To describe an adult tumefactive demyelinating lesion mimicking glioblastoma, diagnosed after two stereotactic biopsies and pathologic review.

Tumefactive demyelinating lesions (TDLs) are uncommon, contrast-enhancing lesions within the Acute Disseminated Encephalomyleitis (ADEM)/MS spectrum that frequently mimic high-grade glioma, primary CNS lymphoma (PCNSL), and abscess. Adult ADEM-spectrum presentations may be monofocal and lack the encephalopathy characteristics of pediatric ADEM, complicating diagnosis.

Single-patient case report with clinical, neuroimaging, cerebrospinal fluid analysis, laboratory evaluations, pathologic, and longitudinal follow-up data.

 A 40-year-old female with no significant past medical history presented with two weeks of subtle behavioral changes and left homonymous hemianopia, beginning approximately two weeks after COVID-19 vaccination. A contrast MRI demonstrated a solitary right parietal lesion; the radiographic differential included glioblastoma, primary CNS lymphoma, and pyogenic abscess. Two stereotactic biopsies were performed and pathologic review was initiated for presumed glioblastoma. Pathology subsequently demonstrated demyelination with reactive astrogliosis, without neoplastic cells. CSF analysis was unremarkable. The diagnosis was revised to a tumefactive demyelinating lesion with the ADEM spectrum; high-dose intravenous corticosteroids were administered, with near-complete clinical and radiographic resolution. Serum MOG-IgG and AQP4-IgG were negative.

TDLs should be considered in the differential of solitary, contrast-enhancing supratentorial lesions in adults, alongside glioblastoma, PCNSL, and abscess. Recognition of MRI features distinguishing demyelination from neoplasm, including open-ring enhancement, T2 hypointense rim, and peripheral facilitated diffusion may avert repeated biopsy and inappropriate oncologic therapy.