DISEASES OF VOLUNTARY MUSCLE Presented by Samiha Hubieshi Reem Al-shaikh

2. Definitions  Myopathy describes diseases of voluntary muscle generally with no pain or stiffness. Myositis indicates inflammation. Muscular dystrophy describes inherited disorders with progressive weakness. Myasthenia means fatiguable (worse on exercise) weakness. Myotonia is sustained contraction/slow relaxation seen in myotonias. Channelopathy describes ion channel disorders in muscle cells.

3. Distinguishing Lower Motor Weakness from Muscle Weakness

4. Classification of muscle disease Acquired 1- inflammatory myopathy 2- metabolic and endocrine myopathy 3- Myasthenic disorders Genetically determined myopathies 1- Muscular dystrophies 2- Myotonias 3- Channelopathies (periodic paralyses) 4- Specific metabolic myopathies

5. INFLAMMATORY MYOPATHIES Polymyositis and dermatomyositis These are connective tissue disorders with inflamatory reaction in skeletal muscles and skin (dermatomyosistis) of autoimmune pathogensis . Pathogenesis : Non-suppurative inflammation of skeletal muscle with predominantly lymphocytic infiltrates and persons with HLA-B8/DR3 appear to be genetically predisposed.

6. Classifications adult polymyositis adult dermatomyositis adult polymyositis, dermatomyositis with malignancies PM/DM in association with other connective tissue diseases childhood DM.

11. Antisynthetase syndrome About 20-30% of patients with PM and DM have antibodies to t RNA synthetase enzyme , these patients are more liable to interstetial pulmonary fibrosis , arthritis , Raynaud’s phenomenon and fissuring of skin over the pulp of the fingers (mechanic’s hand) It has a poor outcome Dysphagia is seen in about 50% of patients owing to esophageal muscle involvement

12. autoimmune rheumatic diseases : There is an association with other ARD (e.g. SLE, RA and systemic sclerosis) with their associated clinical features such as deforming arthritis, malar rash and skin sclerosis. Association with malignancies The relative risk of cancer is 2.4 for male and 3.4 for female patients. The onset and clinical picture does not differ from that of typical DM/PM. The associated cancer may not become apparent for 2-3 years, and recurrent or refractory dermatomyositis should prompt a search for occult malignancy. There is also an association with malignancy (e.g. lung, ovary, breast, stomach), which can predate the onset of myositis. This occurs particularly in males with dermatomyositis.

13. Investigations  Serum creatine kinase (CK), aminotransferases, LDH and aldolase are usually raised and are useful guides to the muscle damage but may not reflect activity. ESR is raised in about 5% of cases. Serum autoantibody studies. Antinuclear antibody testing is commonly positive in patients with DM .Rheumatoid factor is present in up to 50% myositis-specific antibodies (MSAs) have been recognized and correlate with certain subsets e.g Antibodies to Jo-1 (antibodies to histidyl tRNA synthase) are predictive of pulmonary fibrosis but are rarely seen in patients with dermatomyositis. Electromyography (EMG) shows a typical triad of changes with myositis: - spontaneous fibrillation potentials at rest polyphasic or short-duration potentials on voluntary contraction salvos of repetitive potentials on mechanical stimulation of the nerve.

14. Needle muscle biopsy shows fibre necrosis and regeneration in association with an inflammatory cell infiltrate with lymphocytes around the blood vessels and between muscle fibres. Open biopsy allows more thorough assessment. Screening for malignancy is usually limited to relatively non-invasive investigation such as CXR mammography, pelvic/abnormal ultrasound, urine microscopy and a search for circulating tumour markers.

15. Treatment 1- Bed rest is usually helpful but must be combined with an exercise programme. 2- search for neoplasm any where . 3- steroids : Prednisolone is the mainstay of treatment; 0.5-1.0 mg/kg bodyweight as initial therapy given for at least 1 month after myositis has become clinically and enzymatically inactive. Tapering of steroids must be slow. 4- Early intervention with steroid-sparing agents such as methotrexate, azathioprine, ciclosporin, cyclophosphamide and mycophenolate mofetil is common. 5- Intravenous immunoglobulin therapy (IVIG) is helpful in some recalcitrant cases.

