Myopathies

All types have been covered with enough details

1. Myopathies Presented by, Dr. Chandan N Intern, Department of Medicine, MIMS, Mandya

2. Definition Myopathies are disorders with structural changes or functional impairment of muscle. It does not include upper motor neuron lesions, lower motor neuron lesions, myasthenia gravis which also causes muscle weakness.

3. Muscle anatomy and microscopy

4. UMN and LMN lesions

5. Myasthenia gravis

6. Types of myopathies Inflammatory Myopathies Polymyositis Dermatomyositis Inclusion body myositis Muscular dystrophies X-linked Limb-girdle( ar /d) Congenital Fasioscapulohumeral (ad) Oculopharyngeal Myotonic Syndromes Myotonic dystrophy (ad) Inherited Schwarz- Jampel Drug-induced Congenital myopathies Central core disease Nemaline myopathy Myotubular Metabolic myopathies Glycogen storage disorders Mitochondrial Periodic paralysis Endocrine myopathies Thyroid Parathyroid Adrenal/steroid Pituitary Drug-induced/toxic

7. Inflammatory myopathies

8. Characteristic Polymyositis Dermatomyositis Inclusion Body Myositis Age at onset >18 yr Adulthood and childhood >50 yr Familial association No No Yes, in some cases Extramuscular manifestations Yes Yes Yes Associated conditions Connective tissue diseases Yes Scleroderma and mixed connective tissue disease (overlap syndromes) Yes, in up to 20% of cases a Systemic autoimmune diseases Frequent Infrequent Infrequent Malignancy No Yes, in up to 15% of cases No Viruses Yes Unproven Yes c Drugs Yes Yes, rarely No Parasites and bacteria Yes No No

9. Pathogenesis An autoimmune etiology of the inflammatory myopathies is indirectly supported by an association with other autoimmune or connective tissue diseases; the presence of various autoantibodies(anti-Jo-1 antibodies ); an association with specific major histocompatibility complex (MHC) genes; demonstration of T cell–mediated myocytotoxicity or complement-mediated microangiopathy ; and a response to immunotherapy.

10. Clinical features Prevalence is around 1 in 1,00,000. Progressive and symmetrical muscle weakness. Proximal muscle weakness occurs first, later distal muscle weakness, fine movements still later. Ocular muscles are spared even in advanced and untreated cases.

11. Facial muscles are unaffected in polymyositis and dermatomyositis , but mild facial weakness is common in inclusion body myositis. Pharyngeal muscles and neck muscles are involved in all forms causing dysphagia and difficulty in holding head. In advanced and rarely acute cases respiratory muscles are involved. Sensations remains intact. Tendon reflexes are usually preserved.

12. Dermatomyositis is identified by its characterisitic rash often preceding weakness. -B lue-purple discoloration on the upper eyelids with edema (heliotrope rash; see Fig. 55-3), a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption ( Gottron's sign) - Rash may worsen after sun exposure.

13. Diagnosis Polymyositis Criterion Definite Probable Dermatomyositis Inclusion Body Myositis Myopathic muscle weakness a Yes Yes Yes b Yes; slow onset, early involvement of distal muscles, frequent falls Electromyographic findings Myopathic Myopathic Myopathic Myopathic with mixed potentials Muscle enzymes Elevated (up to 50-fold) Elevated (up to 50-fold) Elevated (up to 50-fold) or normal Elevated (up to 10-fold) or normal Muscle biopsy findings c "Primary" inflammation with the CD8/MHC-I complex and no vacuoles Ubiquitous MCH-I expression but minimal inflammation and no vacuoles d Perifascicular, perimysial, or perivascular infiltrates, perifascicular atrophy Primary inflammation with CD8/MHC-I complex; vacuolated fibers with -amyloid deposits; cytochrome oxygenase–negative fibers; signs of chronic myopathy e Rash or calcinosis Absent Absent Present f Absent

14. Treatment Glucocorticoids: Prednisolone 1mg/kg/day for 3-4 weeks then tapered. Immunosuppressive agents: Azathoiprine , methotrexate, mycophenolate , cyclosporine, tacrolimus , cyclophosphamide. IVIg . IBM is resistant to treatment. The combination of above may be tried. Or low dose prednisolone on alternate days can be tried.

15. Muscular Dystrophies Muscular dystrophy refers to a group of hereditary progressive diseases each with unique phenotypic and genetic features

16. Duchenne’s muscular dystrophy Also called pseudo hypertrophic muscular dystrophy. It is an X linked recessive disorder. Dystrophin is deficient. Clinical features : It is present at birth but becomes evident at 3-5 years. Gower’s maneuver Joint contractures, scoliosis, decreased pulmonary functions.

