UNASSIGNED: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis.
UNASSIGNED: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood.
UNASSIGNED: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML).
UNASSIGNED: The results show this assay\'s frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.

BACKGROUND: Epidemiological studies on predisposing conditions and outcomes of progressive multifocal leukoencephalopathy (PML) cases have been carried out exclusively in high-income countries. We aim to report and compare the main characteristics and outcomes of patients with PML and several underlying diseases in a referral center in a middle-income country.
METHODS: We performed a retrospective cohort study of PML cases admitted to a tertiary care hospital in São Paulo, Brazil during 2000-2022. Demographic and PML-specific variables were recorded. One-year case-fatality rate and factors associated with death were identified using a multivariate Cox proportional hazards regression model.
RESULTS: Ninety-nine patients with PML were included. HIV infection (84.8%) and malignancy (14.1%) were the most prevalent underlying conditions. Other predisposing diseases were autoimmune/inflammatory diseases (5.1%) and solid organ transplantation (1.0%). One (1.0%) patient had liver cirrhosis and another (1.0%) patient was previously healthy. Focal motor deficits (64.2%) and gait instability (55.1%) were the most common signs. The one-year case-fatality rate was 52.5% (95% CI 42.2-62.7). The one-year case-fatality rate (95% CI) in patients with or without malignancy (85.7%, 95% CI 57.2-98.2% and 47.1%, 95% CI 36.1-58.2%, respectively) were statistically different (P = 0.009). Crude and adjusted Cox regression models identified malignancy as independently associated with death (adjusted HR = 3.92, 95% CI 1.76-8.73, P = 0.001).
CONCLUSIONS: HIV/AIDS was the predisposing condition in 84.8% of PML cases. The one-year case-fatality rate was 52.5% and having a malignancy was independently associated with death. This study reports emerging data on the epidemiology and outcome of PML in a middle-income country.

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system, is caused by the reactivation of the polyomavirus JC virus (JCV). It favors the cerebrum and typically occurs in patients with immunodeficiencies, with a progressive course and fatal outcome in the majority of cases. However, the cerebellar form of PML, characterized by isolated posterior fossa lesions, such as those in the cerebellum or brainstem at disease onset, is rare, and reports of its occurrence in peritoneal dialysis (PD) patients are lacking. In this paper, we describe a rare case of a cerebellar form of PML in a PD patient. A 64-year-old man undergoing PD was referred to our hospital for anorexia, nausea, and vomiting in the past month. He had finger-to-nose test abnormalities, gaze-directed nystagmus, and scanning speech. He was diagnosed with the cerebellar form of PML based on his progressive cerebellar symptoms, the typical magnetic resonance imaging findings, and the presence of JCV-DNA in the cerebrospinal fluid polymerase chain reaction test. He developed nocturnal delirium, aggravated disquiet, and died of pneumonia on the 69th day. Clinicians should consider the cerebellar form of PML as a differential diagnosis if PD patients develop progressive cerebellar symptoms.

Opportunistic viral infections in individuals with severe immunodeficiency can lead to fatal conditions such as progressive multifocal leukoencephalopathy (PML), for which treatment options are limited. These infections pose significant risks, especially when co-infections with other viruses occur. We describe a combined therapy approach using directly isolated allogeneic Human Polyomavirus 1 (also known as BKV) and Epstein-Barr virus (EBV) specific cytotoxic T-cells for the treatment of PML in conjunction with identified EBV in the cerebrospinal fluid (CSF) of a male patient infected with human immunodeficiency virus (HIV). A 53-year-old HIV-positive male, recently diagnosed with PML, presented with rapidly worsening symptoms, including ataxia, tetraparesis, dysarthria, and dysphagia, leading to respiratory failure. The patient developed PML even after commencing highly active antiretroviral therapy (HAART) 3 months prior. Brain magnetic resonance imaging (MRI) revealed multifocal demyelination lesions involving the posterior fossa and right thalamus suggestive of PML. In addition to the detection of human polyomavirus 2 (also known as JCV), analysis of CSF showed positive results for EBV deoxyribonucleic acid (DNA). His neurological condition markedly deteriorated over the following 2 months. Based on MRI, there was no evidence of Immune Reconstitution Inflammatory Syndrome contributing to this decline. The patient did not have endogenous virus-specific T-cells. We initiated an allogeneic, partially human leukocyte antigen-matched transfer of EBV and utilizing the cross-reactivity between BKV and JCV-BKV specific T-cells. This intervention led to notable neurological improvement and partial resolution of the MRI lesions within 6 weeks. Our case of a patient with acquired immune deficiency syndrome demonstrates that PML and concurrent EBV co-infection can still occur despite undergoing HAART treatment. This innovative experimental therapy, involving a combination of virus-specific T-cells, was demonstrated to be an effective treatment option in this patient.

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Progressive Multifocal Leukoencephalopathy (PML) is a possibly fatal demyelinating disease and John Cunningham Polyomavirus (JCPyV) is believed to cause this condition. The so-called JCPyV was initially reported in lymphoma and Human Immunodeficiency Virus (HIV) cases, whereas nowadays, its incidence is increasing in Multiple Sclerosis (MS) cases treated with natalizumab (Tysabri). However, there are conflicting literature data on its pathology and diagnosis, whereas some misdiagnosed reports exist, giving rise to further questions towards the topic. In reality, the so-called PML and the supposed JCPyV are not what they seem to be. In addition, novel and more frequent PML-like conditions may be reported, especially after the Coronavirus Disease 2019 (COVID-19) pandemic.

This case report describes the development of Progressive Multifocal Leukoencephalopathy (PML) in a 72-year-old male with relapsed/refractory multiple myeloma (RRMM), following a single dose of teclistamab amidst a COVID-19 infection. Shortly after starting teclistamab treatment, the patient developed symptoms, including fever, altered mental status, and right-sided paresis. A diagnosis of PML was confirmed through the detection of JC virus PCR in the cerebrospinal fluid. Our report emphasizes the occurrence of PML after only one dose of teclistamab and highlights teclistamab\'s potential for severe infectious complications, despite its promise in treating RRMM.

BACKGROUND: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva.
METHODS: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4.
RESULTS: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance.
CONCLUSIONS: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety.

UNASSIGNED: Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited.
UNASSIGNED: To characterize outcomes in a cohort of adults with MS who received ICIs.
UNASSIGNED: A single-center retrospective review of medical record data was performed for people with MS treated with ICIs.
UNASSIGNED: Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13).
UNASSIGNED: In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.