When cellular immunity falters, JCV can mount a lytic infection of oligodendrocytes, the myelin-producing cells of the central nervous system. The resulting destruction of myelin produces progressive neurological deficits, typically beginning with insidious weakness, gait instability, or aphasia. The condition is most commonly encountered in the setting of overt immunodeficiency, such as HIV infection, hematologic malignancy, or the use of immunosuppressant medications.

Before the era of antiretroviral therapy, patients with AIDS accounted for nearly 85 percent of PML cases, and the widespread adoption of antiretroviral treatment has since driven the incidence down. The patient in this report arrived at a referring hospital after one month of left-sided weakness, aphasia, dysarthria, and difficulty swallowing. Her primary care physician had ordered a contrast-enhanced magnetic resonance imaging scan of the brain, which revealed multiple T2 hyperintense lesions in the right middle cerebral artery territory along with encephalomalacia in the left anterior temporal lobe, findings initially suggestive of diffuse hemispheric glioma or encephalitis.

Neurologists at the outside institution judged the pattern more consistent with a demyelinating or inflammatory process than a diffuse tumor. Initial laboratory work complicated the picture further: the patient showed anemia, neutropenia, and significant lymphopenia, raising immediate concern for HIV infection, yet extensive HIV testing, including antibody and p24 antigen assays and quantitative RNA viral load testing, returned negative. Cerebrospinal fluid studies proved pivotal.

The fluid showed mildly elevated protein, no pleocytosis, and a positive JCV polymerase chain reaction result, the diagnostic triad that, combined with compatible MRI findings and clinical features, established PML. Hematology-oncology conducted a malignancy workup, with peripheral blood smear demonstrating normocytic, normochromic anemia and leukopenia with absolute neutropenia and lymphopenia, while flow cytometry showed no blasts, B cell monoclonality, or T cell aberrancy. Infectious disease specialists screened for other causes of immunodeficiency.

Based on the MRI findings, the positive CSF JCV PCR, negative HIV testing, and a profoundly low CD4 count, the team diagnosed PML due to probable ICL. Treatment decisions were constrained by the limited evidence base for PML therapy. The team considered pembrolizumab, an immune checkpoint inhibitor, after a recent case report described clinical improvement in a PML patient treated with the drug.

However, they deferred initiation because they feared the immunostimulatory effect could flare latent cytomegalovirus or parvovirus B19, both of which were detected in the patient's serologic testing. Combination regimens of mirtazapine with cidofovir or with mefloquine were also considered but not pursued, given their limited and variable efficacy in published reports. Instead, the patient was started on filgrastim in an effort to improve her lymphopenia before being transferred to the reporting institution for further evaluation.

On admission, the patient's examination revealed oral thrush, dysarthria, left-sided neglect, loss of the left nasolabial fold, and flaccid 0/5 strength in the left upper and lower extremities. Repeat MRI redemonstrated confluent, non-enhancing, T2 hyperintense lesions throughout the white matter of the right cerebral hemisphere, the classic appearance of PML. Immunoglobulin levels were normal, but her CD4 count had fallen below 50 cells per microliter.

Allergy and immunology specialists then undertook a comprehensive immunologic evaluation, testing immunoglobulin E, vaccine titers against diphtheria, tetanus, and pneumococcal serotypes, a genetic immunodeficiency panel, T cell proliferative responses to anti-CD3, CD28, and IL-2 stimulation, and T cell, B cell, and NK cell immunophenotyping by flow cytometry. Most of these studies returned normal, with two notable exceptions. Flow cytometry revealed an increased population of double-negative T cells, CD3-positive cells lacking both CD4 and CD8, at 27 percent, a finding that can indicate autoimmune lymphoproliferative syndrome, a rare disorder of defective lymphocyte apoptosis.

A subsequent ALPS panel, however, was negative. The patient was also found to be immune to diphtheria and tetanus, indicating that her T cells had previously mounted functional immune responses. Taken together, the workup confirmed ICL with poor T cell function and dysregulation but preserved humoral immunity.

ICL was first recognized as a distinct disorder in 1992 during the AIDS epidemic, in HIV-seronegative patients presenting with opportunistic infections, and remains a diagnosis of exclusion requiring extensive multidisciplinary evaluation. With the diagnosis secured, the team administered a single 2-milligram-per-kilogram dose of pembrolizumab, planning a repeat dose in four to six weeks after a follow-up MRI to assess for improvement. After the first dose, her examination showed slight improvement in speech speed, fluency, and dysarthria, and although she retained a right-sided gaze preference, she regained the ability to cross the midline with her gaze.

The improvement proved transient. Her disease continued to progress, she elected to transition to hospice care, and she died one month later. The authors attribute the failure likely to the time lapse between initial symptom presentation and treatment, noting that the most effective intervention for PML is the timely correction of the underlying immunosuppression.

The case sits within a broader and poorly understood clinical landscape. In a review of 38 PML patients without overt immunosuppression, 58 percent had no obvious underlying diagnosis, and 23 percent of those met criteria for ICL. Some investigators have proposed that such patients may harbor permissive factors, such as intercurrent illness or surgery, that induce transient immunodeficient states sufficient to permit JCV reactivation.

The prognosis in these settings is grim: the average time from PML diagnosis to death is 63 days overall, and patients with PML secondary to ICL survive an average of only three months. Studies have shown that mortality is substantially higher in PML patients with primary immunodeficiency or hematologic malignancies than in those with HIV/AIDS, where antiretroviral therapy can restore immune competence. Immune checkpoint inhibitors remain an investigational avenue rather than an established standard.

A retrospective study of checkpoint inhibitor treatment for PML found that patients with pre-existing JCV-specific T cells had better outcomes, suggesting the drugs may work by stimulating virus-specific T cells and reversing T cell exhaustion. Another large retrospective study found improved survival in PML patients with primary immunodeficiency compared with historically reported figures, and individual case reports of pembrolizumab-treated patients have described clinical stabilization or improvement. But pembrolizumab remains off-label for PML, no standard treatment protocol exists, and all checkpoint inhibitors carry the risk of immune-related adverse events.

The authors conclude that clinicians should consider PML in any patient with diffuse white matter hyperintensities and progressive neurological decline, even in the absence of an obvious cause of immunosuppression, and that prompt cerebrospinal fluid testing and coordinated multidisciplinary care are essential in this rapidly progressive, fatal condition.

Subject of Research: A case report of progressive multifocal leukoencephalopathy in an HIV-negative patient with idiopathic CD4+ lymphocytopenia treated with pembrolizumab

Article Title: Progressive Multifocal Leukoencephalopathy Arising in HIV-Negative Idiopathic CD4+ Lymphocytopenia: A Multidisciplinary Case

Article References: Davis, M., Dietz, C. J., Brooks, C., Harrington, C. A., Malvestutto, C., & Greiner, K. (2026). Progressive Multifocal Leukoencephalopathy Arising in HIV-Negative Idiopathic CD4+ Lymphocytopenia: A Multidisciplinary Case. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10874-w

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10874-w

Keywords: progressive multifocal leukoencephalopathy, John Cunningham virus, idiopathic CD4+ lymphocytopenia, pembrolizumab, immune checkpoint inhibitors, demyelination, immunodeficiency, CD4 T cells, HIV-negative, oligodendrocytes, case report, neurology