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Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.

Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML—including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis—provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis.

Eight patients with progressive multifocal leukoencephalopathy associated with chronic lymphocytic leukemia, HIV infection, lymphoma, or idiopathic lymphopenia received pembrolizumab. Five patients had clinical improvement or stabilization of PML, reduction in lesion size on MRI, and decreased JC viral load. Three showed no clinical benefit.

Natalizumab, a monoclonal antibody used to treat multiple sclerosis, can undergo Fab-arm exchange (FAE) with endogenous IgG4, resulting in a monovalent form with reduced avidity and presumed lower potency than the parental bivalent form. Levels of bivalent and monovalent natalizumab depend on the ratio of endogenous IgG4 to total natalizumab, which varies substantially between individuals. The clinical relevance of natalizumab FAE remains unknown. This study investigated the potential clinical implications of bivalent and monovalent natalizumab levels regarding progressive multifocal leukoencephalopathy (PML), extended interval dosing (EID) and wearing-off symptoms, using multiple cohorts of natalizumab-treated patients. Seven natalizumab-associated PML cases were each matched to two controls. Contrary to the hypothesis that higher bivalent levels might increase PML risk, cases showed a trend toward lower bivalent natalizumab levels, although definite conclusions were limited by small sample size. In patients receiving EID, both total and bivalent natalizumab levels decreased compared to standard interval dosing, with a greater median individual decrease in bivalent natalizumab than in total natalizumab (94% versus 78%). Notably, in more than half of patients receiving EID, bivalent natalizumab levels fell below the quantification limit (<0.1 µg/mL). Finally, patients experiencing wearing-off symptoms during natalizumab treatment had lower bivalent natalizumab levels, although this warrants validation in larger cohorts.

Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system—typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.

Background. Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). Methods. STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. Results. We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma–driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. Conclusions. The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating disease of the central nervous system caused by JC virus infection. The disease can be seen in sarcoidosis patients without additional risk factors. Here, we present an individual with PML secondary to sarcoidosis treated with 8 doses of pembrolizumab, a Programmed Cell-Death-1 (PD-1) Immune Checkpoint Inhibitor who showed significant improvement. This report illustrates the objective clinical and radiological improvement in a patient with PML due to sarcoidosis, and suggests further study of immune checkpoint inhibitors as a potential treatment for sarcoidosis patients with PML.

Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly efficient immunosuppressive and immunomodulatory treatments, in recent years, the number of PML cases again increased. PML is prevented by an intact cellular immune response and accordingly immune reconstitution can terminate established disease in the CNS. However, forced immune reconstitution can lead to massive destruction of virus-infected cells. This may result in clinical exacerbation associated with high morbidity and mortality and referred to as PML with immune reconstitution inflammatory syndrome (PML–IRIS). In the present review, we discuss virological properties and routes of infection in the CNS, but mostly focus on the pathology of PML and PML–IRIS and on the role of the immune system in these disorders. We show that PML and PML–IRIS result from predominant JC virus infection of oligodendrocytes and, to a lesser extent, of infected neurons. Inflammation in these encephalitides seems to be driven by a dominant cytotoxic T cell response which is massively exaggerated during IRIS.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with PML. Methods: Nineteen patients meeting the 2013 consensus criteria for “definite PML” were included, and JCV-specific T lymphocytes expanded from autologous or allogeneic peripheral blood mononuclear cells (PBMCs) using JCV antigen-derived peptides were administered. Clinical outcomes were monitored through neuroimaging and biological markers. Results: The mean age at diagnosis was 56.5 years, with a mean time to treatment of three months. Patients received a median of two infusions. At 12 months, six patients (31.6%) survived, while 13 (68.4%) had died, primarily due to PML progression. Survivors had a higher median baseline Karnofsky performance scale (KPS) score (50% vs. 30%, p = 0.41) and a significantly shorter diagnosis delay. MRI assessment showed a reduced disease burden in survivors, and JCV-DNA copy numbers decreased overall. One case of immune reconstitution inflammatory syndrome (IRIS) was observed. Conclusions: Adoptive JCV-specific T lymphocytes may represent a safe therapeutic option for PML patients, and the MRI burden and JCV-DNA copy may serve as biomarkers for disease monitoring.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.