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Miasthenia gravis

Miasthenia gravis. The Anatomy of the Neuromuscular Junction. Motor neurone terminates as a bouton or pre-synaptic nerve terminal separated from the muscle by a thin synaptic cleft (Motor endplate) The blood nerve barrier is relatively deficient at the NMJ (neuromuscular junction)

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Miasthenia gravis

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  1. Miasthenia gravis

  2. The Anatomy of the Neuromuscular Junction • Motor neurone terminates as a bouton or pre-synaptic nerve terminal separated from the muscle by a thin synaptic cleft (Motor endplate) • The blood nerve barrier is relatively deficient at the NMJ (neuromuscular junction) • Nerve and muscle are kept in close proximity by bridging protein (laminin), with release zones and the crests of post synaptic folds aligned • The skeletal neuromuscular junction is the most studied and best understood synapse

  3. Healthy Neuromuscular Junction

  4. The Physiology of Neuromuscular transmission • Neuronal Action potential invades the pre-synaptic nerve terminal • Depolarisation triggers opening of VGCCs (voltage gate calcium channels) • Calcium influx triggers quantal release of ACh (acetil-choline) • ACh binds to post synaptic nAChRs (acetil choline receptor) • Ca and Na ions influx through nAChR triggering muscle membrane depolarisation via VGSCs- CMAP and muscle contraction(voltage gate sodium channels - compund muscle action potential )

  5. Spontaneous and Nerve Evoked Endplate Responses

  6. Myasthenia Gravis (MG) • MG is the most common disorder of neuromuscular transmission • Incidence 2-6 per 106 , prevalence 40 per 106 population • MG is an acquired autoimmune disease characterised by the formation of anti- nAChR antibodies • MG is common in young women, and older men • MG is characterized by fluctuating and fatigable weakness • Weakness may be limited to a few muscles, such as the extraocular muscles, bulbar, limb or be generalised in fashion • As the weakness is often worse with activity and improved by rest, • it is often worse in the evening

  7. Myasthenia Gravis (MG) • Ocular features: ptosis, diplopia, ophthalmoplegia • Facial weakness esp ob oculi and oris (snarl) • Bulbar weakness: nasal speech, reduced gag, swallowing problems, aspiration (silent), weak neck (dropped) • Limb weakness: proximal, fatiguable • Reflexes: normal • Respiratory weakness: diaphragm and intercostal Fatigue (palpebral ptosis) in MG

  8. Myasthenia Gravis (MG) • MG is a defect of neuromuscular transmission with • reduced efficacy of Acetyl Choline at the post synaptic motor endplate due to pathogenic antibodies which • Block the nAChR, • Down regulate the nAChR • & cause complement dependent destruction of the motor endplate

  9. Myasthenia Gravis (MG) • The immunopathogenesis of MG is unclear but involves • Genetic factors (HLA B8) • Thymus • Vast majority of young onset cases are autoimmune and associated with thymic hyperplasia • Around 10% of patients with MG, often older patients) have an associated thymic tumour (oft striated muscle Abs) • Seronegative (10% gen, 50% OMG) • Neonatal MG

  10. Tensilon test – before and after Single fiber EMG – normal Single fiber EMG – increased jitter Myasthenia Gravis (MG) • Diagnosis • Typical clinical picture • Detection of anti-AChR antibodies in serum (90%) • Positive Tensilon test (atropine) • Repeptitive nerve stimulation at low frequency leads to a decrement in compound muscle action potential amplitude

  11. Repetitive Nerve Stimulation (Supramaximal 2Hz)

  12. Myasthenia Gravis (MG) • Treatment • Symptomatic (pyridostigmine often with propantheline) • Thymectomy • Hyperplasia (trans-sternal approach), • Thymoma (locally invasive) • Immunotherapy • steroids, and other agents including Azathioprine • plasma exchange, • IVIG

  13. Lambert Eaton Myasthenic syndrome (LEMS) • A defect of neuromuscular transmission with reduced quantal release of Acetyl Choline from the presynaptic nerve terminal • Pathogenic antibodies directed against voltage gated calcium channels (VGCCS) expressed at the NMJ and autonomic ganglia • 2/3 patients with LEMShave cancer, most commonly Small cell lung Ca (express VGCCs)

