OBJECTIVE: Intravascular lymphoma is a rare subtype of B-cell lymphoma characterized by a clonal proliferation restricted to the lumen of small vessels. Over 50% of patients exhibit central nervous system (CNS) involvement, but diagnosis is often delayed due to the lack of distinctive features. We aimed to identify key phenotypic features for early diagnosis of intravascular lymphoma with CNS involvement through an in-depth cohort study. METHODS: We built up a multicenter retrospective cohort of 17 patients recruited in collaboration with the French Expert Network for Oculo-Cerebral Lymphomas (LOC network), and retrospectively analyzed data from medical records. RESULTS: In this cohort, 15 of 17 (88%) patients developed focal neurological episodes, often fluctuating and/or recurrent, with a sudden onset in 68% of episodes, suggesting a vascular origin. Rapid cognitive deterioration occurred in 15 of 17 (88%) patients, psychiatric manifestations in 8 of 17 (47%), and "B signs" in 14 of 17 (82%). Brain MRI showed polymorphic FLAIR hyperintensities in 14 of 16 (87%) patients, and DWI-positive lesions in 13 of 16 (81%) of patients, which accumulated over time and had unusual characteristics for ischemic lesions (progressive growth, persistent DWI-hyperintensity over 1 month, surrounded by a wider FLAIR hyperintensity). Early-onset inflammatory syndrome, and elevated lactate dehydrogenase (LDH) levels were observed in over 90% of cases. Mild and inconsistent meningitis contrasted with a nearly-constant hyperproteinorachia. An increased interleukin 10/6 ratio over 0,7 was found in 4 of 7 (57%) patients, and skin biopsy led to a pathological diagnosis in 3 of 6 (50%) patients. INTERPRETATION: The results of this study highlight "red flags" that could help accelerate the diagnosis of intravascular lymphoma involving the CNS. ANN NEUROL 2025
97:435-448.