Case Presentation: A 46-year-old previously healthy female presented to a referring hospital with a 1-month of left-sided weakness, dysarthria, and dysphagia. An MRI which showed T2 hyperintense lesions in the right MCA territory and encephalomalacia in the left anterior temporal lobe. Neurology believed these findings to be more consistent with a demyelinating or inflammatory process than a diffuse glioma. Initial labs demonstrated anemia, neutropenia, and severe CD4 lymphopenia, raising concern for HIV infection; however, extensive HIV testing returned negative. CSF studies were unrevealing. Oncological workup showed no evidence of metastatic disease on CT chest/abdomen/pelvis, and an autoimmune paraneoplastic panel returned negative. A broad infectious workup to determine a possible cause for her lymphopenia noted (+) JC virus in serum PCR. A diagnosis of Progressive Multifocal Leukoencephalopathy (PML) was made. She was transferred to our institution for further evaluation and consideration of treatment with pembrolizumab, as a recent case report had indicated its use had led to the clinical improvement in a patient with PML due to ICL [1]. Hematology, Infectious Disease, Neurology, and Allergy/Immunology were consulted. To determine the cause of her CD4 lymphopenia, a detailed immunologic workup was performed, and flow cytometry demonstrated increased double negative T-cells, possibly indicative of autoimmune lymphoproliferative syndrome (ALPS). However, a subsequent ALPS panel returned negative. She was determined to have idiopathic CD4+ T-cell lymphocytopenia (ICL). A dose of pembrolizumab was administered but, unfortunately, her illness progressed despite treatment. She was transitioned to hospice and later passed away.
Discussion: PML is a rare, progressive neurological disease in which JC viral infection of the central nervous system (CNS) leads to demyelination and eventual death. It almost always occurs in the setting of immunosuppression. Patients with AIDS are the most commonly affected, with the incidence of PML estimated at 3-5% in this population, although patients being treated with immunomodulators, such as natalizumab, are also at increased risk of developing PML [2]. Our case illustrates that there are other possible etiologies that must be considered, especially in an HIV-negative patient presenting with the characteristic, insidious neurologic symptoms of PML. ICL is one such rare etiology that requires extensive, multi-specialty workup to diagnose. A diagnosis of PML carries a poor prognosis, and the most effective treatments focus on correcting the underlying condition. Our patient did not have a clear cause of her lymphocytopenia despite extensive viral, immunologic, and genetic testing, limiting her chances of successful treatment. Given that there are no treatments currently available that target the JC virus for direct treatment of PML, it is important to promptly initiate a thorough workup to determine the presence of any potentially treatable underlying cause.
Conclusions: PML is a rare, often fatal demyelinating disease of the CNS that typically occurs in the setting of immunosuppression secondary to HIV. ICL is a rare etiology of PML that requires extensive interdisciplinary workup to diagnose. If PML is suspected, prompt laboratory evaluation and imaging should be initiated to determine if any reversible underlying cause exists.