This second edition of Evaluation and Treatment of Myopathies cannot really be viewed as a sequel to the first edition written by Griggs, Mendell and Miller and published in 1995. The majority of the diseases considered in this new edition had not been identified 18 years ago and although many chapter headings are similar, the only information that has evolved as opposed to being replaced is the still-crucial clinical approach to patients and the clinical neurophysiology of neuromuscular diseases. Virtually everything eke is new. In the process of dealing with the wealth of new material of clinical importance, we realized that our readership would be best served by asking new authors expert in their sub-subspecialty to author chapters. Myopathies, and even subgroups of myopathies, are now too diverse and have too much known about pathogenesis for a single myologist to be an authority on our entire field.A\This book is not intended to be encyclopedic but instead, to focus on what the clinician seeing the patient with myopathy must know to make a diagnosis and plan appropriate treatment. The book presents diseases as they present to a clinician. Although the experimental therapeutics of myopathies is in its infancy, much can be done to prevent complication and maintain normal activities. Major advances in treatment are on the drawing board for most myopathies. We point out where these developments are likely to come from and stress what must be done in the interval. Emma Ciafaloni, M.D.; Patrick F. Chinnery, FRCP FMedSci; Robert C. Griggs, M.D., F.A.A.N.

Foreword xiii

Preface xv

Contributors xvii

SECTION 1 APPROACH TO THE PATIENT WITH MUSCLE DISEASE

1.STRUCTURE AND FUNCTION OF NORMAL MUSCLE 3

      THE MOTOR UNIT 3

      MUSCLE FIBER TYPES 4

      Neural Control of Muscle Fiber Type•Activation of Motor Units According to Muscle Fiber Type

      VOLUNTARY CONTROL OF MOTOR UNIT ACTIVITY 6

      Relationship of Size to the Recruitment of Single Motor Units•Firing Rates of Single Motor Units•Impaired Voluntary Control of Motor Units

      MUSCLE STRUCTURE AND FUNCTION 7

2.EVALUATION OF THE PATIENT WITH MYOPATHY 14

      INTRODUCTION 15

      DEFINITION OF MYOPATHY 15

      The Hereditary Myopatlhies•The Inflammatory Myopathies•Myopathies Due to Systemic Diseases

      CLINICAL EVALUATION 18

      History•Paresthesias and Dysesthesias•Examination•General Examination

      DIFFERENTIAL DIAGNOSIS 28

      Disorders Presenting at Birth With Hypotonia•Disorders Presenting in Infancy•Disorders Presenting in Childhood With Progressive Proximal Weakness•Disorders Presenting in Adulthood

      LABORATORY EVALUATION 35

      Blood Studies•Urine Studies•Muscle Imaging Procedures

      ELECTRODIAGNOSIS 39

      The Technique of Electromyography•Abnormal Spontaneous Activity•Voluntary Activity•Quantitative Electromyography•Electrical Stimulation Tests: Nerve Conduction Studies•Repetitive Nerve Stimulation

      MUSCLE BIOPSY 49

      Indications for Biopsy•Selection of Biopsy Sites•Tissue Removal and Preparation•Histologic Techniques•Differentiating Neuropathy From Myopathy•Preferential Fiber Type Involvement•Sources of Diagnostic Error

      NERVE BIOPSY 57

      Indications for Biopsy•Selection of Biopsy Sites•Tissue Removal and Preparation

3.GENETIC EVALUATION OF THE PATIENT AND FAMILY 60

      CLINICAL EVALUATION 61

      Clinical History•Physical Examination•Clinical Investigations Guiding Genetic Testing

      MOLECULAR GENETIC TESTING IN A CLINICAL CONTEXT 62

      Conventional Genetic Testing•Next-Generation Sequencing

      IMPLICATIONS OF A POSITIVE GENETIC TEST RESULT 64

      Diagnostic Testing for Affected Family Members•Predictive Testing for Unaffected Family Members•Prenatal Diagnosis•Personalized or Precision Medicine

SECTION 2 SPECIFIC MYOPATHIES

4.THE MUSCULAR DYSTROPHIES 69

      DUCHENNE AND BECKER MUSCULAR DYSTROPHIES 70

      Epidemiology•Genetics of Duchenne and Becker Muscular Dystrophies•Carrier Detection and Prenatal Testing•Clinical Features: DMD•Clinical Features: Becker Muscular Dystrophy•Differential Diagnosis•Diagnosis and Tests•Treatment•Other Drugs and Supplements•Respiratory Care•Perioperative Management•Cardiac Care•Bone Health and Orthopedic Management•Nutrition•Physical Therapy•Speech, Cognitive, and Behavioral Management•Palliative Care•Therapies Under Investigation

      EMERY-DREIFUSS MUSCULAR DYSTROPHY 82

      Genetics•Clinical Features•Laboratory Features and Diagnostic Tests•Differential Diagnosis•Treatment

      THE MYOTONIC MUSCULAR DYSTROPHIES 86

      Genetics•Clinical Features•Laboratory Features and Diagnostic Tests•Differential Diagnosis•Treatment•Future Directions

      FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 92

      Genetics•Clinical Features•Laboratory Features and Diagnostic Tests•Differential Diagnosis•Treatment

      LIMB-GIRDLE MUSCULAR DYSTROPHIES 96

      Genetics•Clinical Features•Laboratory Features and Diagnostic Tests•Differential Diagnosis•Treatment•Future Directions

      OCULOPHARYNGEAL MUSCULAR DYSTROPHY 101

      Genetics•Clinical Features•Laboratory Features and Diagnostic Tests•Differential Diagnosis•Treatment

      THE CONGENITAL MUSCULAR DYSTROPHIES 103

      Genetics•Clinical Features•Laboratory Findings•Differential Diagnosis•Treatment

      DISTAL MUSCULAR DYSTROPHY 109

      Miyoshi Myopathy•Welandcr Myopathy•Tibial Muscular Dystrophy•GNE (Nonaka) Myopathy•Distal Myofibrillar Myopathies•Other Distal Dystrophies/Myopathies

5.MYOFIBRILLAR MYOPATHIES 131

      PATHOLOGICAL FEATURES 133

      CLINICAL FEATURES 135

      Desminopathy•αB-Crystallinopathy•Myotilinopathy•Zaspopathy•Filaminopathy•Bag3opathy•FHLlopathy•DNAJB6-Related MFM•Titin-Related MFM

      TREATMENT 140

6.CONGENITAL MYOPATHIES 144

      DEFINITION OF A CONGENITAL MYOPATHY 144

      EPIDEMIOLOGY 146

      PRESENTATIONS OF A PATIENT WITH A CONGENITAL MYOPATHY 146

      DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS 148

      SPECIFIC TYPES OF CONGENITAL MYOPATHIES 149

      Congenital Myopathies With Cores•Congenital Myopathies With Central Nuclei•Congenital Myopathies With Nemaline Rods•Congenital Fiber Type Disproportion

      RARE CONGENITAL MYOPATHIES AND OTHER EARLY-ONSET MUSCLE DISORDERS 157

      MANAGEMENT OF THE CONGENITAL MYOPATHIES 158

7.METABOLIC MYOPATHIES 164

      ENERGY METABOLISM IN EXERCISING MUSCLE 164

      Glycolysis•Other Fuel Substrates in Glyeolysis—Fructose and Galactose•Glycogen and Glycogenolysis•Lipid Metabolism

      DEFECTS OF GLYCOGEN METABOLISM 167

      Disorders Producing Dynamic Symptoms (Exercise Intolerance)•Disorders Producing Static Symptoms (Fixed Weakness)

      DEFECTS OF LIPID METABOLISM 180

      Camitine Deficiency and Related Disorders•Carnitine Pahmtoyltransferase (CPT II) Deficiency•Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency•Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency•Medium-Chain Acyl-CoA Dehydrogenase Deficiency•3-Hydroxyacyl-CoA Dehydrogenase Deficiency

      OTHER DISORDERS OF MUSCLE METABOLISM 190

      Myoadenylate Deaminase Deficiency•Malignant Hyperthermia

8.MITOCHONDRIAL MYOPATHY 197

      MITOCHONDRIAL BIOLOGY 198

      GENERAL PRINCIPLES OF MITOCHONDRIAL MEDICINE 198

      CLINICAL INVESTIGATION OF MITOCHONDRIAL DISORDERS 200

      Muscle Morphology and Histochemistry•Respiratory Chain Enzyme Analysis•Molecular Genetic Analysis

      CLINICAL MANAGEMENT OF MITOCHONDRIAL DISEASE 207

      Disease Surveillance and the Management of Complications•Specific Treatments for Mitochondrial Disorders•Drug Toxicity in Mitochondrial Disease•Genetic Counseling and Prevention

      SPECIFIC SYNDROMES ASSOCIATED WITH MITOCHONDRIAL MYOPATHY 208

      Progressive External Ophthalmoplegia•Mitochondrial DNA Deletion Syndromes•Mitochondrial Enccphalomyopathy with Lactic Acidosis and Strokelike Episodes•Myoclonic Epilepsy with Ragged Red Fibers•Polymerase Gamma-Related Disorders•Leigh Syndrome•Neurogenic Muscle Weakness, Ataxia, and Retinitis Pigmentosa Syndrome•Mitochondria] Neurogastrointestinal Encephalopathy Disease•Mitochondrial DNA Depletion Syndromes (Including Alpers-Huttenlocher Syndrome)

9.MUSCLE CHANNELOPATHIES 218

      PERIODIC PARALYSES 218

      Classification of Periodic Paralysis•Hypokalemic Periodic Paralysis•Hyperkalemic Periodic Paralysis•Andersen-Tawil Syndrome•Thyrotoxic Periodic Paralysis•Other Disorders That Mimic Primary Periodic Paralyses•Evaluation of the Patient with Episodic Weakness•Muscle Biopsy Findings•Provocative Testing•Pathophysiology of Periodic Paralysis•Treatment of Periodic Paralysis

