80,126

Localized posterior wall fibrosis is peculiar to DMD and isnot seen in other types of MD. Pulmonary hypertensionleading to right ventricular enlargement is also known tocause prominent R-waves in V1 and has been demonstratedin patients with DMD.129

Ventricular ectopy is a known complication of the cardiomy-opathy in DMD which likely explains the observed cases of

sudden death.111 Yanagisawa and colleagues reported an age-related increase in the prevalence of cardiac arrhythmiasdetected by ambulatory 24-hour ECG recordings.127 Theyalso noted an association between ventricular arrhythmiasand sudden death in DMD. Clinically evident cardiomyopa-thy is usually first noted after age 10 and is apparent in near-ly all patients over age 18.81 Development of cardiomyopathyis a predictor of poor prognosis.67 Echocardiography has beenused extensively to follow the development of cardiomyopa-thy and predict prognosis in patients with DMD. The onsetof systolic dysfunction noted by echocardiography is associ-ated with a poor prognosis.67 The myocardial impairmentremains clinically silent until late in the course of the disease,possibly caused by the absence of exertional dyspnea, second-ary to lack of physical activity. Death has been attributed tocongestive heart failure in as many as 40-50% of patientswith DMD by some investigators.67,81 Regular cardiac evalu-ations with an ECG, echocardiography, and Holter monitorshould be employed in teenagers with preclinical cardiomy-opathy.

The dystrophin isoform is present in the brain.84,86,109 Therole of dystrophin in the central nervous system (CNS) is notknown but it has been theorized to play a role in neuronalmetabolic transport across the cell membrane.38 Previousstudies on intellectual function on children with DMD havegenerally revealed decreased intelligence quotient (IQ) scoreswhen these children are compared with both control andnormative groups.67,109 A mean score for the DMD popula-tion of 1.0-1.5 standard deviations (SD) below populationnorms has been reported. There has generally been a consid-erable consistency in the degree of impairment across meas-ures reflecting a rather mild global deficit. Some studies havedemonstrated relative deficits in verbal IQ.109 In a longitudi-nal assessment of cognitive function, McDonald and col-leagues found IQ measure in DMD to be stable over time.67

On neuropsychological testing, a large proportion of DMDsubjects fell within the “mildly impaired” or “impaired” rangeaccording to normative data.67 These findings likely reflect amild global deficit rather than focal nervous system impair-ment.

Substantial anthropometric alterations have been describedin DMD. Short stature and slow linear growth with onsetshortly after birth have been reported.28,70,92 Accurate meas-urement of linear height is extremely difficult in this popula-tion. Arm span measurements can be used as an alternativemeasure of linear growth; but this measurement can be diffi-cult as elbow flexion contractures of greater than 30o are fre-quently present in patients older than age 13. Forearm seg-ment length has been proposed as an alternative linear meas-


urement in DMD patients with proximal upper extremitycontractures and radius length can be followed for those withwrist and finger contractures.92

Obesity is a substantial problem in DMD, subsequent to theloss of independent ambulation.20,27,108 Weight control dur-ing early adolescence facilitates ease of care, in particular easeof transfers during later adolescence.

Longitudinal weight measurements in DMD confirm signif-icant rates of weight loss in subjects ages 17-21.27,64 This islikely caused by relative nutritional compromise during thelater stages when boys with DMD have higher protein andenergy intake requirements because of hypercatabolic proteinmetabolism.37 Protein and calorie requirements can often be160% that predicted for able-bodied populations during thelater stages of DMD.112 Restrictive lung disease becomesmore problematic during this time, and this can also influ-ence caloric intake and requirements. Self-feeding oftenbecomes impossible during this period because of bicepsweakness. Some subjects with DMD also develop signs andsymptoms of upper gastrointestinal dysfunction.8,43

Becker Muscular Dystrophy

Becker muscular dystrophy is a form of MD with a similarpattern of muscle weakness seen in DMD. It also has X-linked inheritance, but with later onset and a much slowerrate of progression than DMD. It was first described byBecker and Kiener in 1955.6,96 The disorder has the samegene location as the DMD gene (Xp21) and is allelic. Usingimmunoblotting or immunostaining of muscle biopsy speci-mens, the presence of altered molecular weight or decreasedabundance of dystrophin suggests a BMD phenotype.2 Somesubjects have 20-80% dystrophin levels of the normal quan-tity of dystrophin while other subjects may have reduced orincreased molecular weight dystrophin.2 Becker musculardystrophy has a lower incidence than DMD, with prevalencerates for BMD ranging from 12-27 per million and a recentestimated overall prevalence of 24 per million.30,32,66

The demonstration of a deletion in the Xp21 gene withc deoxyribonucleic acid (DNA) probes is useful in the diag-nostic evaluation of dystrophin deficient myopathies.21 In thegene deletion test, small blood samples are used as a source ofpatient DNA, and the dystrophin (DMD, BMD) gene istested to determine whether it is intact or not. This is per-formed by polymerase chain reaction (PCR) or Southernblotting, and the methods determine whether all segments ofthe gene are present. If any segment is missing, the findingsindicate the presence of a “deletion mutation.” Not all DMDand BMD patients have deletion mutations. Many have

point mutations that cannot be detected by these methods.Since the gene is so large and complex, it is currently not fea-sible to routinely test for the other types of smaller muta-tions. Approximately 55% of DMD patients and 70% ofBMD patients show deletion mutations of the gene on cur-rently available tests.21 A positive DNA test result (presenceof a deletion) is diagnostic of a dystrophinopathy (DMD orBMD). There are no false-positives if the test is performedappropriately.21

