Development Of Progressive Multifocal Leukoencephalopathy Research Articles

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis.

Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach. The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test. A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI -0.08 to 0.09; I2=20.4%; p=0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2=50%; p=0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ±20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID. A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

Generation of JC Polyoma Pseudovirus for High-Throughput Measurement of Neutralizing Antibodies

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses.

Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors?

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

Sequence analysis of the non-coding control region of John Cunningham virus isolates from patients with multiple sclerosis treated with natalizumab

Introduction. The John Cunningham virus (JCPyV) causes a fatal demyelinating disease of the central nervous system known as progressive multifocal leukoencephalopathy (PML). In healthy people, the JCPyV non-coding control region (NCCR) is not rearranged, while NCCRs in immunocompromised patients are characterized by frequent rearrangements and can be associated with PML development. Therefore, patients treated with natalizumab, which decreases the migration of leukocytes and monocytes through the blood-brain barrier to inflammatory foci, are at increased risk of developing PML.&#x0D; The purpose of the study was to analyze NCCR sequences of JCPyV isolates from patients with multiple sclerosis (MS) treated with natalizumab.&#x0D; Materials and methods. A total of 26 blood plasma samples and 8 cerebrospinal fluid samples were analyzed using nested PCR to study the JCPyV NCCR structure in Russian MS patients treated with natalizumab. The NCCRs present in the samples were cloned and sequenced by Sanger sequencing. All the JCPyV NCCR sequences were compared with the archetype sequence and mapped. The NCCR sequences were also examined for presence of putative transcription factor binding sites.&#x0D; Results. A total of 48 NCCR sequences were found. The analysis showed that up to 55% of NCCRs were identified as rearranged NCCRs, while the other were archetype-like NCCRs. All the sequences can be divided into 6 types with one dominant rearrangement pattern. This rearranged NCCR was also found in a patient with the confirmed PML diagnosis and a poor prognosis. All the rearranged NCCRs were characterized by the presence of additional transcription factor binding sites.&#x0D; Conclusion. The study has helped identify previously unknown NCCR patterns typical of MS patients treated with natalizumab in Russia, thus confirming the need for the further research on NCCR rearrangements in MS patients undergoing natalizumab treatment to gain better understanding of the origin of neurovirulent JCPyV variants.

JC polyomavirus: a short review of its biology, its association with progressive multifocal leukoencephalopathy, and the diagnostic value of different methods to manifest its activity or presence

ABSTRACT Introduction : JC polyomavirus is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease resulting from the lytic infection of oligodendrocytes that may develop in immunosuppressed individuals: HIV-1 infected or individuals under immunosuppressive therapies. Understanding the biology of JCPyV is necessary for a proper patient management, the development of diagnostic tests, and risk stratification. Areas covered : The review covers different areas of expertise including the genomic characterization of JCPyV strains detected in different body compartments (urine, plasma and cerebrospinal fluid) of PML patients, viral mutations, molecular diagnostics, viral miRNAs and disease. Expert opinion : The implementation of molecular biology techniques improved our understanding of JCPyV biology. Deep-sequencing analysis of viral genomes revealed the presence of viral quasispecies in the cerebrospinal fluid of PML patients characterized by non-coding control region rearrangements and VP1 mutations. These neurotropic JCPyV variants present enhanced replication and an altered cell tropism that contribute to PML development. Monitoring these variants may be relevant for the identification of patients at risk of PML. Multiplex real-time PCR targeting both the LTAg and the archetype NCCR could be used to identify them. Failure to amplify NCCR should indicate the presence of a JCPyV prototype speeding up the diagnostic process.

Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis: A Multi-Center Case Series

Objective We aim to describe the clinical, laboratory, and radiographic features that characterize patients with progressive multifocal leukoencephalopathy (PML) in the context of sarcoidosis (S-PML). Background Sarcoidosis has been associated with CD4+, CD8+, and CD19+ lymphopenia, T-cell anergy, and increased infection risk. S-PML has been reported in approximately 60 cases. PML is often mistaken for neurosarcoidosis, leading to harmful administration of high-dose steroids. Preliminary evidence suggests that experimental therapies such as interleukins 2 and 7, checkpoint inhibitors, polyomavirus-specific T-cell therapy, and infliximab may offer promise for treatment. To ensure optimal outcome, it is crucial to identify S-PML accurately and with minimal delay. Design/Methods Data and imaging for patients were collected retrospectively from the electronic medical record from Mass General-Brigham network hospitals, National Institutes of Health, Mayo Clinic, Columbia University Irving Medical Center, University of California San Francisco, University of Michigan, and Beth Israel Deaconess Medical Center. Results Twenty-five patients with definite S-PML were identified. Median age at diagnosis of sarcoidosis was 54 years, and median time between sarcoidosis and PML diagnosis was 12 months. Sarcoidosis was isolated to lung in 14/25 patients; 10/25 had multisystem involvement; one patient had isolated dermatologic sarcoidosis. Of all patients, 16/25 patients had never received immunosuppressive medications prior to neurological symptom onset. Median serum lymphocyte count at time of PML diagnosis was 430 cells/uL (range: 50-1490). On MRI, 8/25 patients had infratentorial lesions only, while 8/25 had both infratentorial and supratentorial lesions, and 6/25 showed contrast enhancement. Seven/twenty-five patients progressed to death. Conclusions This study characterizes the clinical, laboratory, and imaging features of S-PML patients from seven major US medical centers. These data will be used to identify risk factors for development of PML in the context of sarcoidosis and to investigate any biomarkers that might aid in accurate and timely diagnosis.

Determining host factors contributing to the reactivation of JC virus in kidney transplant recipients

Background and aimsThe John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study, we aimed to determine the probable predictive factors leading to JCV replication in renal transplant patients.Material and methodsUrine and plasma samples were collected from a total of 120 consecutive renal‐transplanted patients without preliminary screening from Jan 2018 to Mar 2019. After DNA extraction, the simultaneous detection and quantification of JCV and BK polyomavirus (BKV) were conducted using a Real-time quantitative PCR method. Moreover, statistical analyses were performed using the statistical software packages, SPSS version 21.ResultsThe prevalence of JCV viruria and viremia among renal transplant recipients were 26 (21.67%) and 20 (16.67%), respectively. A significant association was observed between the JCV and two risk factors, diabetes mellitus (P = 0.002) and renal stones (P = 0.015). The prevalence of JCV viremia among recipients who were grafted near time to sampling was significantly higher (P = 0.02). There was a statistically significant coexistence between BK and JC viruses among our patients (P = 0.029). The frequency of JCV viruria in males was reported almost three times more than in females (P = 0.005). The JCV shedding in urine was significantly associated with the tropical steroids like prednisolone acetate, which have been the standard regimen (P = 0.039). Multivariable analysis revealed duration of post-transplantation (OR, 0.89; P = 0.038), diabetes mellitus (OR, 1.85; P = 0.034), and renal stone (OR 1.10; P = 0.04) as independent risk factors associated with JCV viremia post-renal transplantation.ConclusionIt seems that the discovery of potential risk factors, including immunological and non-immunological elements, may offer a possible preventive or therapeutic approach in the JCV disease episodes. The results of this study may also help clarify the probable clinical risk factors involving in progressive multifocal leukoencephalopathy development.

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

AbstractVarious effective monoclonal antibodies (mAbs) have been approved for both multiple sclerosis (MS) and anti‐aquaporin‐4‐seropositive neuromyelitis optica spectrum disorders worldwide, including in Japan. As these newer mAbs have distinct modes of action that effectively suppress the recurrence of inflammation and slow disability progression, they can modulate and interfere with the protective immune response against pathogens, resulting in various infectious complications. Among various mAbs, natalizumab (NTZ) has the highest risk of causing progressive multifocal leukoencephalopathy (PML), a rare but fatal opportunistic brain infection caused by John Cunningham polyomavirus. Switching from NTZ to B‐cell‐depleting mAbs, such as ocrelizumab, is also a possible risk factor for PML development. Alemtuzumab carries the risk of reactivation of varicella‐zoster virus (VZV); therefore, prophylactic acyclovir treatment is required. NTZ has also been associated with VZV reactivation. Eculizumab can cause severe meningococcal infection due to Neisseria meningitis, and vaccination prior to treatment induction is required. Attention to the reactivation of hepatitis B or Mycobacterium tuberculosis is also needed during mAb therapy. Additionally, in the era of severe acute respiratory syndrome coronavirus 2 infection (COVID‐19), the risk for of developing severe COVID‐19 may be associated with some mAbs, such as B‐cell‐depleting agents. Thorough understanding and mitigation strategies for infectious risks are essential.

