Typical case and clinical course of RVCL-S. At age 52, this male (Family 2, V235fs mutation) noted progressive bilateral loss of vision. Ophthalmologic examination revealed vascular retinopathy. At age 58 he developed slowly progressive right-sided hemiparesis. He became intermittently irritable and passive, and complained of headaches. His medical history revealed Raynaud’s phenomenon and paroxysmal atrial fibrillation. MRI revealed a rim-enhancing lesion with mass-effect and surrounding oedema in the left frontal white matter (A1: gadolinium-enhanced T1-weighted; A2: non-enhanced T1-weighted) with focal calcifications on CT (not shown). Two smaller rim-enhancing lesions were noted periventricularly in the right frontal (arrows, A3: gadolinium-enhanced T1-weighted; A4: non-enhanced T1-weighted) and parietal lobes (arrows, A5: gadolinium enhanced T1-weighted; A6: non-enhanced T1-weighted). Biopsy of the left fronto-parietal lesion revealed tissue necrosis. Dexamethasone (60 mg for 10 days) slightly improved the hemiparesis. Four months later, his headaches became worse and he developed word-finding difficulties and wide-based gait. Routine laboratory investigation revealed mild anaemia and mildly impaired renal and liver function. CSF protein was mildly increased but cell count was normal; there were no oligoclonal bands. Antinuclear antibodies, extractable nuclear antigens, anticardiolipin IgG and IgM, and anti-neutrophilic cytoplasmic antibodies were all negative. The left frontal lesion had diminished in size on MRI and enhancement was only minimal; the surrounding oedema and gliosis, however, had remained as a large zone of confluent T2 hyperintensities with small nodular foci of faint enhancement (B1: gadolinium enhanced T1-weighted; B2: FLAIR). Half a year later his condition worsened and he became easily agitated with emotional lability, disorientation, apathy, and urinary incontinence. Additionally, he developed left-sided hemiparesis with facial weakness and could walk only with assistance. MRI (C1: gadolinium enhanced T1-weighted; C2: FLAIR) revealed, exactly where previous MRI’s had shown a pre-existing punctate enhancing white matter lesion, a large irregularly rim-enhancing lesion with central necrosis and a large zone of surrounding oedema, which extended into the corpus callosum, basal ganglia, and parietal and temporal lobes, and which exerted some mass-effect on the right lateral ventricle. The pre-existing lesion adjacent to the parietal horn of the right lateral ventricle had not changed significantly. A second biopsy showed mainly necrotic tissue. Corticosteroids temporarily improved his gait. Repeat MRI (D1 and D2: gadolinium enhanced T1-weighted) 2 months later showed a persistent right frontal lesion. Open biopsy and partial debulking of the right frontal lesion were performed. Pathology showed largely necrotic tissue with scattered inflammatory cells, mainly around the vessel walls, which were thickened with adventitial fibrosis. In the following year, his condition deteriorated and he died of aspiration pneumonia at age 60. Autopsy was performed and the data are included in .