Differential diagnosis between DMD and BMD is best per-formed by family history of clinical phenotype. If the patientis still ambulating at 16-20 years of age and has a deletionmutation, then the correct diagnosis is BMD. Some labora-tories will report “the reading frame.” This information candifferentiate between a DMD and BMD diagnosis in approx-imately 90% of deletion-positive cases.65,66 Mutations at theXp21 locus, which maintain the translational reading frame(in-frame mutations), result in an abnormal but partially dys-functional dystrophin, whereas in DMD the mutations shiftthe reading frame (out-of-frame mutations) so that virtuallyno dystrophin is produced.21 The reading frame interpreta-tion is most accurate for deletions in the center of the gene(exons 40-60) and is least accurate for deletions in the begin-ning of the gene (exons 1-20).

Absent dystrophin or levels less than 3% of normal generallyare considered diagnostic of DMD, however, 5% of suchpatients have BMD phenotypes. The dystrophin in BMDtypically has an abnormally small molecular weight (<427kDa). A minority of patients have dystrophin of larger thannormal molecular weight (>427 kDa), or normal molecularweight. Most BMD patients with larger or smaller molecularweight dystrophin also have decreased quantities of the pro-tein.65,66 All BMD patients with normal molecular weightdystrophin have decreased quantities, usually less than 30%normal. Smaller size dystrophin typically is caused by dele-tion mutations, and larger size dystrophin by duplicationmutations. A further refinement is the use of antibodies spe-cific to the carboxy-terminal (C-terminal) region of dys-trophin. Using such antibodies, immuno-histochemistryreveals that the C-terminal region is almost always absent inDMD but invariably present in BMD.2

Studies have shown significant overlap in the observed age ofonset between DMD and BMD.66 Determination of thequantity and molecular weight of dystrophin has substantial-ly improved the early differentiation among BMD, “outlier”DMD, and the more common and rapidly progressive DMDphenotype. However, Bushby and colleagues found no clearcorrelation between abundance of dystrophin and clinicalcourse within the BMD group.13


The series of Bushby and Gardner-Medwin included 67BMD subjects and supported the presence of two major pat-terns of progression in BMD—a “typical” slowly progressivecourse and a more “severe” and rapidly progressive course.12

All of the “severe” BMD cases showed difficulty climbingstairs by age 20, whereas none of the “typical” BMD caseshad difficulty climbing stairs before age 20. Abnormal ECGswere seen in 27% of typical BMD subjects and 88% of sub-jects with more severe phenotype. Bushby and Gardner-Medwin found BMD subjects to have a mean age of onset of12 years in the typical group and 7.7 years in the severegroup.12 Some patients with BMD present with major mus-cle cramps as an isolated symptom.9

The most useful clinical criterion to distinguish BMD fromDMD is the continued ability of the patient to walk into lateteenage years. Those with BMD will typically remain ambu-latory beyond 16 years. Some patients become wheelchairreliant in their late teens or 20s, whereas others continuewalking into their 40s and 50s, or later. Outlier DMD casesgenerally stop ambulating between 13-16 years of age.66,67

As in DMD, preclinical cases are often identified by the find-ing of a grossly elevated CK value. There is also considerableoverlap in CK values between DMD and BMD cases at thetime of presentation, and CK values cannot be used to differ-entiate DMD from BMD.

Patients with BMD have a distribution of weakness that issimilar to those with DMD.66 Proximal lower limb musclesare involved earlier in the disease course. Gradual involve-ment of the pectoral girdle and upper limb musculatureoccurs 10-20 years from onset of disease. Extensors have beennoted to be weaker than flexors.66 The muscle groups, whichare the most severely involved early in the course of diseaseincludes the hip extensors, knee extensors, and neck flexors.66

Calf enlargement is a nonspecific finding in BMD, as is thepresence of a Gowers’ sign. Over time, the gait becomes sim-ilar to other neuromuscular disease conditions with proximalweakness. Patients often ambulate with a lumbar lordosis,forefoot floor contact, decreased stance phase knee flexion,and a modified Trendelenburg or gluteus medius lurch, oftendescribed as a waddle.

Early development of contractures does not appear to be afeature of BMD.45,66 As with DMD, nonambulatory BMDsubjects may develop equinus contractures, knee flexion con-tractures and hip flexion contractures. Subjects with BMDare more likely to develop flexion contractures subsequent towheelchair reliance.

Spinal deformity is not nearly as common or severe in BMDas it is in DMD. Spinal instrumentation is rarely required byBMD patients.66

Compromised pulmonary function is also much less prob-lematic in BMD.7,66 The percent predicted FVC does notappear substantially reduced until the third to fourthdecade.66 The percent predicted maximal expiratory pressureappears relatively more reduced at younger ages than the per-cent predicted maximal inspiratory pressure, a finding seen inDMD and other neuromuscular diseases.7 This might be dueto more relative involvement of the intercostals and abdomi-nal musculature, with relative sparing of contractile functionin the diaphragm of BMD. Predicted maximal expiratorypressure can be a useful quantitative measure of impairmentand perhaps disease progression early in the course of BMD.

