Cases Of Progressive Multifocal Leukoencephalopathy Research Articles

Progressive multifocal leukoencephalopathy and spectrum of predisposing conditions: a 20-year retrospective cohort study in a tertiary center in São Paulo, Brazil.

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. 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. 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). 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.

#1038 Progressive multifocal leukoencephalopathy in kidney transplant recipients: a retrospective multicenter nationwide cohort study

Abstract Background and Aims Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infectious disease affecting the central nervous system caused by JC virus. While extensively studied in patients with HIV infection, haematological malignancies, or undergoing immunotherapies, there is a lack of data concerning kidney transplant recipients (KTRs). Method We performed a retrospective, multicentric, nationwide study. We contacted all kidney transplantation centres in France to gather all cases of PML. We obtained the count of patients with a functional kidney allograft using the registry of the French regulatory agency. Results We collected 24 cases of PML. Between 2012 and 2021, the estimated minimal nationwide incidence of PML was 4.7/100 000 patient-years. The median duration from kidney transplantation to PML was 88 months (interquartile range: 9 to 355). Eight patients (33%) had been exposed to belatacept (median exposure: 18.5 months). Almost all patients underwent reduction or withdrawal of immunosuppressive drug doses and 13 (54%) received a specific treatment. Fifteen patients (65%) died within one year after diagnosis. Conclusion In this nationwide study, PML incidence rate in KTRs was at least 4.7/100 000 patient-years resulting in an alarming 65% mortality rate within a year despite immunosuppressants doses decrease or withdrawal. Further investigations are warranted to demonstrate the efficacy of specific treatments and confirm a potential association between belatacept exposure and PML occurrence, as suggested by our study.

Spinal cord involvement in progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome.

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.

I saw the “shrimp sign”: Cerebellar progressive multifocal leukoencephalopathy

The shrimp sign is characterized by a well-defined lesion in the deep cerebellar white matter, with hyperintense signal on T2- and hypointense signal on T1-weighted imaging, abutting and outlining the dentate nucleus, unilaterally or bilaterally. This sign has high sensitivity and specificity for cerebellar progressive multifocal leukoencephalopathy (PML) within the correct clinical scenario. In this article, we present a case of cerebellar PML in a woman living with human immunodeficiency virus, who was not using antiretroviral therapy, and presented the shrimp sign on brain MRI.

Progressive multifocal leukoencephalopathy as the presenting feature in a patient with occult low-count monoclonal B-cell lymphocytosis.

Low Count Monoclonal B-Cell Lymphocytosis (LC-MBL) is a relatively poorly understood entity which has been suggested to be very common in asymptomatic adults and possibly related to infectious complications despite not progressing to CLL. We describe the first case of Progressive Multifocal Leukoencephalopathy (PML) presenting in a 72-year-old man with LC-MBL but no other immunocompromising conditions. A diagnosis of PML was confirmed with classic MRI findings in association with a high CSF John Cunningham polyomavirus (JCV) viral load (4.09' 105 copies/mL). An extensive search for underlying immunocompromising conditions only demonstrated LC-MBL representing approximately 4% of total leukocytes (0.2' 109/L). This is the first report of PML in association with LC-MBL. Careful review of peripheral blood flow cytometry results is necessary to identify this disorder. Further study of the epidemiology and infectious complications of LC-MBL are warranted.

Progressive Multifocal Leukoencephalopathy in AIDS Patients: A Report on 15 Cases

Progressive Multifocal Leukoencephalopathy (PML) is a degenerative disease of the central nervous system (CNS) caused by a polyoma virus called JC polyoma virus (JCPyV). It affects patients with some diseases like lymphoproliferative diseases and patients with advanced AIDS usually with a CD4 count of less than 100 cells/L and carries a poor prognosis. Its clinical and radiological features are suggestive but could be similar to other diseases like toxoplasmosis and tuberculosis that can affect the CNS in AIDS patients. Here we report on 15 cases of PML, attended and managed in Tripoli University Hospital in Tripoli, Libya. All of the patients were in advanced stages of HIV infection, and were not using medications at presentation. All the patients except one died within a period of 2 days- 2 months of presentation possibly due to associated opportunistic infections (OI). PML has not been reported in the Libyan medical literature and here we report its clinical and radiological features and the prognosis of its course.

