Gabriel Bsteh

Stability and predictive value of anti-JCV antibody index in multiple sclerosis: A 6-year longitudinal study.

Background Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status. Methods MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4–6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results 154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p<10−7). Baseline anti-JCV antibody index >0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and <0.20 stable negative serostatus (sensitivity 61.3%, specificity 97.6%). Conclusions Anti-JCV antibody index remained relatively stable over 6-year follow-up with annual serostatus change of ~3%. Baseline anti-JCV antibody index predicted stable negative and stable positive JCV serostatus.

NMDA receptor antibodies A rare association in inflammatory demyelinating diseases

Objectives: To analyze the frequency of NMDA receptor (NMDAR) antibodies in patients with various inflammatory demyelinating diseases of the CNS and to determine their clinical correlates. Methods: Retrospective case-control study from 2005 to 2014 with the detection of serum IgG antibodies to NMDAR, aquaporin-4, and myelin oligodendrocyte glycoprotein by recombinant live cell-based immunofluorescence assays. Fifty-one patients with acute disseminated encephalomyelitis, 41 with neuromyelitis optica spectrum disorders, 34 with clinically isolated syndrome, and 89 with multiple sclerosis (MS) were included. Due to a known association of NMDAR antibodies with seizures and behavioral symptoms, patients with those clinical manifestations were preferentially included and are therefore overrepresented in our cohort. Nine patients with NMDAR encephalitis, 94 patients with other neurologic diseases, and 48 healthy individuals were used as controls. Results: NMDAR antibodies were found in all 9 patients with NMDAR encephalitis but in only 1 of 215 (0.5%) patients with inflammatory demyelination and in none of the controls. This patient had relapsing-remitting MS with NMDAR antibodies present at disease onset, with an increase in NMDAR antibody titer with the onset of psychiatric symptoms and cognitive deficits. Conclusion: In demyelinating disorders, NMDAR antibodies are uncommon, even in those with symptoms seen in NMDAR encephalitis.

Discontinuation of disease-modifying therapies in multiple sclerosis – Clinical outcome and prognostic factors

Background: Stable disease course may prompt consideration of disease-modifying treatment (DMT) discontinuation in relapsing–remitting multiple sclerosis (RRMS). Objective: To investigate the clinical outcome after DMT discontinuation and to identify predictive factors supporting decision-making. Methods: We included 221 RRMS patients, who discontinued DMT after ⩾12 months and had documented follow-up ⩾2 years after discontinuation. Hazard ratios (HRs) with 95% confidence intervals (CIs) regarding relapse and disability progression after DMT discontinuation were calculated from Cox regression models. Results: Age >45 years at discontinuation (HR = 0.47, CI = 0.23–0.95, p = 0.038), absence of relapses for ⩾4 years on DMT before discontinuation (HR = 0.29, CI = 0.10–0.82, p = 0.020) and absence of contrast enhancing lesions (HR = 0.46, CI = 0.28–0.78, p = 0.004) were independent predictors of absence of relapse after discontinuation. Age >45 years and absence of relapses ⩾4 years on DMT combined had an HR of 0.06 (CI = 0.01–0.44, p < 0.001). Higher Expanded Disability Status Scale (EDSS) at discontinuation, age >45 years and longer disease duration were significantly associated with disability progression after discontinuation. Conclusion: While freedom from further disease activity is generally unpredictable, there is a subset of patients (age ⩾45 years, DMT intake ⩾4 years without evidence of clinical or radiological disease activity) having a high likelihood of remaining relapse-free after DMT discontinuation. However, close clinical monitoring for recurrent disease activity is mandatory after discontinuing treatment.

Long Term Clinical Prognostic Factors in Relapsing-Remitting Multiple Sclerosis: Insights from a 10-Year Observational Study

Background Multiple sclerosis (MS) has a highly heterogenic course making prediction of long term outcome very difficult. Objective The objective was to evaluate current and identify additional clinical factors that are linked to long term outcome of relapsing-remitting MS assessed by disability status 10 years after disease onset. Methods This observational study included 793 patients with relapsing-remitting MS. Clinical factors hypothesized to influence long term outcome measured by EDSS scores 10 years after disease onset were analysed by Kaplan-Meier-estimates. Multinomial logistic regression models regarding mild (EDSS ≤2.5), moderate (EDSS 3.0–5.5) or severe (EDSS ≥6.0) disability were calculated to correct for confounders. Results Secondary progression was the strongest predictor of severe disability (Hazard ratio [HR] 503.8, 95% confidence interval [CI] 160.0–1580.1); p<0.001). Complete remission of neurological symptoms at onset reduced the risk of moderate disability (HR 0.42; CI 0.23–0.77; p = 0.005), while depression (HR 3.59; CI 1.14–11.24; p = 0.028) and cognitive dysfunction (HR 4.64; CI 1.11–19.50; p = 0.036) 10 years after disease onset were associated with severe disability. Oligoclonal bands and pregnancy were not correlated with disability. Conclusion We were able to identify clinically apparent chronic depression and cognitive dysfunction to be associated with adverse long term outcome in MS and to confirm that pregnancy has no negative impact. Additionally, we emphasize the positive predictive value of complete remission of initial symptoms.

Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study

Background There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS. Materials and methods 128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3–10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate. Results CSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p<0.05) and OND (p<0.001), whereas plasma blasts (CD19+CD138+) were increased in bout-onset MS (p<0.001) and PPMS (p<0.05) compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05) and EDSS (p<0.01) was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01) and the presence of ≥9 MRI T2 lesions (p<0.05). Conclusion We detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.

Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc.

This is a single observational study without controls, providing Class IV evidence for the effectiveness of maraviroc in the treatment of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome in MS.

Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis

Background: Peripapillary retinal nerve fibre layer (pRNFL) thickness is emerging as a marker of axonal degeneration in multiple sclerosis (MS). Objective: We aimed to prospectively assess the predictive value of pRNFL for progression of physical and cognitive disability in relapsing-remitting MS (RRMS). Methods: In this 3-year longitudinal study on 151 RRMS patients, pRNFL was measured by spectral-domain optical coherence tomography (OCT). We used proportional hazard models, correcting for age, sex, disease duration, Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) at baseline, to test a pRNFL thickness ≤88 µm at baseline for prediction of EDSS progression and cognitive decline. We also evaluated the decrease in pRNFL thickness from baseline to year 3 in a multivariate linear regression model. Results: pRNFL thickness ≤88 µm was independently associated with a threefold increased risk of EDSS progression (p < 0.001) and a 2.7-fold increased risk of cognitive decline within the subsequent 3 years (p < 0.001). Mean pRNFL delta was −5.3 µm (SD, 4.2). It was significantly negatively impacted by EDSS progression, cognitive decline, higher age and disease duration, while positively impacted by disease-modifying therapy (DMT). Conclusion: Cross-sectional and longitudinal monitoring of pRNFL is useful as a biomarker for prediction of physical and cognitive disability progression in patients with RRMS in everyday clinical practice.

Paroxysmal and unusual symptoms as first clinical manifestation of multiple sclerosis do not indicate benign prognosis—The PaSiMS II study

Background Paroxysmal (PS) and unusual symptoms (US) account for approximately 1.6% of initial manifestations of multiple sclerosis (MS) and have comparable conversion rates to clinically definite MS (CDMS) as classical bout onset symptoms (CS). However, long-term prognosis and clinical outcome of patients experiencing PS or US as first clinical manifestation are unclear. Methods Clinical, MRI and cerebrospinal fluid data were obtained retrospectively and patients presenting with PS or US were compared to patients with CS presentation. Results In a cohort of 532 relapsing onset MS patients followed for a mean period of 11.4 years (SD 3.6), 10 (1.9%) patients initially presented with PS/US. PS/US patients received disease modifying treatment (DMT) in a significantly smaller proportion immediately after the first clinical symptom (30% vs. 61.7%; p = 0.021) and during the observation period (60% vs. 83.5%; p = 0.033). In multivariate models correcting for sex, age at initial symptoms, complete remission of initial symptoms, total number of T2 and contrast-enhancing lesions, presence of oligoclonal bands and DMT exposure, PS/US were not associated with lower annualized relapse rate or lower EDSS over time. Conclusion In addition to a similar conversion rate to CDMS, patients presenting with PS/US at disease onset display very similar relapse and disability rates as patients with CS onset. Consequently, initial presentation with PS/US does not indicate benign or atypical MS, but requires DMT initiation based on the same criteria as in CS patients.

Change of olfactory function as a marker of inflammatory activity and disability progression in MS

Background: Impaired olfactory threshold has been reported in early inflammatory phases of MS, while impaired odor identification was associated with more widespread disability. Objective: To prospectively assess the development of olfactory function and its correlation with relapse and disability progression. Methods: In this prospective, 3-year longitudinal study on 151 MS patients and 30 healthy controls, three different qualities of olfactory function (threshold, discrimination, and identification) were quantified using the Sniffin’ Sticks test. The influence of relapses and disability on olfactory function was analyzed at different time points and in a multivariate model. Results: Discrimination and identification capability significantly worsened over 3 years, while threshold did not. Threshold was markedly impaired in patients with relapse activity within 12 months, recovered in the absence of relapse, and was associated with a 2.5-fold increased risk of relapse. Deterioration of discrimination and identification was irreversible and both strongly associated with and predictive of EDSS progression. Conclusion: Olfactory function changes over time in MS. Threshold impairment is transient and predicts inflammatory disease activity, while odor identification and discrimination are associated with disability progression. Olfactory dysfunction might be a useful and easily obtainable parameter to monitor patients with regard to inflammation and neurodegeneration in MS.

Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-β, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-β, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.