The pattern of occasional life-threatening cardiac involve-ment in otherwise mild and slowly progressive BMD hasbeen reported.82,100,128 A significant percentage of BMD casesdevelop cardiac abnormalities. The rate of progression of car-diac failure can be more rapid than the progression of skele-tal myopathy.111,128 In fact, successful cardiac transplantationhas been increasingly reported in BMD subjects with cardiacfailure.21,26 Approximately 75% of BMD patients have beenfound to exhibit ECG abnormalities.66 The abnormal find-ings most commonly reported include abnormal Q-waves,right ventricular hypertrophy, left ventricular hypertrophy,right bundle branch block, and nonspecific T-wave abnor-malities. Unlike DMD, resting sinus tachycardia has notbeen a frequent finding. Echocardiography has shown leftventricular dilation in 37%, whereas 63% have subnormalsystolic function because of global hypokinesia.23,48 The car-diac compromise can be disproportionately severe, relative tothe degree of restrictive lung disease in some BMD subjects.The evidence for significant myocardial involvement inBMD is sufficient to warrant screening of all of these patientsat regular intervals using ECG and echocardiography. Theslowly progressive nature of this dystrophic myopathy, whichis compatible with many years of functional mobility andlongevity, makes these patients suitable candidates for cardiactransplantation if end-stage cardiac failure occurs.91

Some cases with BMD present with an isolated cardiomyopa-thy with no clinical manifestation of skeletal muscle involve-ment.55 The diagnosis can be established by demonstration ofa deletion in the Xp21 gene or by muscle biopsy. Isolatedcases of cardiomyopathy in children, particularly those withfamily histories indicative of X-linked inheritance, should bescreened for BMD with an initial serum CK estimation andmolecular genetic studies of the Xp21 gene.


Cognitive testing in BMD subjects has shown large variabil-ity in IQ scores and neuropsychological test measures. Mildlyreduced intellectual performance has been noted in a subsetof BMD patients, however, the degree of impairment is notas severe as noted in DMD.66

Other atypical clinical presentations include a complaint ofcramps on exercise in individuals with no muscle weakness.32

Patients with focal wasting of the quadriceps who have previ-ously been diagnosed with quadriceps myopathy have recent-ly been diagnosed with BMD. This is based on moleculargenetic testing and/or dystrophin analysis on muscle biop-sy.66

Myotonic Disorders

Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (MMD) is an autosomal dom-inant multisystem MD with an incidence of 1 per 8000.29,44

The disorder affects skeletal muscle, smooth muscle,myocardium, brain, and ocular structures. Associated find-ings include frontal pattern baldness and gonadal atrophy (inmales), cataracts, and cardiac dysrhythmias. Insulin insensi-tivity can be present. The gene has been localized to theregion of the DM protein kinase gene at 19q13.3.42,93 Patientsdemonstrate expansion of an unstable cytosine thymine gua-nine trinucleotide repeat within the region. Normal individ-uals generally have less than 37 repeats that are transmittedfrom generation to generation. Myotonic muscular dystro-phy patients may have 50 to several thousand CTG repeatswith remarkable instability. The age of onset is inversely cor-related by the repeat links.42 Mild, late onset MMD usuallyis associated with 50-150 repeats, classic adolescent or youngadult onset MMD shows 100-1000 repeats and congenitalMMD patients show greater than 1000 repeats.21,42,93 Theexpanded CTG repeat further expands as it is transmitted tosuccessive generations, providing a molecular basis for“genetic anticipation.” Both maternal-to-child and paternal-to-child transmission occurs. However, it can be more severeif transmitted from the mother with repeat size in offspringexceeding 1000 CTG repeats or more. Affected fathers sel-dom transmit alleles larger than 1000 copies to offspring dueto a lack of sperm containing such alleles, presumably due tothe poor motility of sperm containing alleles of that size,although this has not been proven.

Several characteristic facial features of MMD may be seen oninspection. The adult with long-standing MMD often hascharacteristic facial features. The long thin face with tempo-ral and masseter wasting is drawn and has been described bysome as lugubrious or “hatchet face.” Adults of both sexesoften exhibit frontal balding.

Myotonia is a state of delayed relaxation or sustained contrac-tion of skeletal muscle that is easily identified in childrenwith MMD. Grip myotonia can be demonstrated by delayedopening of the hand with difficulty extending the fingers fol-lowing tight grip. Percussion myotonia can be elicited bystriking the thenar eminence with a reflex hammer, produc-ing adduction and flexion of the thumb with slow return.Needle electromyography (EMG) shows myotonic dis-charges, which are spontaneous waxing and waning spikesthat produce a characteristic “dive bomber” sound.53

Myotonic muscular dystrophy is one of the few dystrophicmyopathies with greater distal weakness than proximal weak-ness.62 Although neck flexors, shoulder girdle musculature,and pelvic girdle musculature can become significantlyinvolved over decades, the weakness is initially most predom-inant in the ankle dorsiflexors, ankle everters and inverters,and hand muscles.44 Significant muscle wasting can occurover time. In MMD patients with infantile onset, a congeni-tal clubfoot or talipes equinovarus frequently occurs. In adultonset MMD, contractures at the wrist, ankle, and elbows arerelatively uncommon and mild.44,45 Patients with congenitalonset MMD may develop spinal deformity requiring surgicalspinal arthrodesis.41

Abnormalities on ECG and echocardiography are demon-strated in approximately 70-75% of patients withMMD.44,59,75 Prolongation of the pulse rate-interval, abnor-mal axis, and infranodal conduction abnormalities are allsuggestive of conduction system disease which might explainthe occurrence of sudden death which occurs in less than 5%of MMD patients.59 Ventricular tachycardia can also con-tribute to the syncope and sudden death associated withMMD. Some patients have required implantation of cardiacpacemakers. Q-waves have been reported on screening ECGsin MMD patients and this abnormality might reflectmyocardial fibrosis.44,59 Any MMD patient with dyspnea,chest pain, syncope, or other cardiac symptoms shouldreceive thorough cardiac evaluation.