17. Gower’s maneuver

18. By 16 to 18 years patients die of severe pulmonary infections or aspiration pneumonia. Respitatory failure in 2 nd or 3 rd decade. IQ <~1 SD of the mean. Laboratory findings Serum CK levels are raised 20 to 100 times EMG shows reduced amplitude. Muscle biopsy: small group of necrotic and regenerating muscle fibres . Connective tissue and fat replace muscle fibres .

19. Definitive diagnosis is by demonstrating dystrophin deficiency and mutation of gene coding for dystrophin . Treatment Prednisolone – 0.75mg/kg/day significantly slows down the progression of disease.

20. Becker’s muscular dystrophy X linked recessive inheritance. Less severe form. Dystrophin muscle protein is deficient. Clinical features: Muscle wasting resembles Duchenne’s . Proximal muscle weakness of lower extremities occur first. Onset 5-15 years or even 3 rd to 4 th decade. Patients may survive till 4 th or 5 th decade.

21. Laboratory findings are similar to that of Duchenne’s muscular dystrophy. No satisfactory treatment yet available.

22. Limb girdle muscular dystrophies(Autosomal Dominant) Disease Clinical Features Laboratory Features Locus or Gene LGMD1A Onset 3d to 4th decade Muscle weakness affects distal limb muscles, vocal cords, and pharyngeal muscles Serum CK 2 x normal EMG mixed myopathy/neuropathy NCS normal Myotilin LGMD1B Onset 1st or 2d decade Proximal lower limb weakness and cardiomyopathy with conduction defects Some cases indistinguishable from Emery- Dreifuss muscular dystrophy with joint contractures Serum CK 3–5 x normal NCS normal EMG myopathic Lamin A/C LGMD1C Onset in early childhood Proximal weakness Gowers' sign, calf hypertrophy Exercise-related muscle cramps Serum CK 4–25 x normal NCS normal EMG myopathic Caveolin-3 LGMD1D Onset 3d to 5th decade Proximal muscle weakness Cardiomyopathy and arrhythmias Serum CK 2–4 x normal NCS normal EMG myopathic Linked to chromosome 7q Gene unidentified LGMD1E Childhood onset Proximal muscle weakness Serum CK usually normal NCS normal EMG myopathic Linked to chromosome 6q23 Gene unidentified

23. Limb girdle muscular dystrophies(Autosomal Recessive) Disease Clinical Features Laboratory Features Locus or Gene LGMD2A Onset 1st or 2d decade Tight heel cords Contractures at elbows, wrists, and fingers; rigid spine in some Proximal and distal weakness Serum CK 3–15 x normal NCS normal EMG myopathic Calpain-3 LGMD2B Onset 2d or 3d decade Proximal muscle weakness at onset, later distal (calf) muscles affected Miyoshi myopathy is variant of LGMD2B with calf muscles affected at onset Serum CK 3–100 x normal NCS normal EMG myopathic Inflammation on muscle biopsy may simulate polymyositis Dysferlin LGMD2C–F Onset in childhood to teenage yrs Clinical condition similar to Duchenne and Becker muscular dystrophies Cardiomyopathy uncommon Cognitive function normal Serum CK 5–100 x normal NCS normal EMG myopathic , , , sarcoglycans LGMD2G Onset age 10 to 15 Proximal and distal muscle weakness Serum CK 3–17 x normal NCS normal EMG myopathic Telethonin LGMD2H Onset 1st to 3d decade Proximal muscle weakness Serum CK 2–25 x normal NCS normal EMG myopathic TRIM32 gene LGMD2I Onset 1st to 3d decade Clinical condition similar to Duchenne or Becker dystrophies Cardiomyopathy (some not all) Cognitive function normal Serum CK 10–30 x normal NCS normal EMG myopathic Fukutin-related protein LGMD2J a Onset 1st to 3d decade Proximal lower limb weakness Mild distal weakness Progressive weakness causes loss of ambulation Serum CK 1.5–2 x normal NCS normal EMG myopathic Titin

24. Type Inheritance Defective Gene/Protein Onset Age Clinical Features Other Organ Systems Involved Facioscapulohumeral AD Deletion, distal 4q Before age 20 Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion Deafness Coats' (eye) disease Oculopharyngeal AD Expansion, poly-A RNA binding protein 5th to 6th decade Slowly progressive weakness of extraocular, pharyngeal, and limb muscles —

25. Facioscapulohumeral dystrophy

26. Treatment of Facioscapulohumeral (FSH) Muscular Dystrophy : No specific treatment. Treatment of oculopharyngeal dystrophy: Cricopharyngeal myotomy may improve swallowing. Eyelid crutches may be used in ptosis to improve vision. Except in severe facial weakness ptosis surgeries can be tried.

