Multifocal Leukoencephalopathy In Patients Research Articles

Progressive multifocal leukoencephalopathy in patients with chronic kidney disease.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection caused by the human polyomavirus 2, leading to demyelination from oligodendrocyte death and rapid neurologic decline. Most commonly, PML affects patients in immunocompromised states. However, rare reports of PML in an immunocompetent host exist. Here, we report two cases of PML in older individuals with chronic kidney disease (CKD). CKD can ultimately lead to immune system dysfunction and place patients in a relatively immunosuppressed state. Testing for JC virus should remain a consideration for rapid, unexplained neurologic decline even without known immunocompromised status in the appropriate clinical setting.

Progressive multifocal leukoencephalopathy in patients treated with chimeric antigen receptor T cells

Using 2 global postmarketing surveillance databases, Goldman and colleagues report that progressive multifocal leukoencephalopathy (PML), a viral disease associated with profound immunosuppression, occurs in approximately 0.9 cases per 1000 recipients of CD19-directed CAR T-cell therapy. The risk of PML appears higher with CAR T-cell therapy than other cancer therapies, but its precise role cannot be distinguished from antecedent therapies that these patients receive.

013 An exploration of risk factors for dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis

Dimethyl fumarate (DMF) is a commonly used first-line immunomodulatory drug used for the treatment of relapsing-remitting multiple sclerosis. It has been found to cause lymphopenia in a proportion of patients, and the incidence of several cases of progressive multifocal leukoencephalopathy in patients taking DMF has given rise to concerns regarding its safety.The purpose of this study was to identify risk factors for DMF-induced lymphopenia.: We performed ret- rospective analysis of 323 patients prescribed DMF in our NHS Lothian MS clinic in Edinburgh since the drug was introduced in 2014.Older age (>45), and lower baseline absolute lymphocyte count (ALC) both increased the risk of devel- oping grade 2 lymphopenia, with the latter also increasing the risk of severe, grade 3 lymphopenia. We also found that the decline in ALC happens within the first 6 months of DMF treatment, and after this point it no longer declines but has a tendency to rise.Increased vigilance with ALC monitoring is required in the first 6 months, especially in those who are older and have a low baseline ALC. By knowing the risk factors for DMF-induced lymphopenia, clinicians will be able to make more informed decisions when choosing a drug to start a patient on with multiple sclerosis.s1504225@sms.ed.ac.uk

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.

Etiopathogenesis and diagnostics of progressive multifocal leukoencephalopathy in patients treated with natalizumab

Etiopathogenesis and diagnostics of progressive multifocal leukoencephalopathy in patients treated with natalizumab

Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: risk reduction, management and possibilities for subsequent immunoregulation

The risk of progressive multifocal leukoencephalopathy (PML) is one of the factors limiting the widespread use of natalizumab (NTZ). As a strategy for potentially reducing the frequency of the NTZ-associated PML, while maintaining the high therapy efficacy, in addition to the widely-used risk stratification strategy based on anti-JC virus antibody index and therapy duration, we propose the administration of NTZ with an extended dosing interval. Opinions vary on the effectiveness of plasmapharesis in confirmed cases of PML. The most challenging problem is how to manage patients, who develop PML, and what MS disease-modifying therapy should be considered for the subsequent use.

"The spectrum of MRI findings of progressive multifocal leukoencephalopathy in patients with multiple sclerosis in the Czech Republic"

"The spectrum of MRI findings of progressive multifocal leukoencephalopathy in patients with multiple sclerosis in the Czech Republic"

Seroconversion of JCV antibodies is strongly associated to natalizumab therapy

Previous infection with John Cunningham virus (JCV) increases the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) undergoing treatment with natalizumab. Patients who test negative for JCV antibodies must be assessed every six months due to the risk of seroconversion. Data from the United States of America, Portugal, Holland, France, United Kingdom and Sweden have shown a strong correlation between the use of natalizumab and JCV seroconversion. The authors present now data on patients from Brazil, as there are no data from Latin American countries published on this subject yet. A group of 86 patients with MS with negative results for antibodies against JCV were included in this analyses with at least two JCV antibodies testing. Twenty-five patients (29% of the total group) did not use natalizumab at any time, while the remaining 71% used natalizumab for a median period of 800 days (equivalent to 28 monthly infusions). Seroconversion was observed in 19 patients (22.1%). There was no association of seroconversion with gender, age, previous pulses of corticosteroid or specific MS-modifying drugs. The use of natalizumab was strongly associated to seroconversion (p < 0.0001). The present results confirm the influence of natalizumab therapy on JCV antibodies in several countries and continents.

Natalizumab-associated Progressive Multifocal Leukoencephalopathy in Patients with Multiple Sclerosis: A Mini Review.