16. Inclusion body myocitis Mainly affects older individuals > 50 Symptoms begin insidiously and progress slowly mailny distal muscles Symptoms are often present 5-6 years before diagnosis Differs from Polymyositis in that IBM: May include focal, distal or asymmetric weakness Neurogenic or mixed neurogenic / myopathic changes on EMG muscle biopsy shows inflammation and basophilic rimmed with diagnostic filamentous inclusions and vacuoles on electron microscopy Dysphagia is noted in more than 50 % of patients A trial of corticosteriods is worthwhile but generally the response is poor .

17. Viral, bacterial and parasitic myositis 

18. Myopathy in sarcoidosis and rheumatoid disease   In sarcoidosis, a subacute myopathy sometimes develops, either with limb muscle swelling and induration, or with wasting. This is usually during pulmonary sarcoidosis, but occasionally it is isolated. Sarcoid nodules are seen on muscle biopsy. Treatment is with steroids. In rheumatoid disease, a rare localized nodular myositis causes painful swelling of limb, trunk and facial muscles.

19. Endocrine and toxic

20. Corticosteroids and Cushing's syndrome  Proximal weakness occurs with prolonged high-dose steroid therapy, particularly with 9-a-fluorinated steroids (e.g. dexamethasone and triamcinolone) and in Cushing's syndrome .Selective type-2 fibre atrophy is seen on biopsy. Factors contributing to muscle weakness in adrenal insufficiency include circulatory insufficiency, fluid and electrolyte imbalance, impaired carbohydrate metabolism, and starvation.

21. Thyroid disease  Thyrotoxicosis it can be accompanied by severe proximal myopathy. There is also an association between thyrotoxicosis and myasthenia gravis, and between thyrotoxicosis and hypokalaemic periodic paralysis In ophthalmic Graves' disease, there is swelling and lymphocytic infiltration of extraocular muscles   Hypothyroidism is sometimes associated with muscle pain and stiffness, resembling myotonia. A proximal myopathy also occurs.

22. Disorders of calcium metabolism  Proximal myopathy develops in hypocalcaemia, rickets and osteomalacia   Hypokalaemia  Acute hypokalaemia (e.g. in diuretic therapy) causes a severe flaccid paralysis reversed by potassium, given slowly . Chronic hypokalaemia (also commonly caused by diuretics) gives rise to mild, mainly proximal, weakness. See also periodic paralysis Alcohol  Severe myopathy with muscle pain, necrosis and myoglobinuria occurs in acute alcoholic excess. A similar syndrome occurs in diamorphine and amfetamine addicts. A subacute proximal myopathy occurs with chronic alcohol abuse.

23. Drugs steroids : proximal myopathy Lithium : muscle weakness Fibrates : painful muscles fibrate combined with a statin :rhabdomyolysis and malignant hyperpyrexia.

24. Metabolic Myopathy

25. Myophosphorylase deficiency (McArdle’s syndrome ) This is an autosomal recessive disorder in which lack of skeletal muscle myophosphorylase causes easy fatiguability and severe cramp on exercise, with myoglobinuria. Venous lactate during ischaemic exercise does not increase this test is specific for the condition. Sucrose ingestion helps

26. Malignant hyperpyrexia  inherited disorder of the skeletal muscle system in which a defect in the calcium regulation is expressed by exposure to triggering anesthetic agents or neuroleptic drugs (e.g. haloperidol) intracellular hypercalcemia results. This is due to a genetic defect in the sarcoplasmic reticulum calcium-release channel in the skeletal muscle ryanodine receptor (RyR1). Sudden death during or after anaesthesia may occur sometimes inherited as an autosomal dominant trait. Dantrolene is useful in controlling rigidity.

27. Mitochondrial diseases  These comprise a complex group of disorders involving muscle, peripheral nerves and CNS. They are characterized by morphological and biochemical abnormalities in mitochondria, with several unusual genetic characteristics, for example the maternal inheritance of mitochondrial DNA. The disease spectrum is wide, ranging from optic atrophy to myopathies, neuropathies and encephalopathy. Types MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is one well-recognized form. Chronic progressive ophthalmoplegia (CPEO) is another, and MERRF describes the occurrence of myoclonic epilepsy and 'ragged red' muscle fibres on biopsy.