Subjects with MMD have a very high incidence of restrictivelung disease.44,117 Involvement of respiratory muscles is amajor cause of respiratory distress and mortality in affectedinfants with MMD. Swallowing difficulties that produceaspiration of material into the trachea and bronchial tree,along with weakened respiratory muscles and a weak coughhave been reported as factors that may result in pulmonarycomplications in MMD patients. Care should be taken dur-ing general anesthesia in MMD due to risk of cardiacarrhythmias and malignant hyperthermia.

Constipation is a fairly common complaint in congenitalMMD, owing to smooth muscle involvement. Myotonic


muscular dystrophy patients should also be screened for dia-betes mellitus as there is an increased incidence of insulininsensitivity.

Those with congenital MMD usually show significantlyreduced IQ, often in the mentally retarded range.44 In adultonset MMD, there is evidence for a generally lower intelli-gence of a mild degree (full-scale IQs have been reported tobe in the 86-92 range).44 However, there is a wide range ofIQ values found in this population with many subjects scor-ing in the above-average range. Cognitive functioning alsoappears to be directly related to the size of the CTG expan-sion at the MMD gene locus.

There is a newly discovered form of MMD, known as type IIMMD (MMD2 or DM2). It has also been referred to asproximal myotonic myopathy.41,91 MMD2 is now known tobe caused by a mutation on chromosome 3 and is thought tobe clinically less severe than either typical MMD or congen-ital MMD, and may be associated with insulin insensitivity,diabetes, and low testosterone levels in males.

Myotonia Congenita

Myotonia congenita (MC) (Thomsen’s disease) is inherited asan autosomal dominant condition. It is a condition in whichthe patient has myotonia but not weakness. Symptoms maybe present from birth, but usually develop later. The myoto-nia can manifest as difficulty in releasing objects or difficultywalking or climbing stairs. Prolonged rest or inactivity exac-erbates the myotonia. Myotonia may be aggravated by cold.Patients may demonstrate grip myotonia or lid lag followingupward gaze or squint, and diplopia following sustained con-jugate movement of the eyes in one direction. The othercommon feature of MC is muscle hypertrophy. Patients canhave a “Herculean” appearance.34,65

A recessive form of MC (Becker form) also exists with lateronset, more marked myotonia, more striking hypertrophy ofmuscles and associated weakness of muscles. The dominantform seems more prone to aggravation of the myotonia bycold.65

The diagnosis is essentially made clinically with confirmationof classical myotonic discharges on electrodiagnostic exami-nation. Muscle biopsy is essentially normal, apart fromhypertrophy of fibers and an absence of type II-B fibers.32,35

Paramyotonia Congenita

Paramyotonia congenita (PC) is an autosomal dominantmyotonic condition characterized by generalized hypertro-phy, mild involvement of proximal muscles, and more severe

involvement of hands and muscles of the face. Myotonicepisodes usually subside within a matter of hours but are sig-nificantly aggravated by cold temperatures. This is usuallynot a severe disease and these patients have a good overallprognosis and normal life expectancy.21,65

Schwartz-Jampel Syndrome

Schwartz-Jampel syndrome is an autosomal recessive disorderwith myotonia, dwarfism, diffuse bone disease, narrow palpe-bral fissures, blepharospasm, micrognathia, and flattenedfaces.56,110 Limitation of joint movement can be presentalong with skeletal abnormalities, including short neck andkyphosis. Muscles are typically hypertrophic and clinicallystiff. The symptoms are not progressive and the overall prog-nosis is good.

Electrodiagnostic studies show continuous electrical activitywith electrical silence being difficult to obtain. There is rela-tively little waxing and waning in either amplitude or fre-quency of complex repetitive discharges. Abnormal sodiumchannel kinetics in the sarcolemma of muscle has beendemonstrated.56 Some therapeutic benefit has been reportedwith procainamide HCL and carbamezapine.110

