Progressive multifocal leukoencephalopathy: epidemiology and spectrum of predisposing conditions.

Population-based data on the epidemiology of progressive multifocal leukoencephalopathy, its predisposing conditions and mortality rate are lacking, although such data are crucial to raise awareness among clinicians and to lay foundations for future therapeutic trials in immunomodulating therapies. In our study, patients were identified by interrogating the French national healthcare reimbursement database from 1 January 2008 to 31 December 2017, using progressive multifocal leukoencephalopathy International Classification of Diseases code and a patient's selection algorithm. Overall incidence rate, 1-year all-cause mortality rate and survival patterns were calculated, and factors associated with death were identified using a multivariate Cox proportional hazards regression model. Our cohort is the largest to date, comprising 584 patients with incident progressive multifocal leukoencephalopathy. The overall incidence in France from 2010 to 2017 was stable during the study period at 0.11 per 100 000 person-years, 95% confidence interval [0.10-0.12]. Predisposing diseases were HIV infection (43.7%), followed by haematological malignancies (21.9%), chronic inflammatory diseases (20.2%), solid organ transplantation (4.3%), solid neoplasm (4.1%) and primary immune deficiency (1.5%). The 1-year mortality rate was 38.2%, with a 95% confidence interval (34.2-42.2). In multivariate analysis, factors independently associated with death were older age [adjusted hazard ratio 0.33 (0.20-0.53) for patients aged 20 to 40 compared with patients aged over 60], male gender [adjusted hazard ratio 0.73 (0.54-0.99) for females compared with males] and predisposing immunosuppressive disease, with the highest risk for solid neoplasms [adjusted hazard ratio 4.34 (2.25-8.37)], followed by haematological malignancies [adjusted hazard ratio 3.13 (1.85-5.30)] and HIV infection [adjusted hazard ratio 1.83 (1.12-3.00)], compared with chronic inflammatory diseases. Immune reconstitution inflammatory syndrome was notified in 7.0% of patients. In conclusion, incidence of progressive multifocal leukoencephalopathy is stable in France, and HIV infection remains the main predisposing disease. This large-size cohort uncovers a higher risk of mortality for male patients compared to females, and the worst prognosis for patients with solid neoplasm, while prognosis in patients with haematological malignancies appeared less dismal than in previous studies.

Neuropsychological Disability in the Case of Natalizumab-Related Progressive Multifocal Leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a viral disease characterized by progressive damage or inflammation of the cerebral white matter that can be encountered in patients with multiple sclerosis (MS). There are cases of PML caused by pharmacological agents including natalizumab. Therefore, in patients treated with this drug, early identification of PML allows changes in the treatment plan, reducing the risks of morbidity and mortality. CASE PRESENTATION: We reported the case of a 57-year-old female diagnosed with relapsing-remitting MS, who presented with PML related to natalizumab. The patient presented with change in behavioral, radiological abnormalities in the left parieto-temporal lobes. We described the longitudinal course of PML, from the diagnosis until the patient's death, documenting the progressive deterioration of her cognitive functioning, supported by changes on sequential brain scans and neurophysiological data. CONCLUSION: The neuropsychological impairment documented in this case study expands the range of treatment-related complications associated with natalizumab, and provides evidence that occurrence of "atypical" cognitive deficits in MS may support the early diagnosis of PML.

Progressive multifocal leukoencephalopathy and Creutzfeldt-Jakob disease: population-wide incidences, comorbidities, costs of care, and outcomes.

Neurological disorders associated with chronic infections are often progressive as well as challenging to diagnose and manage. Among 4.4 million persons from 2004 to 2019 receiving universal health, progressive multifocal leukoencephalopathy (PML, n = 58) and Creutzfeldt-Jakob disease (CJD, n = 93) cases were identified, revealing stable yearly incidence rates with divergent comorbidities: HIV/AIDS affected 37.8% of PML cases while cerebrovascular disease affected 26.9% of CJD cases. Most CJD cases died within 1 year (73%) although PML cases lived beyond 5 years (34.1%) despite higher initial costs of care. PML and CJD represent important neurological disorders with evolving risk variables and impact on health care.

Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients.