27. Congenital muscular dystrophies Disease Clinical Features Laboratory Features Locus or Gene Merosin deficiency Onset at birth with hypotonia, joint contractures, delayed milestones, generalized muscle weakness Cerebral hypomyelination, less often cortical dysplasia Normal intelligence usually, some with MR (~6%) and seizures (~8%) Partial deficiency leads to milder phenotype (LGMD picture) Serum CK 5–35 x normal EMG myopathic NCS abnormal in some cases Laminin 2 chain Fukitin-related protein deficiency b Onset at birth or shortly after Hypotonia and feeding problems Weakness of proximal muscles, especially shoulder girdles Hypertrophy of leg muscles Joint contractures Cognition normal Serum CK 10–50 x normal EMG myopathic NCS normal Fukutin-related protein Fukuyama congenital muscular dystrophy b Onset at birth Hypotonia, joint contractures Generalized muscle weakness Hypertrophy of calf muscles Seizures, mental retardation Cardiomyopathy Serum CK 10–50 x normal EMG myopathic NCS normal MRI shows hydrocephalus and periventricular and frontal hypomyelination Fukutin Muscle-eye-brain disease Onset at birth, hypotonia Eye abnormalities include: progressive myopia, cataracts, and optic nerve, glaucoma, retinal pigmentary changes Progressive muscle weakness Joint contractures Seizures, mental retardation Serum CK 5–20 x normal MRI shows hydrocephalus, cobblestone lissencephaly, corpus callosum and cerebellar hypoplasia, cerebral hypomyelination N-acetyl-glucosaminyl transferase (POMGnT1) Walker-Warburg syndrome b Onset at birth, hypotonia Generalized muscle weakness Joint contractures Microphthalmos, retinal dysplasia, buphthalmos, glaucoma, cataracts Seizures, MR Serum CK 5–20 x normal MRI shows cobblestone lissencephaly, hydrocephalus, encephalocele, absent corpus callosum O-mannoxyl-transferase-1(POMT1)

28. Myotonic dystrophy Also called dystrophia myotonica . Two types: myotonic dystrophy type 1 (DM1 ) and myotonic dystrophy type 2 ( DM 2 ) . Clinical features: Hatchet-faced – temporalis, masseter & facial muscle weakness. Frontal baldness is characteristic. Neck muscles, including flexors and sternocleidomastoids, and distal limb muscles are involved early. Proximal muscles are spared throughout the course of the disease

29. Diaphragm & intercostal muscles involvement causes respiratory insufficiency. Myotonia usually appears by 5 years, demonstrated by percussion of thenar eminence, tongue and wrist extensor muscles. Cardiac involvement- 1 st degree heart block, complete heart block & sudden death, CCF & MVP may also occur. Other associated features include intellectual impairment, hypersomnia, posterior subcapsular cataracts, gonadal atrophy, insulin resistance, and decreased esophageal and colonic motility.

30. Laboratory features: Diagnosis is usually clinical. S.CK may be normal or raised. Muscle biopsy shows muscle atrophy. Typically, numerous internalized nuclei can be seen in individual muscle fibers as well as atrophic fibers with pyknotic nuclear clumps. EMG shows myotonia . Treatment : DM1 rarely requires treatment. Patients with DM2 requires phenytoin. Pace makers may be required for heart blocks.

31. Congenital myopathies

32. Central core disease Autosomal dominant. Decreased foetal movements and breech presentations. Hypotonia & delay in motor milestones. In late childhood difficulty in climbing stairs, running. O/E- Mild neck muscle, proximal muscle weakness present. CDH, scoliosis, pes cavus and CTEV may also occur. Non progressive with exceptions. Malignant hyperthermia risk is common. Lab findings: S.CK- normal. EMG myopathic pattern. Muscle biopsy shows fibers with single or multiple central or eccentric discrete zones ( cores ) devoid of oxidative enzymes . No specific treatment.

33. Nemaline myopathy Nema in Greek means thread. Presence in muscle fibers of rods or threadlike structures. Severe neonatal form presents with hypotonia and feeding and respiratory difficulties, leading to early death. Usually presents in infancy or childhood with delayed motor milestones. The disease is either non progressive or slowly progressive. The long, narrow facies , high-arched palate, and open-mouthed appearance due to a prognathous jaw. Pectus excavatum , kyphoscoliosis , pes cavus , and clubfoot deformities . Lab features: S.CK- normal or slightly raised. EMG- myopathic . Muscle biopsy. No specific treatment.