Limb Girdle Muscular Dystrophies

Advances in molecular biology have shown that LGMD is aheterogeneous group of dystrophic myopathies, usually witha childhood or adolescent onset (although there are late onsetforms), no sex linkage, and a distribution and pattern ofweakness similar to DMD but with a much slower rate ofprogression.69 There are at least 15 different subtypes ofLGMD, most of which have been linked to abnormalities ofthe dystrophin-associated glycoproteins (DAG), especiallyalpha sarcoglycan (adhalin), a 50kD DAG and gamma sarco-glycan.63 The 50 DAG protein has been linked to the 17q12-q21.33 locus and children with this have been referred to assevere, childhood-onset, autosomal recessive muscular dys-trophy (SCARMD), which is also classified as LGMD2D.63,88 Other families with SCARMD have been linked tochromosome 13q12 and individuals with LGMD 2C mayshow a primary deficiency of gamma sarcoglycan and a sec-ondary deficiency of alpha sarcoglycan.61 Limb girdle muscu-lar dystrophy 2E patients (chromosome 4q12) show a pri-mary deficiency in beta sarcoglycan and LGMD 2F patients(chromosome 5q33-q34) show a primary deficiency of deltasarcoglycan.33,61 Most of the primary sarcoglycan abnormali-ties lead to secondary deficiencies of alpha sarcoglycan. Allthe DAGs are reduced in DMD patients because the C-ter-minal portion of dystrophin binds to the dystrophin-associ-ated proteins and maintains their integrity.2,97 A less severeautosomal recessive dystrophic myopathy (LGMD 2A) has


been linked to chromosome 15q1-q21.1, the gene for theprotein Calpain III.21,118 Diagnosis of SCARMD or LGMDsubtypes is confirmed by muscle biopsy.59

Dystrophin analysis is generally normal in subjects withLGMD.21 Of the seven recessive loci identified to date, fourare sarcoglycan genes.21,65 These four proteins make up thesarcoglycan complex, which is believed to interact directlywith the 43kD DAG and with dystrophin.21,86 Dystrophin-associated glycoproteins probably provide connectionsbetween the extracellular matrix (the protein merosin) andthe intracellular membrane cytoskeleton (attached to dys-trophin).21,61,65,86 An abnormality of the dystrophin-glyco-protein complex, resulting from primary deficiencies of oneor more of the dystrophin-associated glycoproteins results ina disruption in the linkage between the intracellular sar-colemmal cytoskeleton and the extracellular matrix.Disruption of the membrane cytoskeleton is common to thepathophysiology of most MDs, the dystrophinopathies.

Patients with SCARMD can exhibit calf hypertrophy and aGowers’ sign. Loss of ambulation generally occurs between10-20 years but occasionally after 20 years of age. In oneseries, several differences between DMD and SCARMD werenoted.69 In contrast to DMD, the limb extensors were notweaker than limb flexors. In particular, ankle dorsiflexorswere similar in strength to ankle plantar flexors, knee exten-sors showed similar strength compared with knee flexors andhip extensors and hip flexors showed similar strength values.The severity and rate of progression often varies between andwithin the families of SCARMD patients. Contracturesappear to be much less prevalent and severe in SCARMDcompared with DMD. The prevalence of joint contracturesin SCARMD subjects was found to be similar to thatobserved in BMD subjects in one series.45

Spinal deformity appears to be less problematic in SCARMDthan DMD. Less than 50% of SCARMD subjects werefound to have curves of mild-to-moderate severity, rangingfrom 5-30°.67 The prevalence and severity of spinal deformi-ty in SCARMD appears to be similar to that observed inBMD.

Restrictive pulmonary insufficiency occurs in SCARMD butis not as severe as that seen in DMD. The prevalence of severerestrictive lung disease in SCARMD is similar to thatobserved in BMD.7,69

Few studies have systematically evaluated the cardiac mani-festations of SCARMD and other limb girdle dystrophies. Inone series, the prevalence of abnormal ECG findings inSCARMD was 62%.69 Electrocardiogram abnormalitiesinclude evidence of infranodal conduction defects, evidence

of left ventricular hypertrophy, increased R/S ratio in V1, andabnormal Q-waves. Intellectual function in SCARMD hasgenerally been found to be normal.69

Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a slow-ly progressive dystrophic myopathy with predominantinvolvement of facial and shoulder girdle musculature. Thecondition is autosomal dominant with linkage to the chro-mosome 4q35 locus.118,119,124 Prevalence has been difficult toascertain because of undiagnosed mild cases, but has beenestimated at 10-20 per million.29,51

Facial weakness is an important clinical feature of FSHD.The initial weakness affects the facial muscles, especially theorbicularis oculi, zygomaticus, and orbicularis oris. Thesepatients often have difficulty with eye closure, but not ptosis.Subjects with FSHD often have an expressionless appearanceand exhibit difficulty whistling, pursing the lips, drinkingthrough a straw, or smiling. Even in the early stages, forcedclosure of the eyelids can be easily overcome by the examin-er. Masseter, temporalis, extraocular, and pharyngeal musclescharacteristically are spared in FSHD.

Patients with FSHD show characteristic patterns of muscleatrophy and scapular displacement. Involvement of the latis-simus dorsi, trapezius, rhomboids, and serratus anteriorresults in a characteristic appearance of the shoulders, withthe scapula positioned more laterally and superiorly, givingthe shoulders a forward-sloped appearance. The upper borderof the scapula rises into the trapezius, falsely giving it a hyper-trophied appearance. From the posterior view, the medialborder of the scapula may exhibit profound posterior and lat-eral winging. The involvement of shoulder girdle muscula-ture in FSHD can be quite asymmetric.

