Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder caused by JC virus, typically affecting immunocompromised patients, This case highlights the complexity of diagnosing PML in a patient with no overt immunodeficiency

A 68-year-old woman, with a medical history of hypothyroidism and a previous episode of immune thrombocytopenic purpura, presented to ED with aphasia and word finding difficulty, which persisted for two weeks. On examination, no additional focal neurological deficits were noted. MRI of the brain showed multiple subcortical FLAIR hyperintensity lesions, most pronounced in the left frontal lobe with DWI signal on the edge of the lesions.

The patient underwent an extensive workup including CBC, CMP, inflammatory, infectious and neoplastic workup from serum and CSF samples including but not limited to ANA, HIV, Syphilis, West Nile virus, Borrelia Burgdorferi, JC virus, HSV1 and 2, EBV, and paraneoplastic panel, which were unremarkable.

 MRI cervical and thoracic spine with no lesions, furthermore, CT scan of the chest, abdomen, and pelvis were noncontributory. The patient remained stable, and was initially diagnosed with Acute Disseminated Encephalomyelitis (ADEM) by exclusion and treated with pulse intravenous methylprednisolone therapy.

One month later, the patient's speech difficulty persisted, and a subsequent brain MRI revealed progression of the lesions. Extensive work-up was repeated and yielded a similar outcome, except for identifying a low CD4 count of 76 cells/mcL. A brain biopsy was performed, confirming PML diagnosis through histopathology.