  14. Lambert Eaton Myasthenic syndrome (LEMS) • Clinical features • Dry mouth • Fatigable weakness of proximal muscles (like MG) • Wasting of proximal muscles • Depressed reflexes • Ocular and bulbar weakness rare

  15. Lambert Eaton Myasthenic syndrome (LEMS) • Diagnosis • Typical clinical picture • Detection of anti-VGCC antibodies in serum • Positive Tensilon test (like MG) • Repeptitive nerve stimulation at low frequency leads to a decrement in compound muscle action potential amplitude (like MG) • Repeptitive nerve stimulation at high frequency leads to a increment in compound muscle action potential amplitude (X MG)

  16. Repetitive Nerve Stimulation (Supramaximal 2Hz)

  17. Lambert Eaton Myasthenic syndrome (LEMS) • Treatment • Treating the underlying lung tumour improves LEMS • Treatment for LEMS per se • Symptomatic (mestinon, 3-4 DAP) • Immunotherapy (steroids, plasma exchange, IVIG)

  18. POLYMYOSITISDERMATOMYOSITIS

  19. CLASSIFICATION OF POLYMYOSITIS (PM) – DERMATOMYOSITIS (DM) • Group I: Primary Idiopathic PM • Group II: Primary Idiopathic DM • Group III: DM or PM associated with neoplasia • Group IV: Childhood DM or PM associated with vasculitis • Group V: PM or DM with associated with collagen diseases

  20. POLYMYOSITIS - DERMATOMYOSITIS • Onset age: Usually > 20 years • Progression: weeks-months • Possibly preceded by upper tract infection • Other possible trigger factors: • Anti hepatitis B vaccination • Growth hormone administration • Drugs: penicilamine • Viral infections: Coxsackie B; Parvovirus; Echovirus • HLA • Class II: antigens DQα1*0501 (88%) • For DM: DMA*0103 si DMB*0102

  21. Clinical Picture • Muscle weakness • Proximal > Distal • Symmetric • Frequently starts at lower limbs • Selective regions of weakness: eophagus (dysphagia); Posterior neck; Quadriceps • Usually does not affect oculomotor muscles • Amiotrophies occur late in the evolution • Reflexes usually normal

  22. Motor deficit • Most often proximal • Distal: inclusion body myositis • Lack of simmetry: inclusion body myositis • cvadriceps: inclusion body myositis; PM with mitochondrial diseases • Extraocular muscles: extraoculary myositis • Swallowing : inclusion myositis, granulomatous myositis, scleroderma associated myositis • Episodic: episodic miopathy with pipestem capilaries • Acute: infectious;

  23. Skin lesions (DM) • Heliotrope rash - reddish violaceous eruption on upper eyelids +/- oedema • Diffuse/localised erythema over chest, neck, or over forehead, chin, malar area • Gottron’s sign - symmetric violaceous erythematous eruption over knuckles • Necrosis Gottron sign

  24. Pain • Pain • 30%; Especially with associated connective tissue disease • Rule out: Polymyalgia; Arthritis; Fasciitis; Rhabdomyolysis • Muscle pain • Associated with contraction, muscle mass compression or spontaneous pain • Joint pain • Arthrites or nondestructive arthralgia • Anti-Jo1 or AntiARNt synthethasys antibody syndromes

  25. Associated disorders • Cardiac: Arhythmias; Inflammatory cardiomyopathy • Pulmonary: Respiratory muscle weakess; Interstitial lung disease • Esophageal paresis: Upper 1/3 with muscle weakness, Lower 2/3 with scleroderma • Abdominal pain: • Gastro-intestinalmucosal involvement • Marked by ulceration, hemorrhages & perforation • Due to associated vasculopathy • Malignancy: Mild increased risk • Autoimmune:Lupus, Sjoegren's, Anti-phospholipid antibodies & syndrome: 5% to 8% • Thyrotoxicosis: Rare • High CK: CK in hyperthyroid is usually low • May resolve with anti-thyroid medication alone • Calcinosis (formation of calcium deposits in any soft tissue) in 1/3 of cases