The typical onset is in adolescence or early adult life. Initially,patients show predominant involvement of facial and shoul-der girdle musculature. Scapular stabilizers, shoulder abduc-tors, and shoulder external rotators may be significantlyaffected, but at times the deltoids are surprisingly spared iftested with the scapulae stabilized. Both the biceps and tri-ceps may be more affected than the deltoids. Over time,ankle dorsiflexion weakness often becomes significant inaddition to pelvic girdle weakness. Late in the disease course,patients can show marked wrist extension weakness. Someauthors have found asymmetric weakness in the dominantupper extremity.46,51

A sensory neural hearing deficit was originally observed inCoates syndrome (early onset FSHD). These individualshave a myopathy that presents in infancy. The disease pro-


gression is fairly rapid with most individuals becomingwheelchair reliant by the late second or third decade.87 Theseindividuals also have a progressive exudative telangiectasia ofthe retina. Early recognition and photocoagulation of theabnormal retinal vessels can often prevent loss of vision.Several audiometry studies have demonstrated hearingdeficits in many late onset FSHD patients in addition tothose with Coates syndrome, suggesting that impaired hear-ing function is more common than expected in FSHD.72,119

All patients with FSHD should have screening audiometryand ophthalmologic evaluation.

Contractures are relatively uncommon in FSHD. In the mostcomprehensive study to date, 22 subjects had range ofmotion (ROM) testing of major upper and lower extremityjoints.51 Clinically significant loss of ROM (defined as areduction in ROM greater than 20°) was present in two sub-jects (9%) at the wrist and in one subject (5%) at the hip,knee, and ankle. This subject had been wheelchair-reliant for15 years at the time of ROM testing. Although active motionis severely restricted, subjects with FSHD typically maintainfull passive ROM.

Spinal deformity is common with 80% of FSHD subjectsexhibiting hyperlordosis, alone or in combination with scol-iosis. Rarely, severe and progressive hyperlordosis is associat-ed with FSHD. The patient with severe hyperlordosis mightutilize their lordotic posturing to compensate for hip exten-sor weakness. Scoliosis alone accounts for only 20% of spinaldeformity in FSHD41 and patients with scoliosis typicallyhave mild and nonprogressive curves.

Mild restrictive lung disease has been reported in nearly one-half of FSHD patients.7,17,51 Expiratory musculature appearsto be more affected than inspiratory muscles in FSHD.17 Arecent Dutch study identified 10 FSHD patients on noctur-nal ventilatory support at home, representing approximately1% of the Dutch FSHD population.125 Severe muscle dis-ease, wheelchair dependency, and kyphoscoliosis appeared tobe risk factors for respiratory failure.125

The presence of cardiac abnormalities in FSHD is still debat-ed. While diverse ECG abnormalities have been noted, onestudy showed no abnormalities on ECG, chest radiography,Holter monitoring, and echocardiography.23 Nuclear scan-ning with thallium-201 has demonstrated diffuse defectsconsistent with diffuse fibrosis.23 Abnormalities in systolictime intervals on echocardiography and elevations in atrialnatriuretic peptide are consistent with subclinical cardiomy-opathy.23,51 Cardiac complications in FSHD are rare andpatients in general have normal longevity. There is usually no

associated intellectual involvement in this dystrophic myopa-thy.

Changes seen with muscle biopsy are relatively slight, withthe most consistent finding being the presence of isolatedsmall atrophic fibers. Other fibers may be hypertrophied.Serum CK levels are normal in the majority of patients.Molecular genetic testing for the FSHD gene is now availablefor diagnostic confirmation.

Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linkedrecessive progressive dystrophic myopathy with a gene locusidentified at Xq28.30,31,122 The muscle protein that is defi-cient in EDMD has been termed as “Emerin.” The conditionusually presents in adolescence or early adult life, and manyclinical features can be seen in early childhood. Patients canpresent with a selective scapulohumeral peroneal distributionweakness with striking wasting of the biceps, accentuated bysparing of the deltoids and forearm muscles. However, this isclinically differentiated from FSHD by the lack of facialinvolvement. Ankle dorsiflexors often are weaker than ankleplantar flexors. Significant atrophy usually is present in theupper arms and legs due to focal wasting of the calf musclesand biceps.

An associated cardiomyopathy usually presents with arrhyth-mia and may lead to sudden death in early adult life.30,123 Thecardiomyopathy can progress to four-chamber dilated car-diomyopathy with complete heart block and ventriculararrhythmias.123 Atrial arrhythmia usually appears prior tocomplete heart block. Reported features include first degreeheart block, followed by Wenckebach phenomenon and thencomplete atrial ventricular dissociation and atrial fibrillationor flutter with progressive slowing of the rate.123 Syncope ornear-syncope commonly occurs later in the second decade orearly in the third decade.123 Evidence of cardiac arrhythmia,sometimes only present at night, might be detected on 24-hour Holter monitoring. The provision of a cardiac pacemak-er to the patient with arrhythmia may be life-saving and canconsiderably improve life expectancy.

Some patients with EDMD may show evidence of nocturnalhypoventilation as a result of restrictive expansion of thechest in association with the rigid spine, and partly due toinvolvement of the diaphragm.30

Creatine kinase can be moderately elevated, with a valuebetween 2 and 5 times the upper limit of normal. NeedleEMG usually shows a myopathic pattern. Muscle biopsy


shows a myopathic process with variation in fiber size, clus-ters of atrophic fibers, mild proliferation of connective tissue,and some focal necrosis of fibers.