This study analyzed serum neurofilament light chains (NfL) in 2 European cohorts of 312 multiple sclerosis (MS) patients to investigate whether NfL are biomarkers of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. The cohort comprised 25 PML, 136 natalizumab-treated, and 151 untreated MS patients. Patients subsequently developing PML had similar NfL to other natalizumab-treated MS patients. At PML onset, NfL were 10-fold higher than in the pre-PML condition and in natalizumab-treated or untreated MS patients, and NfL continued to increase until onset of immune reconstitution inflammatory syndrome. The results suggest that in natalizumab-treated patients, NfL may represent an early and accessible marker of PML. Ann Neurol 2019;85:606-610.

Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: What do we know after 20 years of rituximab.

In 1997, rituximab was the first monoclonal antibody clinically approved for the treatment of cancer. Ten years later, progressive multifocal leukoencephalopathy (PML), until that time a rare opportunistic infection mostly seen in AIDS patients, was added as a black box warning after retrospective case-control studies showed an increased incidence in both B-cell lymphoproliferative disorders and autoimmune diseases. Despite more than 5 million worldwide exposures to date (and about 500 000 new exposures per year), insufficient data collection has hampered identification of risk minimization strategies, and concerns have been raised about a class effect extending to the newer anti-CD20 monoclonal antibodies (ofatumumab, obinutuzumab, and ocrelizumab). Here, we report current PML case counts registered in the FAERS and EudraVigilance databases and comment on severe CD4+ T lymphopenia as a plausible common mechanism of action for anti-CD20 antibodies in causation of PML.

John Cunningham Virus Status, Seroconversion Rate, and the Risk of Progressive Multifocal Leukoencephalopathy in Polish John Cunningham Virus-Seronegative Patients with Relapsing-Remitting Multiple Sclerosis.

INTRODUCTION: Presence of anti-JC-virus antibodies (JCVAbs) is associated with the increased risk of natalizumab (NAT)-related progressive multifocal leukoencephalopathy (PML). Little is known about seroconversion rate and time to seroconversion in relapsing-remitting multiple sclerosis (RRMS) patients treated with NAT in Poland. The aim of the study was to assess the true risk of PML, seroconversion rate, and time to seroconversion in all JCVAb-negative RRMS patients treated with NAT in Poland. METHODS: Demographic and clinical data of all Polish RRMS patients treated with NAT reimbursed by National Health Fund (NFZ) were prospectively collected in electronic files using the Therapeutic Programme Monitoring System provided by NFZ. The assessment of JCVAb presence (without collection of JCVAb index value) in serum (Unilabs, STRATIFY JCV: anti-JCV antibody ELISA) was done at the beginning of therapy and then repeated every 6 months. The maximum follow-up time was 4 years. In Poland, since 2013, according to the NFZ drug program guidance, only patients with negative JCVAb test have started treatment with NAT. RESULTS: In all Polish multiple sclerosis centers, 210 negative JCVAb RRMS patients with at least 9 (±3) months of observation (146 females, 64 males, and the median age at baseline: 33 years) were included in the study. During the follow-up period, JCVAb status changed from negative to positive in 34 patients (16.2%). For half of the patients, the seroconversion was diagnosed 1 year after starting NAT treatment. In 4 patients (1.9%) during follow-up, JCVAb status changed again from positive to negative. In Poland, before establishment of NFZ drug program, 4 cases of PML in patients treated with NAT in clinical trials were diagnosed. In the NFZ drug program, since 2013, no patient treated with NAT has been diagnosed with PML. CONCLUSIONS: NAT therapy in JCV-seronegative RRMS patients is safe and results in the absence of PML cases. In Poland, JCV seroconversion rate is similar to that observed in other European countries.

Progressive multifocal leukoencephalopathy - epidemiology, immune response, clinical differences, treatment.

Progressive multifocal leukoencephalopathy (PML) is a severe disease of the central nervous system with very high mortality. It is caused by the JC virus with high seroprevalence, at up to 80%. Development of PML is typically opportunistic, particularly in acquired immunodeficiency syndrome, and usually affects patients with profound immunodeficiency. Furthermore, as a result of highly efficient immunosuppressive and immunomodulatory treatments in recent years, the number of PML cases has increased in the general population. In this article, the authors mention virological and epidemiological relationships and characteristic manifestations of PML. Possible relationships of humoral and cellular immunity are discussed and limited treatment options including prophylaxis are mentioned.

Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000-50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time.

Smoking is not associated with higher prevalence of JC virus in MS patients.

John Cunningham virus (JCV) causes rare, but potentially life-threatening progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients. Beside JCV index, there is currently no other factor for further risk stratification. Because smoking was reported as potential risk factor for several viral and bacterial infections, we aimed to investigate whether smoking could increase the risk for JCV infection in MS patients. We screened our database of the MS Clinic of the Department of Neurology, Medical University of Innsbruck, Austria, for patients with known smoking status and test result for anti-JCV antibody index as determined by two-step ELISA at Unilabs, Copenhagen, Denmark. In a representative cohort of 200 MS patients with a rate of 36% current smokers plus 6% former smokers, we were not able to detect any association between smoking and JCV status. Furthermore, there was no association between smoking status and anti-JCV antibody index. Smoking does not seem to be a risk factor for JCV infection in MS patients and, therefore, does not represent a suitable marker for PML-risk stratification under treatment with natalizumab.

The safety of vedolizumab for ulcerative colitis and Crohn's disease.

OBJECTIVE: Vedolizumab is a gut-selective antibody to α4ß7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. DESIGN: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. RESULTS: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. CONCLUSIONS: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. TRIAL REGISTRATION NUMBER: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

Progressive multi-focal leucoencephalopathy - driven from rarity to clinical mainstream by iatrogenic immunodeficiency.

Advances in immune-mediated targeted therapies have proved to be a double-edged sword for patients by highlighting the risk of iatrogenic infective complications. This has been exemplified by progressive multi-focal leucoencephalopathy (PML), a hitherto rare devastating viral infection of the brain caused by the neurotrophic JC polyoma virus. While PML achieved prominence during the first two decades of the HIV epidemic, effective anti-retroviral treatment and restitution of T cell function has led to PML being less prominent in this population. HIV infection as a predisposing factor has now been supplanted by T cell immunodeficiency induced by a range of immune-mediated therapies as a major cause of PML. This review focuses on PML in the context of therapeutic immunosuppression and encompasses therapeutic monoclonal antibodies, novel immunomodulatory agents such as Fingolimod and dimethyl fumarate, as well as emerging data on PML in primary immune deficiency.

Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare but potentially fatal opportunistic infection that arises almost exclusively in immunocompromised patients or in those treated with monoclonal antibodies, especially natalizumab. Here, we aimed at exploring if age at treatment start affects the time to onset of natalizumab-related PML. PubMed was searched for the terms "natalizumab and progressive multifocal leukoencephalopathy" in articles published from January 2005 to March 2017. We collected information on each identified PML case, including demographic and clinical variables at natalizumab start and at PML onset. The number of natalizumab infusions until PML onset was investigated in time-to-event analyses. We identified 238 cases who developed PML after a median number of 33 natalizumab infusions (range 6 to 103). Risk factors for an earlier onset of natalizumab-related PML were prior immunosuppressant exposure (hazard ratio [HR] = 1.43, p = 0.017) and older age at treatment start (HR = 1.02, p = 0.016). In particular, patients older than 50 years had a more than doubled-increased risk for an earlier PML onset (HR = 2.11, p = 0.006). Our findings suggest that the age at natalizumab start may represent a risk factor for an earlier PML onset, thus claiming further investigations about the interplay between immunosenescence and MS treatments.

John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause. METHODS: Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. RESULTS: One hundred and thirty-five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index. CONCLUSIONS: Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients.

JCV serology in time: 3 years of follow-up.