  26. Clinical forms (evolutive) • Acute: • Important motor deficit, fast prograssion, muscle pain, fever, inflamation signs, myoglobinuria • Possible death within weeks due to reapiratory destress, heart failure, kidney feilure • Subacute • Cronic • Focal forms – rare; sometimes evoluate towards difuse type

  27. Laboratory • Serum CK: High (3 to 30 times normal); elevated LDH, aldolase, AST, ALT • General inflamation signs (CRP) • EMG: Irritative myopathy • Small amplitude, brief, polyphasic motor units • Fibrillations; Positive sharp waves • spontaneous high frequency discharges • Antibodies: Disease specific & non-specific

  28. EMG aspects Polyphasic action potentials with small amplitude, short duration Long duration positive sharp waves: Initial positive deflaction followed by a negative component Fibrilation: Short duration potentials (arrows) with positive and then negative component

  29. Muscle biopsy Muscle fiber necrosis • Myopathic • Variation in size of muscle fibers • Necrosis + phagocytosis & regeneration of muscle fibers • Mild, patchy increase in endomysial connective tissue • Inflammation • Endomysial & perivascular inflammatory (mononuclear) cells • Macrophages & CD8+ T-cells • Focal invasion of non-necrotic muscle fibers MAC (complement) deposits at the surface of the muscle fibers

  30. Differential diagnosis • Myasthenia Gravis • Electrolyte disturbances • Metabolic, endocrine or toxic myopathies • Muscular dystrophy • Guillain-Barre Syndrome

  31. Tratament • Corticosteroids • Good response to treatment if: • Clinical picture: proximal or diffuse motor deficit, disease duration <1 year; association with mialgia, cutaneous rash, connective tissue diseases • Lab: very high serum CPK,anti Jo-1antibodies • Biopsy: perimisial inflammation, perifascicular atrophy, necrosis and regeneration • Poor response to therapy if: • Focal or asymetric motor deficit; acute or very slow form of evolution; family history • Lab: normal or low seric CK • Biopsy: focal invasion of muscle fibers by inflammatory cells; • Prednisone 1-2mg/kg/day, tapered after strength improves and CK declines, often after 1-3 months.

  32. TREATMENT • Cytotoxic agents • introduced if severe disease, relapsing disease, inadequate steroid response or steroid induced cx’s. • Azathioprinaor methotrexate used with steroids • Cyclosporin, cyclophosphamide, tacrolimus and antiTNF are alternatives. • Intravenous immunoglobulin successful • Child DM, esophageal dysfunction • 1gram/kg/day

  33. Muscular Dystrophy

  34. What is Muscular Dystrophy?(MD) • Muscular Dystrophy: group of genetic disorders that are characterized by progressive loss of muscle integrity, wasting, and weakness. Characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies)

  35. History and Physical Exam in the Newborn and Office • History • Newborn – floppy infant, term or preterm, poor head control, poor feeding, prolonged labor, maternal complications • Childhood development – delay in sitting, standing, walking, toe walking, difficulty stair climbing or running • Teen or adult – difficulty in self-care, swallowing, athletic/endurance activity

  36. Family History • Include enough of family tree to pick up autosomal recessive disorders and X-linked or AD (autosomal dominant)disorders with variable penetrance • Many x-linked or AD represent new mutations • Past diagnoses in older family members may not be accurate • Review of Systems • School functioning/cognitive development • Cardiac function/arrhythmias/syncope • Respiratory

  37. Physical exam findings • Muscle mass: signs of wasting or hypertrophy/pseudohypertrophy • Muscle strength: power – generation of force against resistance or gravity • Observe reaching, getting up from floor • Observe trunk and head/neck control • Test specific proximal groups – position so against gravity • Tone: resistance to passive movement • Note hyper vs. hypotonia in weak areas • Deep tendon reflexes: normal or decreased • Normal sensation: remember proprioception • Joint contracture: reduced passive range of motion not due to tone

  38. Dystrophinopathy: disorders involving dystrophin • Duchenne MD and Becker MD are the muscular disorders – the two most common and severe dystrophies • Dystrophin is a very large gene on the X-chromosome, ubiquitous in the human body • Dystrophin-Associated Protein (DAP) Complex – composed of the extracellular, transmembrane, and intracellular components