      NONDYSTROPHIC MYOTONIAS 236

      Myotonia•Differential Diagnosis and Approach•Pathogenesis of Myotonia•Treatment of Myotonic Disorders

10.INFLAMMATORY MYOPATHIES 254

      DERMATOMYOSITIS, POLYMYOSITIS, IMMUNE-MEDIATED NECROTIZING MYOPATHY, AND INCLUSION BODY MYOSITIS 254

      Introduction•Historical Perspective•Epidemiology•Clinical Features•Differential Diagnosis•Diagnostic Studies•Pathogenesis and Genetics•Treatment•Second-Line Therapies•Third-Line Therapies•Future Perspectives

      OTHER INFLAMMATORY MYOPATHIES 268

      Focal Myositis•Eosinophilic Myositis•Granulomatous Myositis/Sarcoid Myopathy•Infectious Myositis

11.MYOPATHIES OF SYSTEMIC DISEASE AND TOXIC MYOPATHIES 279

ENDOCRINE MYOPATHIES 280

      Thyroid Disorders•Parathyroid Disorders•Adrenal Disorders•Diabetes

      AMYLOID MYOPATHY 284

      Clinical Presentation•Diagnosis•Pathology•Treatment/Prognosis

      MYOPATHY AND ELECTROLYTE ABNOEMALITIES 286

      Hypokalemic Myopathy•Hyperkalemia•Hypophosphatemia•Hypermagnesemia•Hypermagnesemia•Disorders of Calcium•Disorders of Sodium

      MYOPATHY ASSOCATED WITH MALIGNANCY 287

      Cachexia and Myopathy•Metastatic and Embolic Myopathy

      CRITICAL ILLNESS MYOPATHY 288

      Clinical Presentation•Diagnosis•Pathology•Prognosis/Treatment

      TOXIN- AND MEDICATION-RELATED MYOPATHIES 290

      Cholesterol-Lowering-Agent Myopathy•Corticosteroid Myopathy•Chloroquine/Hydroxychloroquine Myopathy•Colchicine Myopathy•Antiviral Medications•Myopathy and Drugs of Abuse•Dietary Agents

SECTION 3 GENERAL STRATEGIES OF CLINICAL MANAGEMENT

12.MUSCLE PAIN AND FATIGUE 305

      INTRODUCTION 306

      PATIIOGENESIS OF MUSCLE PAIN 306

      Pain After Exercise•Eccentric Versus Concentric Muscle Contraction•Muscle Cramp•Differential Diagnosis for Cramps

      EXERTIONAL MUSCLE PAIN 309

      Tubular Aggregates and Cylindrical Spirals

      DRUG-INDUCED MUSCLE PAIN 310

      Alcohol-Related Myopathy•Statin Myopathy

      SYSTEMIC DISORDERS CAUSING MUSCLE PAIN 312

      Thyroid Disease•Parathyroid Disease and Vitamin D•Adrenal and Pituitary Disease•Diabetes•Vasculitis

      MUSCLE PAIN ARISING FROM BONE AND JOINT DISORDERS 314

      Pain in Inflammatory Muscle Disease and the Other Connective Tissue Diseases•Apparent Muscle Pain in Nonmuscle Diseases•Fibromyalgia•Polymyalgia Rheumatica

      MYOPATHIES ASSOCIATED WITH MUSCLE PAIN 317

      X-Linked Myalgia and Cramp • Eosinophilic Myopathies • Macrophagic Myofasciitis

      OTHER NEUROLOGIC CONDITIONS WITH MUSCLE PAIN 320

      Restless Legs Syndrome•Intermittent Claudication•Assessment of Fatigue in the Neuromuscular Clinic

      THE ROLE OF PAIN AND FATIGUE IN ESTABLISHED MUSCLE DISEASE 322

      Chronic Fatigue Syndrome

13.PREVENTION AND MANAGEMENT OF SYSTEMIC COMPLICATIONS OF MYOPATHIES 328

      RESPIRATORY MANAGEMENT 329

      Normal Respiratory Muscle Function•Abnormalities of Respiratory Function•Recognition of Impending Respiratory Failure•Prevention of Respiratory Complications

      ACUTE RESPIRATORY FAILURE 333

      Anticipation of Respiratory Failure•Precipitating Factors•Management

      CHRONIC VENTILATORY FAILURE 334

      The Decision to Have Long-Term Respiratory Support•Sleep-Related Breathing Complications

      CARDIAC MANAGEMENT 334

      Cardiac Symptoms and Signs•Laboratory Evaluation•Routine Surveillance and Treatment

      PREVENTION OF EDEMA 337

      DIETARY MANAGEMENT: COMPLICATIONS OF OBESITY AND WEIGHT LOSS 337

      SWALLOWING ABNORMALITIES 338

      Symptoms and Recognition•Management

      OTHER GASTROINTESTINAL COMPLICATIONS 339

      ORTHOPEDIC COMPLICATIONS 340

      Scoliosis•Other Orthopedic Complications

      ORTHOTIC INTERVENTION 342

      MOBILITY AIDS AND ADAPTIVE EQUIPMENT 342

      PREGNANCY 342

Index 349

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