OBJECTIVES: Although many neurologists are reluctant to use natalizumab in MS (multiple sclerosis) given the increased risk for PML (progressive multifocal leukoencephalopathy), trust was regained with the introduction of JCV antibody titres as a potent disease-modifying therapy. Literature shows that in patients with a negative JCV serology, the risk of PML is virtually non-existent. Unfortunately, seroconversion causes concern amongst many neurologists. Furthermore, when patients seroconvert, it is still unclear what the risk is of passing the important threshold of 1.5. MATERIALS & METHODS: JCV serology data of 161 patients were analysed, upon treatment with natalizumab at the University Hospital in Lille, France, between May 2012 and November 2014. RESULTS: Of the 81 patients who tested negative for JCV antibody at baseline, 23 (28.3%) seroconverted but only seven (8.6%) passed the threshold of 1.5. Of the 80 patients testing positive for JCV antibody at baseline, eight had an initial JCV antibody titre of 0.9 or lower of which only one of eight (12.5%) patients passed the threshold of 1.5 in the following 3 years. Eight of 15 (53.3%) patients passed this threshold if the initial serology was higher than 0.9. CONCLUSIONS: JCV-negative patients and JCV-positive patients with antibody levels below or equal to 0.9 both have a low risk of surpassing the 1.5 threshold.

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

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group.

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy.

BACKGROUND AND PURPOSE: Progressive multifocal leucoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML-IRIS in HIV-infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy. METHODS: Single-center retrospective analysis of HIV-infected patients diagnosed with PML from 1996 to 2012 who received HAART. RESULTS: Among 59 PML patients treated with HAART, 18 (30.51%) developed PML-IRIS (five delayed PML-IRIS, 13 simultaneous PML-IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, P < 0.05) and experienced a greater decline in HIV-RNA levels in response to HAART (2.5log vs. 2.95log, P < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML-IRIS cases versus 2.56% of PML non-IRIS (P < 0.01). Survival rates were higher in patients with PML-IRIS compared to those with PML non-IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred. CONCLUSIONS: Nearly one-third of HIV-infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML-IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.

Anti-JC virus seroprevalence in a Finnish MS cohort.

BACKGROUND: The risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV) is increased in patients with multiple sclerosis receiving biological therapies. OBJECTIVES: To determine the seroprevalence of anti-JCV antibodies in Finnish patients with multiple sclerosis (MS) and clinically isolated syndrome and to assess the clinical risk factors for JCV seropositivity. METHODS: The JCV seroprevalence was analyzed in 503 patients using a second-generation two-step ELISA. Sixty-seven patients underwent longitudinal serological evaluation over 4.5 years. RESULTS: The overall seroprevalence of JCV was 57.4%. The seropositivity was higher in men than in women, tended to increase with age, and was not affected by different immunomodulatory therapies. However, in patients with ongoing natalizumab treatment (n = 72), the anti-JCV antibody screening index was lower than in patients without such therapy [median 0.3 (range 0.1-3.1) vs 0.6 (0.1-3.1), respectively, P = 0.01]. Over 4.5 years, 4/19 (21%) initially seronegative patients converted to seropositivity, whereas 4/48 (8.3%) initially seropositive patients reverted to seronegativity. Fluctuations in serostatus were observed in 3/67 patients. CONCLUSION: The study confirmed a high anti-JCV antibody prevalence in patients with MS and its association with age and male gender but not with disease-modifying therapies. Our data suggest that therapy with natalizumab may cause a decrease in anti-JCV antibody levels, suggesting an immunosuppressive effect of natalizumab without an impact on JCV seroprevalence. The results of studies performed until now confirm the predictive value of anti-JCV antibody measurement in the assessment of PML risk; however, changes in serostatus need to be considered.

Age-Dependent Seroprevalence of JCV Antibody in Children.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection, caused by the John Cunningham virus (JCV). PML may occur during treatment with immunosuppressive agents or monoclonal antibodies such as natalizumab. The JCV seroprevalence increases with age with a seropositivity of 60% in the adult human population. In this study, we analyzed sera from 109 pediatric multiple sclerosis (MS) patients (mean age 14 years) as well as sera from 162 patients with a wide range of suspected neurologic disorders (mean age 6.3 years). Our results showed a considerably lower seroprevalence for JCV in our pediatric cohort with 33.3% and equal distribution in both subgroups, compared with reported seropositivity in adult population. This could result in a lower risk for drug-induced PML in pediatric patients compared with adult patients and can influence the indication for natalizumab therapy in pediatric MS patients.