To report a rare case of Progressive Multifocal Leukoencephalopathy (PML) in a patient with well-controlled HIV, initially suspected to be Posterior Reversible Encephalopathy Syndrome (PRES) based on imaging. This case highlights the diagnostic challenges, rarity of PML in well-controlled HIV, and the role of pembrolizumab.

PML is caused by JC virus (JCV), mostly in immunocompromised individuals. PML in well-controlled HIV with high CD4 counts and undetectable viral load is rare. Pembrolizumab, a PD-1 inhibitor, has shown promise in PML (1), although the mortality rate remains high, with survival often less than a year.

A 52-year-old woman with well-controlled HIV on Biktarvy (viral load undetectable, CD4+ consistently >1000) presented with visual disturbances, ataxia, and dysarthria. MRI revealed asymmetric T2/FLAIR hyperintensities in the occipital lobes, thalami, midbrain, cerebral peduncles, and pons, without enhancement. Initially suspicious for PRES, no triggers were identified, and there was no improvement. With suspicion of PML, further CSF analysis revealed JC virus DNA (444 IU/mL), confirming diagnosis. Stroke and CNS lymphoma were considered as differentials before the JC virus results. CNS escape of HIV was ruled out by negative HIV RNA in the CSF. Pembrolizumab (2 mg/kg every 4 weeks for 3 cycles) was initiated due to progressive neurological decline.

After three cycles of pembrolizumab, the patient’s motor and visual symptoms improved modestly. Follow-up MRI showed stable lesions without enhancement. CSF analysis showed a slight reduction in JC viral load (444 to 411 IU/mL). The patient’s gait improved, though continued using a rollator, and her diplopia stabilized. She survived 17 months, exceeding typical PML survival rates. Unfortunately, she expired before her next follow-up due to cardiac arrest with anoxic brain injury.

This case underscores the challenge of differentiating PML from PRES and stroke. It also suggests pembrolizumab may provide prolonged stabilization in rare PML cases, warranting further research.