  39. General Diagnostic Testing • Creatine kinase : • Aids in narrowing the differential diagnosis if greatly elevated (50 times normal) • Increased in Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, polymyositis, and rhabdomyolysis • Nonspecific if mildly elevated 2-3x normal • Lower late in MD course due to severely reduced muscle mass • Not helpful for carrier detection

  40. Muscle biopsy • Dystrophic changes include necrosis, degeneration, regeneration, fibrosis and fatty infiltration, sometimes mild inflammation • Specific diseases may have inflammation, intracellular vacuoles, rods, and other inclusions on biopsy • Biochemical muscle protein analysis • Useful for specific identified protein that is missing and many specific mutations may cause the same deficiency • Immunohistochemical protein staining • Western blot – quantitates percent of normal protein present

  41. Genetic analysis • PCR for specific known defects • Southern blot for nucleotide repeats • Electromyography • Useful if diagnosis not clear (biopsy has mixed features) • Differentiates neuropathic vs. myopathic • Characteristic myotonic discharges in adults with myotonia – “dive bomber” sound • Perform after the CK

  42. Duchenne Muscular Dystrophy • Presentation: 3-5 y/o with pseudohypertrophy of calf muscles, frequent falls, slow running, and waddling gait • Prevalence of 1:3500 • Other organs affected • Heart – cardiomyopathy • Respiratory • Intellect - 30 % with impairment IQ <75 • Testing • Immunostaining with absence of dystrophin • PCR testing available for common mutations (X21.2)

  43. Becker Muscular Dystrophy • Slowly progressive form with same gene affected as Duchenne MD • Muscle biopsy immunostaining for dystrophin with patchy staining • Disorder of function or decreased amount of dystrophin rather than absence of the protein

  44. Congenital Muscular Dystrophy • Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures • Merosin negative/CMD A1 • White matter hypodensities on brain scan but normal mental capacity • Diagnosis by muscle biopsy immunohistochemistry showing loss of α2-laminin (AR-chromosome 6q22-23)

  45. FascioScapularHumeral Muscular Dystrophy • Presentation: • Facial weakness with trouble blowing up a balloon, sipping through a straw, whistling, trouble closing the eyes at night, scapular winging that may be asymmetric, pain • May have absence of pectoralis, biceps, or brachioradialis • Also affected: mild high pitched hearing loss, retinal abnormalities, mental retardation in early onset • Genetics/Testing • Southern blot testing available (chromosome 4q35) for decrease in repeats normally present • Muscle biopsy may show lymphocytic infiltrates

  46. Limb Girdle Muscular Dystrophy • Presentation: variable age of onset with weakness and wasting of the limb-girdle • May have calf hypertrophy, involvement of scapular muscle and deltoid in sarcoglycanopathies • Many types involve dysfunctional sarcoglycans – transmembrane proteins of the DAP that interact with cytoplasmic proteins • Table 2 – types of LGMD

  47. Oculopharyngeal Muscular Dystrophy • Presentation: mid-adult with ptosis, facial muscle weakness with difficulty swallowing, proximal muscle weakness, may have extraocular muscle weakness, more common in French-Canadian and Hispanic population • Genetics • Muscle biopsy shows filamentous nuclear inclusions and ubiquitin containing vacuoles • Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen – Southern blot (chromosome 14q11-13)

  48. Emery-Dreifuss Muscular DystrophyScapuloperoneal MD • Presentation: stiff joints, shoulder and upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contractures • Genetics • X-linked type affects emerin • Diagnose by protein analysis of leukocytes or skin fibroblasts • DNA testing available (chromosome Xq28) • AD affects lamin A or lamin C (chromosome 1q21) • Nuclear membrane proteins

  49. Myopathies • Central core disease: • Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD – chromosome 19q13) • Associated with Malignant Hyperthermia • Myotubular myopathy • Myotubularin, important in myogenesis (Xq28) • Nemaline Myopathy • Caused by many defects, disorder of thin filaments • Rod-like stuctures on muscle biopsy • Inflammatory • Juvenile Dermatomyositis • Inclusion Body Myositis (usually distal) • Adult Polymyositis (associated with malignancy)

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