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Concept: Progressive multifocal leukoencephalopathy

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BACKGROUND: The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVE: To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. METHODS: An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. RESULTS: Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. CONCLUSIONS: Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.

Concepts: Antibody, Density, Multiple sclerosis, ELISA, Progressive multifocal leukoencephalopathy, JC virus, Serology, Natalizumab

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BACKGROUND: The use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML). METHODS: JCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic. RESULTS: Perforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naive CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed. CONCLUSION: The presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.

Concepts: Immune system, Antibody, DNA, Polymerase chain reaction, Natural killer cell, Multiple sclerosis, Progressive multifocal leukoencephalopathy, JC virus

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Since their discovery in 1971, the polyomaviruses JC (JCPyV) and BK (BKPyV), isolated from patients with progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy, respectively, remained for decades as the only known members of the Polyomaviridae family of viruses of human origin. Over the past five years, the application of new genomic amplification technologies has facilitated the discovery of several novel human polyomaviruses (HPyVs), bringing the present number to 10. These HPyVs share many fundamental features in common such as genome size and organization. Infection by all HPyVs is widespread in the human population, but they show important differences in their tissue tropism and association with disease. Much remains unknown about these new viruses. In this review, we discuss the problems associated with studying HPyVs, such as the lack of culture systems for the new viruses and the gaps in our basic understanding of their biology. We summarize what is known so far about their distribution, life cycle, tissue tropism, their associated pathologies (if any), and future research directions in the field.

Concepts: Human genome, Biology, Virus, Genome, Pathology, Progressive multifocal leukoencephalopathy, JC virus, Polyomavirus

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Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment.

Concepts: Multiple sclerosis, According to Jim, Progressive multifocal leukoencephalopathy, Progressive lens, Natalizumab, Treatment of multiple sclerosis

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JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

Concepts: AIDS, Multiple sclerosis, Oligodendrocyte, Progressive multifocal leukoencephalopathy, JC virus, Rituximab, Polyomavirus, Natalizumab

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Progressive multifocal leukoencephalopathy is a rare but potentially lethal adverse event in natalizumab treated multiple sclerosis patients. We report on a 40-year old Caucasian man with typical relapsing progressive multiple sclerosis, who developed a reversible leukoencephalopathy syndrome after 43 natalizumab infusions mimicking progressive multifocal leukoencephalopathy. To our knowledge, this is the first case of its kind. Our case suggests that awareness ought to be sharpened for reversible leukoencephalopathy syndrome in the follow-up of natalizumab treated multiple sclerosis patients.

Concepts: Developed country, Multiple sclerosis, Progressive multifocal leukoencephalopathy, Progressive lens, Natalizumab, Posterior reversible encephalopathy syndrome, Treatment of multiple sclerosis

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BACKGROUND: The StratifyJCV® test is a qualitative assay to classify MS patients as anti-JC virus (JCV) antibody positive or negative. Quantification of anti-JCV antibody levels in serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients might add to the progressive multifocal leukoencephalopathy (PML) risk assessment. OBJECTIVE: The objective of this study is to test sera of patients in a quantitative anti-JCV antibody assay, and to compare the results with preexisting data from the StratifyJCV® test. METHODS: Sera of a total of 175 MS patients and matched non-MS-controls were tested for anti-JCV antibodies using glutathione S-transferase-tagged-VP1 as antigen. Antibody reactivity was quantified in arbitrary units using human immunoglobulin as standard. RESULTS: The comparison of our assay with StratifyJCV® showed good inter-assay agreement (kappa 0.6), and strong correlation for antibody reactivity (r(2) = 0.94). Discordant samples had low-reactive positivity, and a higher proportion (13% vs. 4%) tested positive in the StratifyJCV® test only. CONCLUSIONS: The method presented is a tool for the reliable quantification of anti-JCV antibodies, which demonstrates good agreement with results from StratifyJCV®. In contrast to StratifyJCV®, we pre-adsorbed all of the sera with BK virus (BKV) VP1 protein to reduce cross-reactivity. This step may account for a higher species-specificity of our assay. As such, our assay might be a promising additional tool for PML risk assessment.

Concepts: Immune system, Antibody, Protein, Multiple sclerosis, Antigen, ELISA, Cerebrospinal fluid, Progressive multifocal leukoencephalopathy

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OBJECTIVE: Natalizumab, a highly effective treatment for multiple sclerosis (MS) and Crohn’s disease, is associated with progressive multifocal leukoencephalopathy (PML). Upon suspicion or diagnosis of PML, plasma exchange (PLEX) is performed to remove natalizumab from the circulation, allowing immune reconstitution of the central nervous system. Since PLEX may also remove other circulating antibodies, we examined the effects of PLEX on serum immunoglobulin (IgG) and anti-JC virus (JCV) antibody levels in MS patients with and without PML. METHODS: Serum samples from 12 natalizumab-treated patients without PML collected before, during and after PLEX were tested for IgG isotypes using a commercial assay, and for anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay. Five natalizumab-treated PML patients who underwent PLEX were also tested for anti-JCV antibodies. RESULTS: PLEX produced a two- to three-fold reduction in all IgG isotypes. Among patients without PML, 42% (five of 12 patients) had detectable anti-JCV antibodies before PLEX; in these patients, anti-JCV antibodies were reduced approximately two- to five-fold, with levels returning to 50-100 percent of baseline two weeks after the final PLEX. The five PML patients, all of whom had detectable anti-JCV antibodies before PLEX, experienced similar reductions in anti-JCV antibody levels following PLEX. CONCLUSIONS: Our results indicate that PLEX effectively removes circulating antibodies; however, levels of endogenous anti-JCV antibody, unlike exogenously administered natalizumab, were replenished relatively quickly following PLEX. While interpretation of anti-JCV antibody levels during or within two weeks after PLEX may be problematic, humoral JCV immunity is not abolished by PLEX and antibody levels are rapidly restored.

Concepts: Immune system, Antibody, Immunology, Immunity, Multiple sclerosis, ELISA, ELISPOT, Progressive multifocal leukoencephalopathy

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Clinically isolated syndrome (CIS) describes a first symptomatic neurologic episode that is consistent with multiple sclerosis (MS), lasts at least 24 hours, occurs in the absence of fever or infection, and presents without encephalopathy.(1) Its cause is inflammation or demyelination in one (i.e., monofocal episode) or multiple areas (i.e., multifocal episode) of the CNS. Symptoms are those commonly found in MS and include, for example, optic neuritis, sensory or motor signs, partial myelitis, and bladder or bowel dysfunction.(1).

Concepts: Inflammation, Infection, Multiple sclerosis, Clinically isolated syndrome, Pain, Fever, Progressive multifocal leukoencephalopathy, Optic nerve

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The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated PML: (1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed.

Concepts: Multiple sclerosis, Oligodendrocyte, Progressive multifocal leukoencephalopathy, Progressive lens, JC virus, Rituximab, Polyomavirus, Natalizumab