28. NEUROMUSCULAR JUNCTIONCONDITIONS

29. Myasthenia gravis (MG) def , pathology, clinical features “symptoms and signs “, investigation and management , TTT

30. pathology, clinical features “symptoms and signs “, investigation and management , TTT A second group of antibodies against muscle-specific receptor tyrosine kinase (anti-MuSK antibodies) has more recently been identified in anti-AChR antibody negative cases. Ocular muscle MG is another subgroup.A second group of antibodies against muscle-specific receptor tyrosine kinase (anti-MuSK antibodies) has more recently been identified in anti-AChR antibody negative cases. Ocular muscle MG is another subgroup.

31. pathology, clinical features “symptoms and signs “, investigation and management , TTT

33. pathology, clinical features “symptoms and signs “, investigation , course management and TTT Serum anti-AChR and anti-MuSK antibodies Anti-AChR antibodies are present in some 80–90% of cases of generalized MG. These antibodies are not found in healthy controls but are seen rarely in other muscle disorders. In pure ocular MG, anti-AChR antibodies are detectable in less than 30% of cases.

34. A characteristic decrement occurs in the evoked muscle action potential during repetitive stimulation. Electromyography is otherwise normal.

35. Edrophonium 10 mg is given intravenously following a 1–2 mg test dose from the 10 mg vial. When the test is positive, there is substantial improvement in weakness within seconds and this lasts for up to 5 minutes. Occasionally edrophonium (an anticholinesterase) causes bronchospasm and syncope. Resuscitation facilities must be available.

36. Mediastinal MR provides optimal structural imaging for thymoma. Routine blood studies are normal: the ESR is not raised, and CPK is normal. Antibodies to striated muscle suggest a thymoma; intrinsic factor and thyroid antibodies may be found. Rheumatoid factor and anti-nuclear antibody tests can be positive. Muscle biopsy is usually not performed, though ultrastructural neuromuscular junction abnormalities are well described.

37. Myasthenia gravis fluctuates in severity. most cases have a protracted, lifelong course. Respiratory impairment, nasal regurgitation and dysphagia occur; emergency assisted ventilation may be required. Simple monitoring tests, such as the duration for which an arm can be held outstretched, and the vital capacity are useful. pathology, clinical features “symptoms and signs “, investigation , course management and TTT

38. pathology, clinical features “symptoms and signs “, investigation , course management and TTT Oral anticholinesterases Immunosuppressant drugs -Thymectomy intravenous immunoglobulin During exacerbations.

39. Lambert–Eaton myasthenic–myopathic syndrome (LEMS) This para neoplastic manifestation of small-cell bronchial carcinoma is due to defective acetylcholine release at the neuromuscular junction Proximal limb muscle weakness, sometimes with ocular/bulbar muscles develops, with some absent tendon reflexes. Weakness tends to improve after a few minutes of muscular contraction, and absent reflexes return. Diagnosis is confirmed by EMG and repetitive stimulation Antibodies to P/Q-type voltage-gated calcium channels are found in most cases (90%). 3,4-Diaminopyridine (DAP) is a reasonably safe and sometimes effective treatment.

40. MUSCULAR DYSTROPHIES

41. MUSCULAR DYSTROPHIES(DMD) and Becker’s muscular dystrophy, Limb-girdle andfacioscapulohumeral dystrophy

43. Dystrophin

44. mutants. DMD occurs in1 in 3000 male infants. DMD is usually obvious by the fourth year, and often causes death by 20. Becker’s muscular dystrophy is less severe than Duchenne and weakness only becomes apparent in young adults.

45. Duchenne and Becker’s MD patho, Clinical features, investigation, ttt

46. Duchenne and Becker’s MD patho, Clinical features, investigation, ttt

47. Limb-girdle andfacioscapulohumeral dystrophy

48. MYOTONIAS characterized by continued, involuntary muscle contraction after cessation of voluntary effort.

49. Dystrophia myotonica (DM) ormyotonic dystrophy (MD)

52. Myotonia congenita(Thomsen’s disease)

54. CHANNELOPATHIES

55. Hypokalaemic periodic paralysis

56. Hyperkalaemic periodic paralysis

57. Stiff person syndrome