Monday, June 15, 2009

A Primer on Myasthenia Gravis

General
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by immune-mediated loss of acetylcholine receptors and exhibiting characteristic clinical signs as well as drug responses. The disease prevalence is about 3 per 100,000, with a female predominance in cases arising before the age of 40. In some cases, MG represents a paraneoplastic syndrome, typically bronchogenic carcinoma, although Lambert-Eaton Syndrome is the myasthenic syndrome most commonly associated with malignancy.


Pathophysiology
MG is associated with a decrease in the number of neuromuscular junction acetylcholine receptors (AChRs) as well as the presence of circulating antibodies to the AChR. Light microscopic examination of muscle biopsies from affected patients is usually unremarkable, although fiber type 2 atrophy may be seen in cases where there is secondary muscle disuse. Ultrastructurally, the post-synaptic membrane is simplified, with loss of AChRs. Electron microscopy can also reveal immune complexes and the membrane attack complex (C5-Cq) along the postsynaptic membrane. Autoantibodies block acetylcholine binding of receptors, and increases degradation of receptors. Complement fixation on AChRs also causes direct injury to the post-synaptic membrane.

Clinical Presentation and Course
Classically, physical examination of MG patients demonstrates decreased muscle strength with repeated use. As the extraocular muscles are often the first to be affected, ptosis and diplopia are frequently the presenting signs. But, in some cases, fluctuating generalized weakness is the patient's initial complaint. Sensory and autonomic findings are usually unremarkable. Thymic hyperplasia is present in 65% of patients with MG, and thymoma is found in 15%. With improved methods of ventilatory support in recent decades, five-year survival now exceeds 95%.

Diagnostic tests
Electrophysiologic testing reveals a decrement in motor response with repeated stimulation, while nerve conduction studies are normal. Patients show improvement in strength in response to anticholinesterase agents. Although most MG patients exhibit elevated serum anti-AChR antibodies, there is not always a good correlation between antibody levels and extent of neurologic deficit.

Treatment
Even though the link between thymic abnormalities and the presence of anti-AChR antibodies is unclear, most patients improve clinically after thymectomy. Other effective treatments include anticholinesterase drugs, prednisone, and plasmapheresis.

Reference
Kumar V et al, eds., Robbins and Cotran Pathologic Basis of Disease, 7th edition. (2005). p1344.

1 comment:

agent 86 said...

Read this this am & recommend it:

Lancet Neurol 8:475-90 (May 09)

Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity.
Meriggioli MN, Sanders DB.

Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular
junction in which patients experience fluctuating skeletal muscle weakness that
often affects selected muscle groups preferentially. The target of the autoimmune
attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in
others, non-AChR components of the neuromuscular junction, such as the
muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological
result is muscle endplate dysfunction and consequent fatigable muscle weakness.
Clinical presentations vary substantially, both for anti-AChR positive and
negative MG, and accurate diagnosis and selection of effective treatment depends
on recognition of less typical as well as classic disease phenotypes.
Accumulating evidence suggests that clinical MG subgroups might respond
differently to treatment. In this Review, we provide current information about
the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and
treatment of MG, including emerging therapeutic strategies.