Glioblastoma is the most common malignant brain tumor in adults and is one of the most aggressive malignancies, with poor prognosis and bad outcomes. It accounts for about 48.6% of malignant tumors of the central nervous system. However, it can present with atypical clinical and radiological features, resulting in delays in diagnosis.

A 49-year-old right-handed man with no significant medical history presented to the emergency department with confusion and fluent (receptive) aphasia. Initial brain MRI (Figure.1) showed diffuse cortical/subcortical T2 and FLAIR hyperintensity involving left insular cortex, left frontal lobe (including cingulum), and left temporal lobe anteriorly with no contrast enhancement. Initial concern was HSV encephalitis and patient was treated empirically with Acyclovir. However, initial as well as repeated CSF analysis came back negative for HSV PCR antibiodies. EEG monitoring showed recurrent subclinical seizures arising from the left parietotemoporal region which was managed with Levetiracetam,  Lacosamide and Valproic acid.

Eventually patient underwent brain MR spectroscopy suggestive of a proliferative disease in the left frontal-temporal area. Subsequently, biopsy of this area was performed, and results came back morphologically consistent with glioblastoma (Figure 2), WHO grade 4 with no reported alterations were identified in the targeted regions of the IDH1 and IDH2 genes

Glioblastoma may present with atypical imaging features and can mimic many non-neoplastic processes, including herpes encephalitis. A high index of suspicion is required to prevent delays in diagnosis and poor outcomes.