Progressive Multifocal Leukoencephalopathy (PML) is a rapidly progressive demyelinating disease caused by JC Virus infection, typically affecting immunocompromised patients. Mortality in PML is high, but there are no approved treatments for non-HIV induced PML.

A 66-year-old right-handed female with no immunosuppressive history presented with one month of progressive receptive and expressive aphasia. MRI Brain showed diffuse confluent subcortical white matter T2/FLAIR hyperintensities with speckled post-gadolinium enhancement in bilateral cerebral and cerebellar hemispheres. PML was diagnosed by serum and CSF JCV PCR and histopathology demonstrating scattered SV40 positivity with loss of myelin. IRIS was suspected given enhancement on MRI. HIV, CBC, and immunoglobulin levels were negative. Serologic findings showed substantial lymphopenia, with absolute lymphocyte counts persistently low at 300–400/µL despite a normal neutrophil count. Lymphocyte subset testing revealed CD4 lymphocytopenia (67/µL vs. normal 490-1600). Bone marrow biopsy did not reveal an underlying etiology. Her PML was therefore attributed to primary, idiopathic CD4 lymphocytopenia.

IRIS was treated with pulse steroids resulting in resolution of the enhancement. She received one dose of Pembrolizumab 2 mg/kg in hospital. At one-month follow-up, her CD4 count was still low (140/µL) and CSF JC Virus was still positive. Outpatient Pembrolizumab was denied by insurance. She was approved for Filgrastim 300 mcg daily for 7 days due to continued lymphocytopenia. At three-month follow-up, her CD4 count was 466/µL, and her comprehensive aphasia had notably improved. Serum JCV PCR was now negative. LP and MRI results are pending.