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INTRODUCTION

An autoimmune neuromuscular disorder resulting in weakness and fatigability of skeletal muscles, due to autoantibodies directed against acetylcholine receptors (AChRs) at neuromuscular junctions (NMJs).

CLINICAL FEATURES

May present at any age. Symptoms fluctuate throughout the day and are provoked by exertion. Characteristic distribution: cranial muscles (eyelids, extraocular muscles, facial weakness, "nasal" or slurred speech, dysphagia); in 85%, limb muscles (often proximal and asymmetric) become involved. Reflexes and sensation normal. May be limited to extraocular muscles only. Complications: aspiration pneumonia (weak bulbar muscles), respiratory failure (weak chest wall muscles), exacerbation of myasthenia due to administration of drugs with neuromuscular junction blocking effects (quinolones, macrolides, aminoglycosides, procainamide, propranolol, nondepolarizing muscle relaxants).

PATHOPHYSIOLOGY

Anti-AChR antibodies reduce the number of available AChRs at the NMJ. Postsynaptic folds are flattened or "simplified," with resulting inefficient neuromuscular transmission. During repeated or sustained muscle contraction, decrease in amount of ACh released per nerve impulse ("presynaptic rundown," a normal occurrence), combined with disease-specific decrease in postsynaptic AChRs, results in pathologic fatigue. Thymus is abnormal in 75% of pts (65% hyperplasia, 10% thymoma). Other autoimmune diseases may coexist: Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus.

DIFFERENTIAL DIAGNOSIS

  • Lambert-Eaton syndrome (autoantibodies to calcium channels in presynaptic motor nerve terminals)—reduced ACh release; may be associated with malignancy

  • Neurasthenia—weakness/fatigue without underlying organic disorder

  • Drug-induced myasthenia—penicillamine may cause MG; resolves weeks to months after discontinuing drug

  • Botulism—toxin inhibits presynaptic ACh release; most common form is food-borne.

  • Diplopia from an intracranial mass lesion—compression of nerves to extraocular muscles or brainstem lesions affecting cranial nerve nuclei

  • Hyperthyroidism

  • Progressive external ophthalmoplegia—seen in rare mitochondrial disorders that can be detected with muscle biopsy

LABORATORY EVALUATION

  • AChR antibodies—levels do not correlate with disease severity; 85% of all MG pts are positive; only 50% with pure ocular findings are positive; positive antibodies are diagnostic. Muscle-specific kinase (MuSK) antibodies present in 40% of AChR antibody–negative pts with generalized MG.

  • Tensilon (edrophonium) test—a short-acting anticholinesterase—look for rapid and transient improvement of strength; false-positive (placebo response, motor neuron disease) and false-negative tests occur. Atropine IV should be on hand if symptoms such as bradycardia occur.

  • EMG—low-frequency (2–4 Hz) repetitive stimulation produces rapid decrement in amplitude (>10–15%) of evoked motor responses.

  • Chest CT/MRI—search for thymoma.

  • Consider thyroid and other studies (e.g., ANA) for associated autoimmune disease.

  • Measurements of baseline respiratory function are useful.

TREATMENT Myasthenia Gravis (See Fig. 206-1)

  • The anticholinesterase drug pyridostigmine (Mestinon) titrated to assist pt with functional activities (chewing, swallowing, strength during exertion); usual initial dose of 30–60 mg 3–4 times daily; long-acting tablets help at night but have variable absorption so are not reliable during the day. Muscarinic side effects (diarrhea, abdominal cramps, salivation, nausea) blocked with atropine/diphenoxylate or loperamide if required.

  • Plasmapheresis or IV immune globulin (IVIg; 400 mg/kg per day ...

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