34. Centronuclear ( Myotubular ) Myopathy Three variants: A neonatal form presents with severe hypotonia and weakness at birth . The late infancy–early childhood form presents with delayed motor milestones . Later, difficulty with running and stair climbing A marfanoid , slender body habitus, long narrow face, and high-arched palate are typical. Progressive external ophthalmoplegia with ptosis and varying degrees of extraocular muscle impairment are characteristic of both the neonatal and the late-infantile forms. The late childhood–adult form, has an onset in the second or third decade. Patients have full extraocular muscle movements and rarely exhibit ptosis. Normal or slightly elevated CK levels EMG is myopathic . Muscle biopsy specimens in longitudinal section demonstrate rows of central nuclei, often surrounded by a halo. In transverse sections, central nuclei are found in 25–80% of muscle fibers. No specific treatment is available

35. Hypokalemic Periodic Paralysis ( HypoKPP ) HypoKPP type1 & type 2 Calcium channel disorder Onset at adolescent Men are more affected than women Attacks are often provoked by meals high in carbohydrates or sodium and may accompany rest following prolonged exercise Weakness takes >24hrs to resolve. Respiratory muscles are usually spared Lab diagnosis: A low serum potassium level during an attack, excluding secondary causes, establishes the diagnosis. Interattack muscle biopsies show the presence of single or multiple centrally placed vacuoles or tubular aggregates . Treatment: Oral KCl (0.2–0.4 mmol /kg) should be given every 30 min . Rarely IV KCl is required. Mannitol is the preferred vehicle for administration of IV potassium

36. Hyperkalemic Periodic Paralysis ( HyperKPP ) Misnomer as patients will be normokalemic Mutations of the voltage-gated sodium channel SCN4A gene Onset is in the first decade Potassium administration precipitates attacks Onset in first decade Attacks are brief and mild, usually lasting 30 min to 4 h . Weakness affects proximal muscles. Attacks are precipitated by rest following exercise and fasting. Lab features: Potassium usually will be normal. EMG shows reduced amplitude. The EMG will often demonstrate myotonic discharges during and between attacks . The muscle biopsy shows vacuoles that are smaller, less numerous, and more peripheral Acetazolamide (125–1000 mg/d) is helpful.

37. Paramyotonia Congenita Autosomal dominant condition; voltage-gated sodium channel mutations Attacks of weakness are cold-induced or occur spontaneously and are mild Myotonia is a prominent feature but worsens with muscle activity (paradoxical myotonia ). Over time patients develop interattack weakness as they do in other forms of periodic paralysis. Serum CK is usually mildly elevated. Routine sensory and motor nerve conduction studies are normal. Patient is either normo or hyperkalemic . Thiazide diuretics (e.g., chlorothiazide , 250–1000 mg/d) and mexiletine (slowly increase dose from 450 mg/d) are reported to be helpful. Patients should be advised to increase carbohydrates in their diet.

38. Drug induced myopathies Drugs Major Toxic Reaction Lipid-lowering agents Fibric acid derivatives HMG-CoA reductase inhibitors Niacin (nicotinic acid) Drugs belonging to all three of the major classes of lipid-lowering agents can produce a spectrum of toxicity: asymptomatic serum creatine kinase elevation, myalgias, exercised-induced pain, rhabdomyolysis, and myoglobinuria. Glucocorticoids Acute, high-dose glucocorticoid treatment can cause acute quadriplegic myopathy. These high doses of steroids are often combined with nondepolarizing neuromuscular blocking agents but the weakness can occur without their use. Chronic steroid administration produces predominantly proximal weakness. Nondepolarizing neuromuscular blocking agents Acute quadriplegic myopathy can occur with or without concomitant glucocorticoids. Zidovudine Mitochondrial myopathy with ragged red fibers. Drugs of abuse Alcohol Amphetamines Cocaine Heroin Phencyclidine Meperidine All drugs in this group can lead to widespread muscle breakdown, rhabdomyolysis, and myoglobinuria. Local injections cause muscle necrosis, skin induration, and limb contractures. Autoimmune toxic myopathy D -Penicillamine Use of this drug may cause polymyositis and myasthenia gravis. Amphophilic cationic drugs Amiodarone Chloroquine Hydroxychloroquine All amphophilic drugs have the potential to produce painless, proximal weakness associated with autophagic vacuoles in the muscle biopsy. Antimicrotubular drugs Colchicine This drug produces painless, proximal weakness especially in the setting of renal failure. Muscle biopsy shows autophagic vacuoles.

39. Other myopathies Glycogen Storage and Glycolytic Defects Carnitine Palmitoyltransferase Deficiency Mitochondrial Myopathies - Progressive External Ophthalmoplegia Syndromes with Ragged Red Fibers. - Kearns-Sayre Syndrome (KSS) - Autosomal Recessive Cardiomyopathy and Ophthalmoplegia (ARCO ) - Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

40. Thyroid disorders Adrenal disorders Pituitary disorders Diabetes mellitus Vitamin K deficiency Myopathy of systemic illness Drugs of Abuse and Related Myopathies Drug-Induced Autoimmune Myopathies

41. References Harrison's Principle of Internal Medicine 19 th Edition

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