A case of progressive multifocal leukoencephalopathy in a post-kidney transplant patient with improvement after discontinuation of immunosuppressive drugs and combination therapy with mefloquine and mirtazapine

BackgroundProgressive multifocal leukoencephalopathy is a rare disease, but the prognosis is very poor, especially in the immunosuppressed state with a non-HIV background, and there is no established treatment.Case presentationsA 49-year-old patient who had undergone a renal transplant and was receiving prednisolone and mycophenolate mofetil treatment was admitted for peritoneal dialysis initiation. While hospitalized, he experienced aphasia and other percutaneous symptoms. Magnetic resonance imaging of the brain revealed a subcortical demyelinating lesion. JC virus DNA was identified in cerebrospinal fluid, and he was diagnosed with progressive multifocal leukoencephalopathy. Immunosuppressant was ceased, and he was treated with mefloquine and mirtazapine. The patient subsequently underwent a head MRI scan, confirming lesion reduction, improved activities of daily life, and survival.ConclusionsProgressive multifocal leukoencephalopathy is commonly observed in patients with compromised immune systems, which was the case for this patient due to long-standing immunosuppressive medication usage and end-stage renal failure necessitating dialysis.

Association of temozolomide with progressive multifocal leukoencephalopathy: a disproportionality analysis integrated with network pharmacology

ABSTRACT Background Temozolomide (TMZ) is an alkylating agent approved for the management of glioblastoma. The TMZ is not known for progressive multifocal leukoencephalopathy (PML). The main objective of the current study is to find out the association of TMZ with PML using disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data integrated with network pharmacological approaches. Research design and methods OpenVigil tool was used to query the FAERS database. The disproportionality measures were calculated. The network has been constructed using Cytoscape. Finally, the possible binding interactions were studied using Glide, Schrödinger Inc. Results A total number of 3502 cases of PML were reported in the FAERS database. Out of these, 10 cases were found with TMZ. The subgroup analysis results have shown a greater number of cases in females. The network has indicated the involvement of human mitogen-activated protein kinase, 3-phosphoinositide-dependent protein kinase 1 protein, human mTOR complex protein, phosphatidylinositol 4,5-bisphosphate 3-kinase protein, and glycogen synthase kinase-3 beta protein. The docking results have indicated good interactions of TMZ with active site of glycogen synthase kinase-3 beta and mitogen-activated protein kinase 1 as compared to other identified targets. Conclusion The PML is identified as novel signal with temozolomide.

Lessons learned after 20 years of real-world experience with natalizumab

BackgroundWhile natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002–2022) of experience with NTZ at our center, we observed no cases of PML. ObjectivesWe evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. MethodsFor this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. Results766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. ConclusionsThe utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.

Serum Neurofilaments are a reliable biomarker to early detect PML in Multiple Sclerosis patients.

The earliest detection of progressive multifocal leukoencephalopathy (PML) is crucial in Natalizumab (NTZ)-treated Multiple Sclerosis (MS) patients. This study aims to assess serum Neurofilaments (sNFL) ability to early detect PML in longitudinal patients' follow-up. NFL were retrospectively measured in four PML cases occurred at the Regional Referring Center for MS (CRESM, Italy), in samples collected since one year before PML diagnosis, at PML diagnosis, during PML and in post-PML follow-up. sNFL levels were interpreted according to previously defined reference values. Clinical examination and EDSS were performed at each NTZ infusion. Routinary MRI was undertaken every six months; after PML diagnosis, MRI was performed according to clinical evaluation. sNFL were also measured in 45 NTZ-treated patients experiencing NEDA-3 status for at least 12 months. Patients showed different PML onsets and manifestations: in 3 patients routinary brain MRI revealed radiological signs of PML preceding different clinical manifestations, while in one patient brain MRI was performed after the clinical onset. PML diagnosis was defined at the time of the first detection of JCV DNA in cerebrospinal fluid. The following different PML phases were considered: 1. Basal (up to 4 months before PML diagnosis): sNFL values were in the normal range in all patients' samples, except for one (median 9.1 pg/ml, range 6.2-15.1 pg/ml) 2. Pre-PML (within 3 months before PML diagnosis): sNFL were elevated in all available samples (median 19.50 pg/ml, range 15.50-33.80 pg/ml). 3. PML diagnosis: sNFL were elevated in all patients (median 59.20 pg/ml, range 11.1-101.50 pg/ml). 4. PML/IRIS: during this phase, sNFL levels reached their peak (median 96.35 pg/ml, range 20.5-272.9) in all patients. 5. Post-PML (recovery phase, starting from the first MRI without enhancement, up to the end of follow-up): sNFL levels showed a decrease (median 12.80 pg/ml, range 9.30-30.60); however, based on reference values, sNFL were still elevated in 2 out of 4 patients at the end of their follow-up (622 and 887 days after PML diagnosis). sNFL were always elevated when MRI scan suggested a suspicious of PML. In NEDA-3 patients, sNFL levels were in the normal range in all patients' samples (median 4.7 pg/ml, range 1.4-8.6 pg/ml). Elevated sNFL were observed not only at PML diagnosis, but also in pre-PML phase. At PML recovery, sNFL weren't normalized in all patients' samples, suggesting ongoing neuronal degeneration. sNFL represent a reliable biomarker and should be introduced in clinical practice as an additional/alternative parameter to MRI to early detect and monitor PML.

