196

MYASTHENIA GRAVIS (MG)

Clinical Features
Pathophysiology
Differential Diagnosis
Laboratory Evaluation
Bibliography

An autoimmune neuromuscular disorder resulting in weakness and fatiguability 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 (lids, 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—particularly in elderly. 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 (tetracycline, aminoglycosides, procainamide, propranolol, phenothiazines, lithium).
Pathophysiology
Specific anti-AChR antibodies reduce the number of 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, combined with decrease in postsynaptic AChRs, results in pathologic fatigue. Thymus is abnormal in 75% of pts (65% hyperplasia, 10% thymoma). Other autoimmune diseases in 10%; thyroiditis, Graves’ disease, rheumatoid arthritis, lupus erythematosus, red cell aplasia.
Differential Diagnosis

1.
Lambert-Eaton syndrome (autoantibodies to calcium channels in presynaptic motor nerve terminals)—reduced ACh release; associated with malignancy or idiopathic

2.
Neurasthenia—weakness/fatigue without underlying organic disorder

3.
Penicillamine may cause MG; resolves weeks to months after discontinuing drug

4.
Hyperthyroidism

5.
Botulism—toxin inhibits presynaptic ACh release

6.
Intracranial mass lesion—compression of nerves to extraocular muscles

7.
Progressive external ophthalmoplegia—seen in mitochondrial disorders
Laboratory Evaluation

AChR antibodies—no correlation with disease severity; 80% of all MG patients positive; 50% with ocular findings only are positive; positive antibodies are diagnostic.

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.

EMG—low frequency (2–4 Hz) repetitive stimulation produces decrement in amplitude of evoked motor responses.

Chest CT/MRI—search for thymoma.

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

TREATMENT
(See Fig. 196-1) The anticholinesterase drug pyridostigmine (Mestinon) titrated to assist pt with functional activities (chewing, swallowing, strength during exertion); usual initial dose of 60 mg 3–5 times daily; long-acting tablets help at night. Muscarinic side effects (diarrhea, abdominal cramps, salivation, nausea) blocked with propantheline if required. Plasmapheresis and IV immune globulin [IVIg; 400 (mg/kg)/d × 5 d] provide temporary boost for seriously ill pts; used to improve condition prior to surgery or during myasthenic crisis (severe exacerbation of weakness). Thymectomy improves likelihood of long-term remission in adult (less consistently in elderly) pts. Glucocorticoids are a mainstay of treatment; begin prednisone at low dose (15–25 mg/d), increase by 5 mg/d q2–3 d until marked clinical improvement or dose of 50 mg/d is reached. Maintain high dose for 1–3 months, then decrease to alternate-day regimen. Long-term treatment with low-dose prednisone usual. Immunosuppressive drugs (azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide) may spare dose of prednisone required to control symptoms; azathioprine [2–3 (mg/kg)/d] most often used. Myasthenic crisis is defined as an exacerbation of weakness, usually with respiratory failure, sufficient to endanger life; expert management in an intensive care setting essential.

FIGURE 196-1. Algorithm for the management of myasthenia gravis. FVC, forced vital capacity. (From DM Drachman: HPIM-15, p. 2518)

Bibliography

For a more detailed discussion, see Drachman DB: Myasthenia Gravis and Other Diseases of the Neuromuscular Junction, Chap. 380, p. 2515, in HPIM-15.