Incomplete Susac syndrome exacerbated after natalizumab

A 66-year-old man with hypertension presented with right-sided numbness and slurred speech. MRI revealed a large left frontoparietal area of T2-weighted hyperintensity with focus of central enhancement (figure, A and B). The patient’s symptoms self-resolved within weeks. Over the next 2 years, he experienced multiple relapses including encephalopathy characterized by headache with motor aphasia and sudden incomplete hearing loss. All symptoms except hearing loss were transient, improved with IV methylprednisolone, and were accompanied by new T2 lesions involving the periventricular white matter, corpus callosum, and subcortical white matter, with some demonstrating partial enhancement (figure, C and D). Extensive workup revealed only anti-endothelial cell antibodies (AECA) (1:50, indirect immunofluorescence, Cornell Dermatopathology Laboratory, New York). CSF analysis performed during remission was unrevealing; oligoclonal bands were absent. Fluorescein angiogram and optical coherence tomography did not show any abnormalities. The patient was presumed to have multiple sclerosis (MS) and started on natalizumab. Within days of the first infusion, he developed motor aphasia, with MRI revealing extensive T2-hyperintense lesions with corresponding leptomeningeal enhancement (figure, G and H). Repeat CSF analysis revealed elevated protein of 116 mg/dL. Natalizumab antibodies were negative. The patient underwent brain biopsy, which revealed predominantly perivenular demyelination (figure, I) with relative preservation of axons, although axons were focally distended and showed evidence of axonal injury (figure, M) suggestive of demyelinating etiology. In addition, there was evidence of focal microangiopathy. Scattered vessels contained perivascular CD3 CD8 T lymphocytes whereas other vessels showed endothelial cell detachment and early fibrin deposition suggestive of an acute endothelial injury. CD68 and CD163 macrophages were present in the perivascular space (figure, J). Vascular deposits of C3d (figure, K) with lesser but still discernible deposits of C4d and C5b-9 were noted. There was focal red cell extravasation and hemosiderin deposition along with focal basement membrane zone reduplication compatible with antecedent episodes of vascular injury (figure, L). Glial fibrillary acidic protein stain showed massive reactive gliosis. There was no histopathologic evidence of infection or lymphoma. Overall morphologic features were those of perivenular demyelination and complement-induced endothelial injury.