Progressive multifocal leukoencephalopathy is a fatal demyelinating disease caused by the John Cunningham virus. It causes white matter inflammation in multiple areas of the brain. Although rare, it has been known to occur in patients with immunodeficiency states and those taking chronic immunosuppressive medications for diseases such as multiple sclerosis and psoriasis. In this article, we will discuss about the drug-induced progressive multifocal encephalopathy and its diagnosis and management in patients taking natalizumab and other disease-modifying therapies among patients with multiple sclerosis.

What Is the Risk of Progressive Multifocal Leukoencephalopathy in Patients With Ulcerative Colitis or Crohn's Disease Treated With Vedolizumab?

BackgroundProgressive multifocal leukoencephalopathy is a serious condition linked to certain diseases and immunosuppressant therapies, including the α4 integrin antagonist natalizumab. No cases have been reported to date with vedolizumab, a selective antagonist of the α4β7 integrin expressed on gut-homing lymphocytes. This analysis aimed to describe the current and future expected occurrence of progressive multifocal leukoencephalopathy with vedolizumab use, were the risk the same as in other populations in which this disease has been studied.MethodsThe expected number of vedolizumab-associated progressive multifocal leukoencephalopathy cases was estimated up to May 19, 2016, and modeled up to 2034. These estimates were based on the cumulative exposure to the drug, assuming an equivalent risk to that of patients treated with natalizumab or those from other reference populations where progressive multifocal leukoencephalopathy has been examined. Future cases were modeled based on similar risks and projected sales.ResultsThe cumulative vedolizumab exposure was estimated at 54,619 patient-years, with a 95% confidence interval of 0.0 to 6.75 cases per 100,000 patient-years. An estimated 30.2 (95% confidence interval, 19.4–40.9) cases of progressive multifocal leukoencephalopathy would have occurred if vedolizumab had the same risk as that of natalizumab. There would be a 50% chance of the first case occurring by 2018, assuming an equivalent risk to the general population.ConclusionsThese analyses indicate that the risk of progressive multifocal leukoencephalopathy with vedolizumab is small, and unlikely to be above 6.75 cases per 100,000 patient-years.

Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector

Glioblastoma multiforme (GBM), the most common malignant brain tumor, has a short period of survival even with recent multimodality treatment. The neurotropic JC polyomavirus (JCPyV) infects glial cells and oligodendrocytes and causes fatal progressive multifocal leukoencephalopathy in patients with AIDS. In this study, a possible gene therapy strategy for GBM using JCPyV virus-like particles (VLPs) as a gene delivery vector was investigated. We found that JCPyV VLPs were able to deliver the GFP reporter gene into tumor cells (U87-MG) for expression. In an orthotopic xenograft model, nude mice implanted with U87 cells expressing the near-infrared fluorescent protein and then treated by intratumoral injection of JCPyV VLPs carrying the thymidine kinase suicide gene, combined with ganciclovir administration, exhibited significantly prolonged survival and less tumor fluorescence during the experiment compared with controls. Furthermore, JCPyV VLPs were able to protect and deliver a suicide gene to distal subcutaneously implanted U87 cells in nude mice via blood circulation and inhibit tumor growth. These findings show that metastatic brain tumors can be targeted by JCPyV VLPs carrying a therapeutic gene, thus demonstrating the potential of JCPyV VLPs to serve as a gene therapy vector for the far highly treatment-refractory GBM.

Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index). Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort. 156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00-0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8-4·0) in patients with previous immunosuppressant use and 1·7% (1·4-2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00-0·03) in year 1 (1-12 infusions) to 0·6 (0·0-1·5) in year 6 (61-72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0-0·2) in year 1 to 3·0 (0·2-5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0-0·5) in year 1 to 10·0 (5·6-14·4) in year 6 for those with an index of more than 1·5. Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit-risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants. Biogen.

Erratum to: Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6–110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6–72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31months (range 6-110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23months (range 6-72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 2-Surveillance for Treatment Complications and Disease Progression.

An understanding of the new generation of MS drugs in conjunction with the key role MR imaging plays in the detection of disease progression, opportunistic infections, and drug-related adverse effects is of vital importance to the neuroradiologist. Part 1 of this review outlined the current treatment options available for MS and examined the mechanisms of action of the various medications. It also covered specific complications associated with each form of therapy. Part 2, in turn deals with the subject of pharmacovigilance and the optimal frequency of MRI monitoring for each individual patient, depending on his or her unique risk profile. Special attention is given to the diagnosing of progressive multifocal leukoencephalopathy in patients treated with natalizumab as this is a key area in which neuroradiologists can contribute to improved patient outcomes. This article also outlines the aims of treatment and reviews the possibility of "no evidence of disease activity" becoming a treatment goal with the availability of more effective therapies. Potential future areas and technologies including image subtraction, brain volume measurement and advanced imaging techniques such as double inversion recovery are also reviewed. It is anticipated that such advancements in this rapidly developing field will improve the accuracy of monitoring an individual patient's response to treatment.

Assessing understanding of individual risk and symptoms of progressive multifocal leukoencephalopathy in patients prescribed natalizumab for multiple sclerosis.

