Three young adult patients with no demonstrable immunodeficiency presented to Harbor-UCLA Medical Center within a few months of each other, with rapidly progressive visual loss and multiple neurological deficits associated with rapidly expanding, nonenhancing white matter lesions in the brainstem and cerebral hemisphere over one to four months time. Gradual visual loss following an episode of flu-like illness was the common presenting symptom in all three cases. All three patients underwent a brain biopsy when multiple therapies including high dose intravenous steroids and plasmapheresis failed to halt the progression of the symptoms and lesions. The first case, a l8 year old young girl, rapidly deteriorated and became comatose during her hospital stay. Post-mortem brain evaluation was obtained when she succumbed to her death from a pulmonary embolus.Light microscopic examination revealed irregular patchy macrophagic demyelination with lymphocytic cuffing of venules, hypertrophic gliosis, and no necrosis of the vasculature. Electron microscopy of the three biopsy and the one autopsy specimens revealed 100nm viral particles within nuclei and cytoplasm of astrocytes and oligodendrocytes, with morphology and maturation sequence most compatible with herpes virus. In all four . specimens, immunohistochemisty revealed the presence of human herpes virus six (HHV-6) in astrocytes and oligodendrocytes but not in macrophages. Polymerase chain reaction (PCR) confirmed large quantities of HHV-6 DNA in the autopsy and biopsy tissue from the most severely affected patient. Monoclonal antibodies against CMV, HSV-l, HSV-2, EBV, and HIV-1 did not reveal antigens in any of the specimens and furthermore, DNA of CMV, HSV-l, HSV-2 and EBV were found to be absent by PCR.OBJhC 1 1VE/HYFO 1 HhSiS: Multiple Sclerosis (MS) is due to a virus m active plaques. Accordmgly, the viral expression should be exclusively or highly significantly more frequent within actively demyelinating plaques than in inactive plaques and in surrounding normal appearing white (NAWM) or gray matter (NAGM). Since different viruses could cause demyelinating lesions in different cases, our experimental design incorporates case by case analysis. RATIONALE FOR CURRENT RESEARCH: Active and latent phases of herpesviruses are recognized. It is our notion that the active phase of virus could be correlated with clinical relapses and/or new lesions on MRI and/or gadolinium positive lesions. So our search for a candidate virus has commenced with HHV-6 which has been attributed to be involved in MS etiopathogenesis. (Challoner et al. 1995 Proc Nat'l Acad Sci).METHODOLOGY: 13 postmortem cerebrums were formalin fixed and coronally sectioned at 7 to 10 mm. All white matter plaques seen grossly were dissected which included a minimal amount of surrounding NAWM. Adjacent NAWM and the nearest NAGM were also dissected. This resulted in 525 samples. The samples were cryopreserved and then snap frozen. Cryosections were taken for classification of demyelinating activity (Sanders...To...

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