Progressive multifocal leukoencephalopathy in multiple myeloma: a case report of a patient with SARS-CoV-2 infection and an updated systematic literature review.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the human polyomavirus 2 (HPyV-2, previously known as JCV) in immunosuppressed individuals. Few cases of PML have been described in multiple myeloma (MM) patients. We described a case of PML in a patient with MM with fatal worsening that occurred during SARS-CoV-2 infection. We also performed a literature review to update the 16 cases series of MM patients with PML already collected until April 2020. A 79-year-old female patient with refractory IgA lambda MM in Pomalidomide- Cyclophosphamide-Dexamethasone regimen developed gradual lower limbs and left arm paresis along with a decreased consciousness 3.5 years after the MM diagnosis. Symptoms developed shortly after the recognition of hypogammaglobulinemia. After SARS-CoV-2 infection, her neurological status quickly worsened until she deceased. MRI features and JCV-positive PCR on CSF confirmed the PML diagnosis. Our literature review adds sixteen clinical cases of PML in MM published between May 2020 and March 2023 to the 16 cases already collected in the previously published review by Koutsavlis. PML has been increasingly described in MM patients. It remains questionable if the HPyV-2 reactivation is determined by the severity of MM itself, by the effect of drugs or by a combination of both. SARS-CoV-2 infection may have a role in worsening PML in affected patients.

Progressive multifocal leukoencephalopathy with natalizumab extended or standard interval dosing in the United States and the rest of the world

ABSTRACT Background Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited. Research design and methods A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems. Results Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis. Conclusions This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Progressive Multifocal Leukoencephalopathy (PML) With Anti-CD20 and Other Monoclonal Antibody (mAb) Therapies in Multiple Sclerosis (P8-3.016)

<h3>Objective:</h3> To review the incidence of progressive multifocal leukoencephalopathy (PML) associated with monoclonal antibody (mAb) therapies, specifically anti-CD20 medications used in multiple sclerosis (MS). <h3>Background:</h3> PML is an opportunistic and fatal inflammatory disease of the central nervous system, which occurs almost exclusively in immunocompromised hosts; therefore, patients receiving mAb immunotherapy become an at-risk population. B cell-depleting mAbs targeting CD20+ cells have become widely used in MS. Although their efficacy is well-known, their associated risk of PML, especially among those without previous disease-modifying therapy (DMT) exposure, has been insufficiently studied. <h3>Design/Methods:</h3> A systematic literature review of PubMed, Google Scholar, EMBASE, and Scopus was conducted by two independent researchers from June 1, 1997, to July 10, 2022. Further data was obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and individual pharmaceutical companies (Genentech, Novartis, and TG Therapeutics). Carryover cases from prior exposure to other immunosuppressants were excluded. <h3>Results:</h3> Between 2015 and 2017, 10 cases of PML were reported in the FAERS database among 334 MS patients taking rituximab; two had previously received natalizumab, leaving eight cases in total. Rituximab-associated PML was also seen in lymphoproliferative disorders (n=52), rheumatoid arthritis (n=9), and granulomatosis with polyangiitis (n=2). Two fatal PML cases were found in MS patients taking ocrelizumab. No cases of PML were reported with ofatumumab in MS; however, 5 cases were reported in chronic lymphocytic leukemia. PML has not been observed with ublituximab, which is currently under FDA review. Among other DMTs, PML was frequently reported with natalizumab (n=884), fingolimod (n=30), dimethyl fumarate (n=12), and alemtuzumab (n=1). <h3>Conclusions:</h3> Anti-CD20 therapies are a safe class of medications with a low infectious risk for PML, especially compared to other mAbs used in MS, such as natalizumab. Nonetheless, risk stratification in susceptible individuals, as done with natalizumab, could prove beneficial with all mAb treatments. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. JENA has nothing to disclose. Dr. Kakara has nothing to disclose. Dr. Sriwastava has nothing to disclose. Maha Daimee has nothing to disclose. Dr. Xu has nothing to disclose.