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.

Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.

Progressive multifocal leukoencephalopathy in patients with immunovirological control and at least 6 months of combination antiretroviral therapy.

: Progressive multifocal leukoencephalopathy (PML) has rarely been reported in people with HIV (PWH) with long-term HIV immune-virological control. We describe the clinical and biological characteristics of patients with confirmed PML among PWH with a CD4+ cell count more than 200 cells/μl and an undetectable HIV RNA viral load after at least 6 months of combined antiretroviral therapy (cART) at the time of PML diagnosis, in the large French multicenter Dat'AIDS cohort. : Among 571 diagnoses of PML reported in the Dat'AIDS cohort between 2000 and 2019, 10 cases (1.75%) occurred in PWH with a CD4+ cell count greater than 200 cells/μl and an undetectable HIV RNA viral load after at least 6 months of cART. Median CD4+ cell count at PML diagnosis was 395 cells/μl (IQR 310-477). The median duration between the last detectable HIV viral load and the PML diagnosis was 41.1 months (IQR 8.2-67.4). Only one patient treated with rituximab-based chemotherapy for a large B-cell lymphoma had an established risk factor for PML. Among the nine other patients with no apparent severe immunodeficiency, multiple factors of impaired immunity could have led to the development of PML: hepatitis C virus (HCV) co-infection (n = 6), cirrhosis (n = 4), HHV-8 co-infection (n = 3) with Kaposi's sarcoma (n = 2) in association with Castleman's disease (n = 1) and indolent IgA multiple myeloma (n = 1). : This study highlights that factors other than low CD4+ cell count and high HIV viral load may be associated with the occurrence of PML. Further studies are warranted to investigate in greater detail the immunologic characteristics of PWH with immune-virological control who develop PML.

Mutations in the John Cunningham virus VP1 gene could predispose to the development of progressive multifocal leukoencephalopathy in multiple sclerosis patients undergoing treatment with natalizumab

BackgroundPatients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management. ObjectiveTo identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index. MethodsEighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples. ResultsIn MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G → C), leading to an amino acid change (Lys → Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection. Conclusions. The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.

Type O blood group associates with higher anti-JC polyomavirus antibody levels.

BackgroundPatients with multiple sclerosis (MS) and high anti‐JC polyomavirus (JCPyV) antibodies in blood have an increased risk for the development of progressive multifocal leukoencephalopathy (PML) when treated for MS. To test the hypothesis that type O blood group associates with anti‐JCPyV antibody levels and the risk of developing PML, we characterized ABO blood group antigen on blood samples of 62 patients with PML, and 64 MS controls without PML.MethodsMonocentric retrospective cohort study. Anti‐JCPyV antibody levels in arbitrary units (AU) were determined in sera using an ELISA‐based method, and blood group specific antibodies using standardised test erythrocytes.ResultsAnti‐JCPyV antibody levels were higher in individuals with blood group O compared with all other blood groups (O: median AU: 129; not O: median AU: 53; p = .005). This association was not observed for the closely related BK virus. Of the 62 patients with PML, 29 (47%, 95% confidence interval (CI) 35%–59%) were of blood group O, which showed a nonsignificant trend to differ from the expected distribution in the German population (41%), and the MS controls studied (36%, 95% CI 25%–48%).ConclusionThe ABO blood group O antigen associates with higher anti‐JCPyV antibody levels and may impact the risk of the later development of PML. The overrepresentation of blood group O in cases with PML was in line with a previous publication. Larger studies are warranted to assess a potential value of host genetic markers, such as the ABO status, for PML risk prediction during immunotherapy.

CNS inflammation after natalizumab therapy for multiple sclerosis: A retrospective histopathological and CSF cohort study.

Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing‐remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab‐treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab‐treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab‐treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab‐treated patients may potentially play a role in PML development.

Risk of Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis Patient Treated With Natalizumab: A Systematic Review.

