To report a case of progressive multifocal leukoencephalopathy (PML) with immune reconstitution inflammatory syndrome (IRIS) in an immunocompetent patient with a favorable outcome.

PML is a demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV). It typically occurs in patients with cellular immunosuppression or those receiving immunomodulatory therapies such as natalizumab. IRIS represents an excessive inflammatory response following immune recovery. PML is often fatal, and in many reports, development of IRIS has been associated with clinical worsening in patients with established PML. Thus, the prognostic impact of IRIS remains uncertain.

A 65-year-old woman with a remote history of cervical squamous cell carcinoma treated with hysterectomy and radiation presented with two weeks of behavioral and cognitive changes, including apathy, executive dysfunction, and expressive language difficulty. Brain MRI showed multifocal heterogeneously enhancing necrotic-appearing lesions with surrounding edema. Cerebrospinal fluid revealed mild lymphocytic pleocytosis, elevated protein (81 mg/dL), normal glucose, and a negative infectious panel. Extensive evaluation excluded autoimmune disease, malignancy, or immunodeficiency. Brain biopsy demonstrated lymphocytic and plasmacytic infiltration with positive SV40 immunostaining, confirming PML with associated IRIS. JCV PCR in CSF was positive (107 copies). The patient received no specific therapy and showed gradual cognitive improvement over several months. Notably, she also had a chronic ulcerated nasal plaque extending to the right cheek, biopsy-proven invasive basal cell carcinoma (BCC).

This case highlights that PML can occur in apparently immunocompetent patients, although an occult immunodeficiency potentially predisposing to both PML and invasive BCC is suspected. It also suggests that PML-IRIS in such patients may not invariably predict poor outcomes.