To describe a rare case of progressive multifocal leukoencephalopathy (PML) occurring in a patient treated with Ruxolitinib for polycythemia vera, highlighting diagnostic considerations, neuro-imaging, and the role of JAK inhibition in predisposing to opportunistic CNS infection.

This is a single-patient case report where clinical course, imaging findings, and laboratory data were reviewed. Relevant literature was also reviewed to contextualize the case.

A 74-year-old man with polycythemia vera and prior pulmonary embolism on Ruxolitinib and Eliquis presented with neck pain and progressive cognitive decline over a few months, including disorientation, impaired concentration, and difficulty with activities of daily living. Neurological examination revealed impaired attention and short-term recall without focal motor or sensory deficits. MRI brain demonstrated confluent T2/FLAIR hyper-intensities in bilateral frontal white matter, corpus callosum, and left temporal lobe without enhancement. CSF analysis was negative for EBV and positive for JCV, highly suggestive of PML. Given the temporal association with Ruxolitinib use and absence of other comorbidities and immunosuppressants, drug-related immunomodulation was suspected as the precipitating factor.

This case adds to the limited reports of PML associated with Ruxolitinib. Early recognition of neurologic symptoms in patients on JAK inhibitors is essential for prompt diagnosis and management. Increased awareness may help inform risk–benefit discussions and monitoring strategies prior to Ruxolitinib initiation.