Susac's syndrome (SS) is a neuro-ophthalmic disorder characterized by a clinical triad of encephalopathy, branch retinal artery occlusion (BRAO), and hearing loss. It appears to result from microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear. While magnetic resonance imaging (MRI) consistently shows a distinctive white matter disturbance in the corpus callosum, lesions commonly detected by MRI in other regions of the brain may lead to misdiagnosis as multiple sclerosis (MS). Further complicating definitive diagnosis is the fact that the three components of the disorder rarely occur simultaneously. Despite over 30 years of observation since the identification of this disorder, there has been little progress in the understanding of its etiology. However, the apparent (but variably) successful treatment of SS with immunosuppressive agents implies an immunologic basis for this disorder. The experiments described in this proposal, based upon our findings of a consistent pattern of 3 endothelial-reactive antibodies in sera of 10 SS patients, are designed to test the hypotheses that SS patients harbor circulating endothelial-reactive autoantibodies, and that the protein targets of these antibodies, once identified, can be exploited for the development of a definitive diagnostic test. We currently have access to de-identified serum samples from over 40 confirmed SS patients, symptomatic at the time of serum acquisition. We will test these sera (as well as sera of MS patients and of healthy individuals) for the presence of endothelial-reactive antibodies by immunofluorescent staining of cultured endothelial cells (EC) using the sera as the """"""""primary antibody"""""""". Molecular weights of the protein targets of these antibodies will be determined by western blot of EC protein extracts, again using the sera as the """"""""primary antibody"""""""". Protein targets will then be identified by mass spectrometry following resolution of EC protein extracts on 2-D gels and localization of reactive proteins by immunoblot with patient sera. As a prototype diagnostic test, these proteins (and selected non-reactive control proteins) will be immobilized in individual wells of a microtiter plate and reactive antibodies will be quantitated in patient sera by colorimetric ELISA. Specificity will evaluated by testing sera of confirmed SS patients and of patients with other neurological disorders (particularly multiple sclerosis), as well as of healthy individuals.

Public Health Relevance

Susac's syndrome is a disorder characterized by visual defects, hearing loss, and a variety of brain dysfunctions (headaches, memory loss, personality changes, dementia). In the absence of a diagnostic test the disease is often misdiagnosed. The goal of this project is the development of such a test, which would facilitate prompt treatment and thus prevent or minimize residual defects associated with the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Koenig, James I
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Ohio State University
Schools of Medicine
United States
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