Myasthenia Gravis Victor Politi,M.D. Medical Director, SVCMC School of Allied Health, Physician Assistant Program

Pathophysiology The underlying defect is a decrease in the number of available Ach receptors at neuromuscular junctions due to an antibody mediated autoimmune attack

Pathophysiology Pathophysiology ACh synthesized in the motor nerve terminal and stored in vesicles ACh released causes miniature end plate potentials Action potential release ACh and combined with postsynaptic receptors Postsynaptic channels are open allowing entry of sodium producing depolarization of muscle fiber

Pathophysiology A process is terminated by hydrolysis of ACh by AChE The fundamental defect is a decrease in the number of ACh receptors at the postsynaptic muscle membrane, therefore, although ACh is released normally it produces small end plate potentials which fail to trigger muscle action potentials

MG- Autoantibodies protect against the postsynaptic acetylcholine receptors

Pathophysiology The neuromuscular abnormalities caused by an autoimmune response mediated by specific anti AChR antibodies These antibodies reduce the available AChR’s at neuromuscular junctions

Myasthenia gravis (MG) Neuromuscular disorder characterized by weakness and fatigability of skeletal muscles There is no cure for MG but treatment is highly effective

Pathology The neuromuscular abnormalities in MG are brought about by an autoimmune response mediated by specific anti-AChR antibodies the thymus is abnormal in approximately 75% of patients with MG In 65% of patients the thymus is hyperplastic

Clinical Features Prevalence rate 1 in 10,000 people Can affect any age group women - peak incidence 20’s-30’s men - peak incidence 50’s-60’s Women affected more than men Cardinal features - weakness and fatigability

Clinical Features Weakness typically increases during repeated use (fatigue) and may improve during rest or sleep Course of MG - variable Remissions - rarely complete or permanent

Clinical Features Unrelated infections or systemic disorders may lead to increased myasthenic weakness and may precipitate a “crisis” A crisis is if weakness in respiration or swallowing becomes severe and respiratory assistance or intubation is necessary

Clinical Features Characteristic pattern of muscle weakness early involvement -lids and extraocular muscles diplopia and ptosis common initial complaints Difficulty in swallowing may occur

Clinical Features In 85% of cases, weakness becomes generalized, affecting limb muscles as well Limb weakness is often proximal and may be asymmetric deep tendon reflexes are preserved

Diagnosis and Evaluation Suspect on basis of weakness and fatigability as previously described No loss of reflexes or impairment of sensation or other neurologic function Edrophonium- initial dose 2mg IV, second dose 8mg IV ACh receptor antibody detectable in 80% of all myosthenic patients

Differential Diagnosis Several other conditions that cause weakness or the cranial and/or somatic musculature must be considered in the differential diagnosis of MG: drug induced myasthenia, Lambert-Eaton myasthenic syndrome,neurasthenia hyperthyroidism, botulism, intracranial mass lesions and progressive external ophthalmoplegia

Differential Diagnosis Drugs that may exacerbate MG penicillamine aminoglycoside antibiotics procainamide

Lambert-Eaton myasthenic syndrome Presynaptic disorder of neuromuscular junction - causes muscle weakness similar to MG proximal muscles of lower limbs most commonly affected ptosis of the eyelids and diplopia in up to 70% of patients

LES- Autoantibodies against the presynaptic voltage-gated calcium channels

Lambert-Eaton myasthenic syndrome MG and Lambert-Eaton myasthenic syndrome are readily distinguished patients with Lambert-Eaton syndrome have depressed or absent reflexes, autonomic changes (dry mouth, impotence) and show incremental responses on repetitive nerve stimulation

Lambert-Eaton myasthenic syndrome LES is caused by auto antibody directed against calcium channels on the motor nerve terminals resulting in impaired release of ACh

Lambert-Eaton myasthenic syndrome Majority of patients with this syndrome have an associated malignancy - most commonly small cell carcinoma of the lung The diagnosis of Lambert-Eaton may signal the presence of the tumor long before it would otherwise be detected

Lambert-Eaton myasthenic syndrome Treatment involves plasmapheresis and immunosuppression, as for MG

Myasthenic patients have an increased incidence of several associated disorders Thymic abnormalities - 75% of cases thymoma Hyperthyroidism - 3-8% of cases may worsen the myasthenic weakness other autoimmune disorders blood tests for rheumatoid factor, antinuclear antibodies

Thymoma on CT of chest

Chronic infection of any kind can exacerbate MG measurements of ventilatory function are valuable because of the frequency and seriousness of respiratory impairment in myasthenic patients

Because of the side effects of glucocorticoids and other immunosuppressive agents used in the treatment of MG, a through medical history/exam should be made Particular attention should be paid to evidence of chronic or latent infection (tuberculosis/hepatitis), HTN, diabetes, renal impairment, and glaucoma

Therapy The prognosis has improved greatly for MG cases due to advances in treatment virtually all MG patients can be returned to productive lives with proper therapy

Therapy Anticholinesterase medications immunosuppressive agents pyridostigmine immunosuppressive agents glucocorticoids, azathiopriane thymectomy plasmapheresis

Management of myasthenic crisis Exacerbation of weakness sufficient to endanger life respiratory failure aspiration The possibility that the deterioration should be due to excessive anti -ChE medication (cholinergic crisis) is best excluded by temporarily stopping anti-ChE drugs

Management of myasthenic crisis The most common cause of crisis is intercurrent infection The myasthenic patient with fever and early infection should be treated like other immunocompromised patients with early antibiotic therapy, respiratory assistance, and pulmonary physiotherapy. Plasmapheresis is frequently helpful in hastening recovery

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