Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis, dermatomyositis, inclusion body myositis, motor neuron diseases including post-polio syndrome, demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, metabolic myopathies, Hypokalemic Periodic Paralysis, dystrophies, myasthenia gravis, diabetic neuropathies and stiff-man syndrome. Persistent or mutant poliovirus is sought in these patient's tissues with post-polio syndrome and ALS using tissue cultures, PCR and in situ hybridization. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is examined by analysis of the neuroendocrine axis, Magnetic Resonance Spectroscopy and sleep studies. The role of cytokines, especially TGF-beta and IL-1, in promoting amyloid formation and persistent inflammation is studied in patients with inclusion body myositis. The antigenic specificity and in situ clonal expansion of the endomysial T cells of patients with inflammatory myopathies and neuropathies is studied by examining the cell Receptor profile and sequencing of the CD3 region. In neuromuscular disorders associated with HIV infection, the role of the virus and the induced cytokines is investigated with a variety of immunocytochemical studies, in situ hybridization and PCR. The antiretroviral drug ddC was found to cause a unique neuropathy characterized by abnormal mitochondria. Various morphological, molecular and biochemical studies are now performed to confirm mit DNA deletions in the nerve specimens. The cytotoxic basis of anti-GAD antibodies in patients with stiff-man syndrome is investigated and changes in the antibody titers are studied in vivo and in vitro as well as during therapy.The role of amphiphysin and GAD in this disease, as well as other autoimmune disorders affecting synaptic transmission, are being explored. In patients with Stiff Person Syndrome we have found statistically reduced GABA in the brain using MRS spectroscopy. Efforts are intensified to search for abnormal metabolites in the brains of patients with ALS in an attempt to form the basis for specific therapeutic interventions. Randomized-controlled clinical trials are conducted using High-Dose IntravenousIimmunoglobulin in patients with polymyositis, dermatomyositis, inclusion body myositis, chronic inflammatory and paraproteinemic demyelinating polyneuropathies, and stiff-man syndrome. A similar study in Myasthenia Gravis and Diabetic Autoimmune Neuropathy will be conducted as soon as the drug is available. An experimental trial using monoclonal antibodies against integrin Beta-4 is planned for inclusion body myositis. A controlled study using Dichlorophenamide, a carbonic anhydrase inhibitor, has been conducted in patients with hypokalemic periodic paralysis. Another controlled study using L-carnitine has been also conducted in patients with AZT-induced mitochondrial myopathy with carnitine depletion and showed no benefit.
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