A clinical hallmark of EDMD is the early presence of con-tractures of the elbow flexors with limitation of full elbowextension. Heel cord tightness might be present early in thedisorder, concomitant with ankle dorsiflexion and toe walk-ing. Unlike DMD, the toe walking in EDMD usually is sec-ondary to ankle dorsiflexion weakness and not a compensa-tory strategy to stabilize the knee due to proximal limb weak-ness. Tightness of the cervical and lumbar spinal extensormuscles, resulting in limitation of neck and trunk flexion,with the inability to flex the chin to the sternum and to touchthe toes, also has been reported in EDMD.

A dominantly inherited disorder with a similar phenotypehas been reported, but the gene locus is unknown. Somereported cases of “rigid spine syndrome,” a form of congeni-tal MD (CMD), may be EDMD cases in view of the markedpredominance of males with this disorder and the associatedcontractures reported at the elbows and ankles.30

Congenital Muscular Dystrophy

The term “congenital muscular dystrophy” has been widelyused for a group of infants presenting with hypotonia, mus-cle weakness at birth or within the first few months of life,congenital contractures, and a dystrophic pattern on musclebiopsy. The dystrophic changes noted on biopsy separate thisgroup of disorders from the congenital myopathies. The con-dition tends to remain relatively static. However, some sub-jects show slow progression, whereas others gain develop-mental milestones and achieve the ability to walk.

There are several syndromes of CMD with CNS abnormali-ty. Fukuyama CMD is associated with mental retardation,structural brain malformations evident on magnetic reso-nance imaging (MRI) imaging and a dystrophic myopathy.The gene loci has recently been identified to be at 9q31-33.35,114

Muscle-eye-brain disease describes a syndrome comprisingCMD, mental retardation, and ocular abnormality. Infantspresent with congenital hypotonia, muscle weakness, elevat-ed CK, myopathic EMG, and a dystrophic changes on mus-cle biopsy.101,102,103 Ophthalmologic findings include severevisual impairment with uncontrolled eye movements associ-ated with severe myopia. Patients often deteriorate around 5years of age with progressive occurrence of spasticity.Computerized tomography scans have shown ventricular

dilatation in low density of the white matter. Walker-Warburg syndrome is described as CMD with mental retar-dation and consistent CNS abnormalities on imaging (type IIlissencephaly, abnormally thick cortex, decreased interdigita-tions between white matter and cortex and cerebellar malfor-mation). Ocular abnormalities and cleft lip or palate may alsobe present.

Cases with more pure CMD without CNS involvement havebeen identified. The main clinical features are muscle weak-ness and hypotonia, congenital contractures, histologicalchanges of a dystrophic nature—often with extensive con-nective tissue or adipose proliferation—but no substantialevidence of necrosis or regeneration, normal to moderatelyelevated CK, normal intellect, and brain imaging which maybe either normal or show changes in the white matter on CTor MRI imaging. One form results from merosin deficiency,an extracellular protein important for maintenance of sar-colemmal membrane stability in the muscle fiber.115 The locifor merosin deficient CMD has been linked to chromosome6q.21 A further subtype of congenital muscular dystrophywithout CNS involvement and normal merosin has beenreported, but the genetic locus has not been established.

Patients with CMD often exhibit early contractures, includ-ing equinovarus deformities, knee flexion contractures, hipflexion contractures, and tightness of the wrist flexors andlong finger flexors. The contractures can become more severeover time with prolonged static positioning and lack of ade-quate ROM and splinting/positioning.

THE CONGENITAL MYOPATHIES

The term congenital myopathy is used to describe a group ofheterogeneous disorders usually presenting with infantilehypotonia due to genetic defects causing primary myopathieswith the absence of any structural abnormality of the CNS orperipheral nerves. The specific diagnosis of each entity ismade on the basis of specific histological and electron micro-scopic changes found on muscle biopsy. While patients canbe hypotonic during early infancy, they later develop muscleweakness that is generally nonprogressive and static. Theweakness is predominantly proximal, symmetric, and in alimb girdle distribution.

The serum CK values are frequently normal and the needleEMG findings may be normal or may show mild, nonspecif-ic changes, usually of a myopathic nature (small amplitudepolyphonic potentials). The only congenital myopathy con-sistently associated with needle EMG abnormalities is


myotubular (centronuclear) myopathy.24,53 In this disorder,the needle EMG shows myopathic motor unit action poten-tials with frequent complex repetitive discharges and diffusefibrillation potentials.68 These myopathies can be consideredprimarily structural in nature. Patients do not actively losemuscle fibers.

Central Core Myopathy

This is an autosomal dominant disorder with autosomaldominant gene locus at 19q13.1, the same gene locus as themalignant hyperthermia gene.49 Indeed, these patients have ahigh incidence of malignant hyperthermia with inhalationanesthetic agents. Muscle fiber histology shows amorphous-looking central areas within the muscle that may be devoid ofenzyme activity. Electron microscopy shows the virtualabsence of mitochondria and sarcoplasmic reticulum in thecore region, and a marked reduction in the interfibrillaryspace and an irregular zig-zag pattern (streaming) of the Z-lines.86 There is a predominance of high oxidative, low gly-colytic type I fibers and a relative paucity of type II fibers,resulting in a relative deficiency of glycolytic enzymes.

Patients generally demonstrate mild and relatively nonpro-gressive muscle weakness, either proximal or generalized, pre-senting in either early infancy or later. Mild facial weaknesscan be seen. Patients often achieve gross motor milestonesrather late, such as walking, and have difficulty climbingstairs. They may show a Gowers’ sign. The disorder typicallyremains fairly static over the years. A frequent occurrence ofcongenital dislocation of the hip is observed.