Natalizumab, a monoclonal antibody acting on alpha4 integrin receptors, is frequently used to treat multiple sclerosis patients. The biggest downside is the risk of development of progressive multifocal leukoencephalopathy, an immune-related condition affecting mainly the central nervous system. The presence of the John Cunningham virus (JCV) and its reactivation is an important factor in the development of progressive multifocal leukoencephalopathy (PML). This study highlights its different proposed mechanism and risk factors strongly related to natalizumab-induced progressive multifocal leukoencephalopathy. The pieces of literature will also be reviewed to look for a relation between the JCV and natalizumab-induced progressive multifocal leukoencephalopathy in multiple sclerosis treated patients.The articles were searched from three databases and reviewed systematically. The inclusion criteria for this study were patients aged 20-50 years, English language paper, full-text availability, and human studies, whereas articles on patients with AIDS and cancer-related disease prior to natalizumab treatment were excluded.Out of 6531 articles identified after applying the search strategy on three main databases PubMed, Google Scholar, and ResearchGate, a total of 32 articles were finalized for the review. This study follows the guidelines listed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 2009. The data collected from these finalized articles were pertaining to the risk factor related to natalizumab induced progressive multifocal leukoencephalopathy and the mechanism related to its pathogenesis. Natalizumab is known to have the potential to cause progressive multifocal leukoencephalopathy in treated patients; here, we evaluate a close relationship of its related risk factors. The articles studied exhibit a close relationship between the length of natalizumab treatment and the presence of the JCV before infusion of natalizumab. From our analysis, it seems that the mechanism related to natalizumab-induced PML is strongly related to antigen-specific T cells and its effects. The frequency of monitoring and vigilance on the management of patients treated with natalizumab will help detect progressive multifocal leukoencephalopathy.

JCPyV miR-J1-5p in Urine of Natalizumab-Treated Multiple Sclerosis Patients.

The use of Natalizumab in Multiple Sclerosis (MS) can cause the reactivation of the polyomavirus JC (JCPyV); this may result in the development of progressive multifocal leukoencephalopathy (PML), a rare and usually lethal disease. JCPyV infection is highly prevalent in worldwide population, but the detection of anti-JCPyV antibodies is not sufficient to identify JCPyV infection, as PML can develop even in patients with negative JCPyV serology. Better comprehension of the JCPyV biology could allow a better understanding of JCPyV infection and reactivation, possibly reducing the risk of developing PML. Here, we investigated whether JCPyV miR-J1-5p—a miRNA that down-regulates the early phase viral protein T-antigen and promotes viral latency—could be detected and quantified by digital droplet PCR (ddPCR) in urine of 25 Natalizumab-treated MS patients. A 24-month study was designed: baseline, before the first dose of Natalizumab, and after 1 (T1), 12 (T12) and 24 months (T24) of therapy. miR-J1-5p was detected in urine of 7/25 MS patients (28%); detection was possible in three cases at T24, in two cases at T12, in one case at T1 and T12, and in the last case at baseline and T1. Two of these patients were seronegative for JCPyV Ab, and viral DNA was never found in either urine or blood. To note, only in one case miR-J1-5p was detected before initiation of Natalizumab. These results suggest that the measurement of miR-J1-5p in urine, could be a biomarker to monitor JCPyV infection and to better identify the possible risk of developing PML in Natalizumab-treated MS patients.

Прогресуюча мультифокальна лейкоенцефалопатія після трансплантації нирки: літературний огляд і власний клінічний випадок

This article discusses the development of progressive multifocal leukoencephalopathy after a kidney transplantation on the background of immunosuppressive therap. It’s the example of a clinical case. Based on the literature review, it is known that progressive multifocal leukoencephalopathy is a progressive demyelinating disease of the central nervous system, which is caused by reactivation of the latent JC virus; such reactivation usually occurs in immunodeficient conditions. In the clinical case, the appearance of this disease was demonstrated and its severe and potentially fatal multifocal lesion of the white matter of the brain was proved. The disease was developed on the background of immunosuppressive therapy after a history of kidney transplantation. The understanding of the clinical course of progressive multifocal leukoencephalopathy, the absence of specific neurological manifestations and course were expanded. It is noted that MRI results in addition to the clinical picture and anamnestic data help to establish the diagnosis of PML and make a differential diagnosis. Progressive multifocal leukoencephalopathy in transplant recipients receiving immunosuppressive therapy have an unfavorable prognosis.