Real-world use of natalizumab in Austria: data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR)

IntroductionWith the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years.Patients/methodsData retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits.ResultsA total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death.ConclusionThe effectiveness of natalizumab in patients with active relapsing–remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab’s favourable safety profile during long-term use.

Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Progressive multifocal leukoencephalopathy in multiple myeloma.

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus in the context of immune suppression such as HIV, malignancy, and certain immunomodulatory medications. PML has been reported only rarely in multiple myeloma patients, and its presenting features and natural history in this population are not well known. We describe six cases of PML among multiple myeloma patients treated at our institution between 2013 and 2022, including two that developed on or shortly after treatment with recently developed BCMA-directed immunotherapies.

JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient.

JC virus (JCV) is common among healthy individuals and remains latent but may be reactivated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML). Here, we present a rare case of PML caused by JC virus infection in a previously healthy and immunocompetent patient. A 67-year-old female without any disease history was admitted after presenting with rapidly progressive dementia. The preoperative diagnosis was progressive multifocal leukoencephalopathy, and corticosteroid treatment did not improve the symptoms. Brain lesions were surgically sampled, and JCV infection was confirmed by high-throughput DNA gene detection. This patient received a combined treatment of mirtazapine, mefloquine, and traditional Chinese herbs, and had stabilization of the disease on followed-up. Although it is a rare, this case demonstrates that JC virus infection within the brain occurs in apparently healthy people. This case may increase our understanding of virus infection when facing the coronavirus epidemic in recent years, considering that similar medications were used.

A Case of Progressive Multifocal Leukoencephalopathy in a Child with Hyper-Immunoglobulin M Syndrome: The Impact of Missed Care during the COVID-19 Pandemic

A Case of Progressive Multifocal Leukoencephalopathy in a Child with Hyper-Immunoglobulin M Syndrome: The Impact of Missed Care during the COVID-19 Pandemic

Hepatitis B virus-induced CD4 lymphocytopenia: A rare cause of progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare subacute-onset fatal demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus. It usually occurs in impaired cell-mediated immunity settings such as lymphoproliferative disorders, chronic infective or granulomatous conditions on immunosuppressive medications, and human immunodeficiency virus infection. It also appears very rarely with idiopathic CD4 lymphocytopenia. We present a case of PML with visual field defect, progressive motor impairment, behavioral alteration, and dementia. Magnetic resonance imaging had features of asymmetric non-enhancing hyperintense subcortical white matter lesions in the background of chronic active hepatitis B infection. To the best of our knowledge, this is the first case report of CD4 lymphocytopenia associated PML following chronic hepatitis B infection.

Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate.

Dimethyl fumarate (DMF), an oral disease-modifying therapy with an established benefit and well-described safety profile, is among the most commonly used therapies for relapsing forms of multiple sclerosis. As of 31 December 2021, >560,000 patients have been treated with DMF, representing >1,190,000 person-years of exposure. Of these, 6413 patients (14,292 person-years) were from clinical trials. Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of lymphopenia (<0.91 × 109/L) in patients treated with DMF. We present detailed clinical characteristics and outcomes of the 12 confirmed PML cases occurring in MS patients on DMF as of 21 July 2021. The PML incidence in DMF-treated patients is 1.07 per 100,000 person-years of DMF exposure. Lymphopenia is the common risk for PML in DMF treatment. DMF-related PML is rare but has occurred in the setting of lymphopenia, supporting the current recommendations for absolute lymphocyte count monitoring in all patients, regardless of age and time on therapy.