Central core myopathy and familial malignant hyperthermiaappear to be allelic as the ryanodine receptor chain implicat-ed in malignant hyperthermia has the same locus.21,86

Nemaline Myopathy

Nemaline myopathy, also referred to as rod body myopathy,represents a varied group of disorders with different modes ofinheritance, but the most typical form is autosomal recessive.While the rods can be easily overlooked using routine hema-toxylin-eosin staining, they can readily be demonstrated withthe Gomori trichrome stain. The rods are readily demonstrat-ed with an EM. They are thought to be abnormal depositionsof Z-band material of a protein nature and possibly alpha-actinin.54

A severe form of the disease may present in the neonatal peri-od with very severe weakness, respiratory insufficiency, andoften a fatal outcome. Most cases present with a mild, non-progressive myopathy with hypotonia and proximal weak-ness. In more severe cases, swallowing difficulty can be pres-ent in the neonatal period. Skeletal abnormalities, such as

kyphoscoliosis, pigeon chest, pes cavus feet, high archedpalate, and an unusually long face has been noted.Cardiomyopathy has been described in both severe neonataland milder forms of the disease.

Autosomal dominant inheritance has been described in a fewinstances with the gene localized to chromosome 1, q21-q23.54 The locus of the more common autosomal recessiveforms have not yet been located.

Myotubular Myopathy (Centronuclear Myopathy)

Patients with non-X-linked myotubular myopathy have mus-cle biopsies showing a striking resemblance to the myotubesof fetal muscle. Patients typically present with early hypoto-nia, delay in motor milestones, generalized weakness of bothproximal and distal musculature. They also present with pto-sis with weakness of the external ocular muscles as well asweakness of the axial musculature. Nocturnal hypoventila-tion has been described.57 The gene locus has not been iden-tified to date, but most known non-X-linked forms appear toshow autosomal dominant inheritance.

Severe X-linked (Congenital) Myotubular Myopathy

Cases with neonatal onset and severe respiratory insufficien-cy have been identified with an X-linked recessive mode ofinheritance. The gene for this disorder has been located toXq28.21 Muscle biopsy shows characteristic fetal-appearingmyotubes.

Patients present with severe generalized hypotonia, associatedmuscle weakness, swallowing difficulty, and respiratory insuf-ficiency. They often become ventilator-dependent at birth. Ifthey are able to be weaned from the ventilator, subsequentdeath due to pulmonary complications is not uncommon.Aspiration pneumonias are common. Additional clinical fea-tures include congenital contractures, facial weakness, andweakness of the external ocular muscles. Needle EMG showsmany fibrillations and positive sharp waves.53

Minicore Disease (Multi-Core Disease)

Minicore disease is a relatively rare congenital myopathy withmuscle biopsies showing multiple small randomly distributedareas in the muscle with focal decrease in mitochondrialoxidative enzyme activity and focal myofibrillar degenerativechange. Characteristic changes are present on EM. There is apredominance of type I fiber involvement.11

Clinically, patients present with hypotonia, delays in grossmotor development and nonprogressive symmetric weaknessof the trunk and proximal limb musculature. There may bemild facial weakness and there is also associated diaphragmat-


ic weakness, placing patients at risk for nocturnal hypoventi-lation. Subtle ultrastructural changes allow this condition tobe distinguished from central core disease. Inheritance isautosomal recessive, but the gene location is not yet known.

Congenital Fiber-Type Disproportion

Congenital fiber-type disproportion represents a heteroge-nous group of conditions most likely with varied geneticdefects. The condition was initially delineated by Brooke onthe basis of the muscle biopsy picture demonstrating type Ifibers which are smaller than type II fibers by a margin ofmore than 12% of the diameter of the type II fibers.26,79

Congenital MD, MMD, and severe spinal muscular atrophyall may show small type I fibers and should be excluded. Thediagnosis of congenital fiber-type disproportion should bemade only in the presence of normal-sized or enlarged type IIfibers and not in cases where both type I and type II fibers aresmall. There may also be abnormalities on ischemic exercisetesting.83

Patients typically present with infantile hypotonia and delayin gross motor milestones. The severity has been noted to bequite variable, but it is generally nonprogressive. There isgenerally short stature and low weight. Patients may exhibit along narrow face, high-arched palate, and deformities of thefeet, including either flat feet or occasionally high-archedfeet. Kyphoscoliosis has been reported. Lenard and Goebeldocumented a case with fairly severe weakness and associatedrespiratory deficit, necessitating tracheostomy.57 The mode ofinheritance for congenital fiber-type disproportion is variedwith both autosomal recessive and autosomal dominant pat-terns of inheritance reported. Genetic loci have not beenidentified to date.

SUMMARY

The past few decades have seen an explosion of new discov-eries regarding the underlyng molecular genetic causes andsubsequent pathophysiological deficits in many major myo-pathic disorders. Hopefully this increased understanding ofthese disorders will turn in to a functional treatment modal-ity such as gene transfer. This is a real possibility in the next25 years, but such a great achievement will take the coopera-tive efforts of the international scientific community workingtogether. It is this author’s sincerest hope that this scientificgoal will soon become a reality.

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