Natalizumab, a monoclonal antibody directed against α4 integrin, is a highly efficacious treatment commonly used in relapsing remitting multiple sclerosis. Natalizumab is associated with the potentially fatal, rare, demyelinating, opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Prognosis and disability from PML are determined by early diagnosis. Written tools are mandated in Australia and other prescribing countries with the aim to help patients understand the risks associated with treatment and ensure familiarity with the early symptoms of PML. We aimed to assess if these tools achieve such an outcome. A cross-sectional survey was conducted using a convenience sample of multiple sclerosis patients prescribed natalizumab presenting to the infusion centre at a major tertiary hospital. Patients were offered a multi-choice questionnaire to assess their knowledge on the treatment risks and surveillance requirements of their therapy. Three specific questions were highlighted by the researchers as crucial to patient understanding of PML and defined as basic knowledge. A total of 48 patients in our hospital was prescribed natalizumab; 37 responded. A total of 16 (43.2%) patients answered all three basic knowledge questions correctly. There was no difference in the ability to answer these questions based on length of treatment or co-ownership knowledge between patients with base knowledge and without. Natalizumab is associated with an increased risk of PML. Early detection and treatment of PML results in improved patient outcomes. Patient knowledge and co-partnership in the utilisation of PML risk tools is relevant in ensuring early detection. Our findings question the ability of currently sanctioned tools to inform patients of basic knowledge of PML and their risk of developing PML. A future study with a repetitive education approach and repeating the questionnaire at multiple time points would be of interest.

Can We Cure Progressive Multifocal Leukoencephalopathy in Patients With High-Grade Lymphoma and Acquired Immunodeficiency Syndrome?

Can We Cure Progressive Multifocal Leukoencephalopathy in Patients With High-Grade Lymphoma and Acquired Immunodeficiency Syndrome?

Design of TRUST, a non-interventional, multicenter, 3-year prospective study investigating an integrated patient management approach in patients with relapsing-remitting multiple sclerosis treated with natalizumab.

BackgroundNatalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification.Methods/DesignTRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored.DiscussionTRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study’s results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions.

Real World Experience With Natalizumab at a Tertiary Care Pediatric IBD Center.

Natalizumab is a humanized monoclonal antibody inhibiting lymphocyte migration and prescribed in patients with Crohn disease (CD) failing anti-tumor necrosis factor (TNF) therapies. Because of the risk of progressive multifocal leukoencephalopathy in patients with John Cunningham virus (JCV) positive, natalizumab is not widely used in clinical practice. Published experience of the use of natalizumab in pediatric patients is lacking. We aimed to describe the experience of natalizumab in patients with CD, including those who are JCV positive, at a tertiary care pediatric inflammatory bowel disease center. A retrospective chart review was performed in patients with CD <21 years receiving natalizumab therapy before March 2014. Patient and disease information, prior treatments and response to natalizumab, including Harvey Bradshaw Index (HBI), were recorded. Descriptive statistics were computed. Nine patients received natalizumab with a median age at diagnosis of 10 (range 7-16) years and median disease duration 72 (range 13-156) months. All of the patients had failed at least 1 anti-TNF agent. At baseline, the median HBI was 8 (IQR 6.5-11). By week 10, the median HBI was 4.5 (IQR 2-6), with 4 of 8 (50%) patients with CD being in remission. Forty-four percent (4/9) of patients were JCV antibody positive at baseline and had anti-JCV antibody index >0.9 (median 3.36). There were no serious adverse events, including progressive multifocal leukoencephalopathy. All of the patients were transitioned to vedolizumab. In our experience, natalizumab is a safe and efficacious medication in pediatric in patients with inflammatory bowel disease. Given the favorable results with natalizumab, pediatric studies with the more gut targeted anti-integrin agent vedolizumab are warranted.

Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review.

To determine risk factors for progressive multifocal leukoencephalopathy (PML) in systemic lupus erythematosus (SLE) patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. Studies published in English between January 1, 1984 and October 31, 2014 that reported PML in adult SLE patients were included. Immunosuppression was defined as exposure to ≥1 immunosuppressant drug of interest at PML diagnosis: belimumab, rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate and high-dose corticosteroids (>15 mg/day). Minimal immunosuppression was defined as low-dose corticosteroids (≤15 mg/day) and/or anti-malarials. Thirty-five publications met our inclusion criteria: four observational studies, two large case series, and 29 case reports that described 35 cases. Reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases/100,000 person-years. Of the 35 case reports, three cases were exposed to no immunosuppressant drugs at PML diagnosis, five cases had minimal immunosuppression, 23 cases had immunosuppression, and four cases were indeterminate. The evidence from this literature review suggests that, while PML is a very rare disease in SLE patients, there does appear to be an increased risk of PML associated with SLE compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments prescribed to manage disease, or some combination of these factors. Additional large observational studies, designed to assess exposure to drugs of interest and complicated treatment histories, are needed to provide further evidence about potential mechanisms contributing to the onset of PML in SLE patients.