JC Virus Seroprevalence and JCVAb Index in Polish Multiple Sclerosis Treatment-Naïve Patients.

Multiple sclerosis (MS) treatment with new agents is associated with the risk of the development of progressive multifocal leukoencephalopathy (PML). The seropositivity and a high index of anti-John Cunningham virus (JCV) antibodies are some of the risk factors for PML development. The aim of this study was to assess the seroprevalence of anti-JCVAb and JCVAb index (AI), as well as its correlations with demographic and clinical characteristics in treatment-naïve Polish MS patients. This is a multicenter, prospective, and cross-sectional study involving 665 MS patients. The overall prevalence of anti-JCVAb was 65.3%, while 63.1% of seropositive patients had an index level of >1.5. The seroprevalence was shown to increase along with the patient’s age. Except for age, the prevalence of anti-JCVAb was not associated with demographic or clinical data. No correlations between the index levels and the demographic or clinical data were observed. In Poland, the seroprevalence of anti-JCVAb in treatment-naïve MS patients is one of the highest in Europe. The majority of seropositive patients had an anti-JCV antibody level denoting a high-risk category. This means that we need further studies to be conducted on the individualization of MS treatment in order to provide patients with an appropriate therapeutic safety level.

High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients

Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration. Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk. Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts. Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before (n = 2) or at diagnosis (n = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange (n = 4). Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.

Progressive multifocal leukoencephalopathy in multiple myeloma. A literature review and lessons to learn.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection with high mortality rate usually seen in the context of immunosuppression. Although cases have been reported largely in patients with HIV/AIDS, following the use of monoclonal antibodies and occasionally in haematological malignancies, there is no review to date of patients with smouldering or treated myeloma who developed PML. Here, we conducted a literature search of PML cases in patients with multiple myeloma (MM), analyse patient and disease characteristics and describe the possible mechanisms that could lead to the development of PML. The lack of data and case reports until 2010 may indicate that PML in MM is underdiagnosed. Simultaneously, with an expanding field of new therapeutic options, patients with MM live longer, albeit continually immunosuppressed, and at risk of opportunistic infections. Emerging new treatments for PML in the horizon render the need to look out for this complication mandatory, and more case reports are needed to enrich our knowledge in this field.

Rapid cognitive decline in a patient with chronic lymphocytic leukaemia: a case report

BackgroundThe use of monoclonal antibodies in various settings has been linked to the development of progressive multifocal leukoencephalopathy (PML). Whilst this association is well-described with agents such as rituximab and natalizumab, the literature describing the occurrence of PML with ofatumumab therapy (especially in a haematology setting) is sparse. This case aims to draw attention to the above association with a particular focus on the mechanisms by which B-cell-depleting therapy can precipitate PML during the treatment of haematological malignancy.Case presentationA 68-year-old Caucasian man presented with acute-on-subacute confusion and reduced mobility. He had a history of chronic lymphocytic leukaemia for which he had completed six cycles of ofatumumab and chlorambucil 2 months prior to presentation. Biochemistry, physical examination and imaging were unremarkable on admission. Subsequent neurological examination demonstrated diminished reflexes and an extensor right plantar, while magnetic resonance imaging (MRI) assessment revealed white matter hyperintensities in the frontal lobes with restricted diffusion surrounding these areas. Cerebrospinal fluid (CSF) analysis demonstrated normal cell counts and chemistry but detected John Cunningham virus (JCV) via polymerase chain reaction (PCR), with a quantitative value of 41,850 gEg/ml. CSF immunophenotyping excluded malignant processes. A diagnosis of PML was confirmed, and with the support of palliative care, the patient was discharged to a hospice for ongoing care with the family’s agreement.ConclusionPML remains a rare complication of ofatumumab treatment. Nevertheless, clinicians should maintain a certain level of suspicion for this risk, especially in the context of patients presenting with clinical syndromes of encephalopathy and focal neurologic deficits. Furthermore, research to better our understanding of the manifold links between B-cell function and JCV regulation could provide valuable information for use in the future prevention and treatment of PML.