Search

Peter Joseph Jongen,1,2 Ludovicus G Sinnige,3 Björn M van Geel,4 Freek Verheul,5 Wim I Verhagen,6 Ruud A van der Kruijk,7 Reinoud Haverkamp,8 Hans M Schrijver,9 Jacoba C Baart,10 Leo H Visser,11 Edo P Arnoldus,12 Herman Jacobus Gilhuis,13 Paul Pop,14 Monique Booy,15 Marco Heerings,16 Anton Kool,17 Esther van Noort17 1Department of Community and Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, 2MS4 Research Institute, Nijmegen, 3Multiple Sclerosis Centre Leeuwarden, Medical Centre Leeuwarden, Leeuwarden, 4Department of Neurology, Medical Centre Alkmaar, Alkmaar, 5Department of Neurology, Groene Hart Hospital, Gouda, 6Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, 7Department of Neurology, Slingeland Hospital, Doetinchem, 8Department of Neurology, Zuwe Hofpoort Hospital, Woerden, 9Multiple Sclerosis Centre, Westfries Gasthuis, Hoorn, 10Department of Neurology, Ziekenhuisgroep Twente, Almelo-Hengelo, 11Multiple Sclerosis Centre Midden Brabant, St Elisabeth Hospital, Tilburg, 12Multiple Sclerosis Centre Midden Brabant, Tweesteden Hospital, 13Department of Neurology, Reinier de Graaf Gasthuis, Delft, 14Department of Neurology, Viecuri Medical Centre, Venlo-Venray, 15Multiple Sclerosis Centre, Amphia Hospital, Breda, 16MH Advies en organisatiebureau, Assen, 17Curavista bv, Geertruidenberg, the Netherlands Background: MSmonitor is an interactive web-based program for self-management and integrated, multidisciplinary care in multiple sclerosis.Methods: To assess the utilization and valuation by persons with multiple sclerosis, we held an online survey among those who had used the program for at least 1 year. We evaluated the utilization and meaningfulness of the program’s elements, perceived use of data by neurologists and nurses, and appreciation of care, self-management, and satisfaction.Results: Fifty-five persons completed the questionnaire (estimated response rate 40%). The Multiple Sclerosis Impact Profile (MSIP), Medication and Adherence Inventory, Activities Diary, and electronic consultation (e-consult) were used by 40%, 55%, 47%, and 44% of respondents and were considered meaningful by 83%, 81%, 54%, and 88%, respectively. During out-patient consultations, nurses reportedly used the MSmonitor data three to six times more frequently than neurologists. As to nursing care, more symptoms were dealt with (according to 54% of respondents), symptoms were better discussed (69%), and the overall quality of care had improved (60%) since the use of the program. As to neurological care, these figures were 24%, 31%, and 27%, respectively. In 46% of the respondents, the insight into their symptoms and disabilities had increased since the use of the program; the MSIP, Activities Diary, and e-consult had contributed most to this improvement. The overall satisfaction with the program was 3.5 out of 5, and 73% of the respondents would recommend the program to other persons with multiple sclerosis.Conclusion: A survey among persons with multiple sclerosis using the MSmonitor program showed that the MSIP, Medication and Adherence Inventory, Activities Diary, and e-consult were frequently used and that the MSIP, Medication and Adherence Inventory, and e-consult were appreciated the most. Moreover, the quality of nursing care, but not so neurological care, had improved, which may relate to nurses making more frequent use of the MSmonitor data than neurologists. Keywords: patient-reported outcome, impact, adherence, diary, inventory, e-consult

Peter Joseph Jongen,1,2 Ludovicus G Sinnige,3 Björn M van Geel,4 Freek Verheul,5 Wim l Verhagen,6 Ruud A van der Kruijk,7 Reinoud Haverkamp,8 Hans M Schrijver,9 J Coby Baart,10 Leo H Visser,11 Edo P Arnoldus,12 H Jacobus Gilhuis,13 Paul Pop,14 Monique Booy,15 Wim Lemmens,16 Rogier Donders,16 Anton Kool,17 Esther van Noort17 1Department of Community and Occupational Medicine, University Medical Center Groningen, University Groningen, Groningen, 2MS4 Research Institute, Nijmegen, 3Multiple Sclerosis Centre Leeuwarden, Medical Centre Leeuwarden, Leeuwarden, 4Department of Neurology, Medical Centre Alkmaar, Alkmaar, 5Department of Neurology, Groene Hart Hospital, Gouda, 6Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, 7Department of Neurology, Slingeland Hospital, Doetinchem, 8Department of Neurology, Zuwe Hofpoort Hospital, Woerden, 9Multiple Sclerosis Centre, Westfries Gasthuis, Hoorn, 10Department of Neurology, Ziekenhuisgroep Twente, Almelo-Hengelo, 11Multiple Sclerosis Centre Midden Brabant, St Elisabeth Hospital, 12Multiple Sclerosis Centre Midden Brabant, Tweesteden Hospital, Tilburg, 13Department of Neurology, Reinier de Graaf Gasthuis, Delft, 14Department of Neurology, Viecuri Medical Centre, Venlo-Venray, 15Multiple Sclerosis Centre, Amphia Hospital, Breda, 16Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, 17Curavista bv, Geertruidenberg, the Netherlands Background: There is a growing need to offer persons with multiple sclerosis (PwMS) possibilities for self-management and to integrate multidisciplinary health data. In 2009–2014 we developed a patient-reported outcome based, interactive, web-based program (MSmonitor) for (self-)monitoring, self-management and integrated, multidisciplinary care in MS.Methods: The notions underlying the MSmonitor concept and the program’s elements are described. We analyze MSmonitor’s role in the self-management of fatigue by retrospective comparison of fatigue and health-related quality of life (HRQoL) before and after usage of specific elements of MSmonitor, and by a correlative analysis between frequency of usage and fatigue change.Results: After a step-wise development the program comprises six validated questionnaires: Multiple Sclerosis Impact Profile, Modified Fatigue Impact Scale-5 items (MFIS-5), Hospital Anxiety and Depression Scale, Multiple Sclerosis Quality of Life-54 items, and the 8-item Leeds Multiple Sclerosis Quality of Life (LMSQoL) questionnaires; two inventories: Medication and Adherence Inventory, Miction Inventory; two diaries: Activities Diary, Miction Diary; and two functionalities: e-consult and personal e-logbook. The program is now used in 17 hospitals by 581 PwMS and their neurologists, MS nurses, physical therapists, rehabilitative doctors, continence nurses, and family doctors. Those PwMS (N=105) who used the LMSQoL and MFIS-5 questionnaires at least twice in a period of up to 6 months, showed improved HRQoL (P

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform – MSBase – has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool. [ABSTRACT FROM AUTHOR]

Purpose: Cognitive impairments frequently occur in children and adolescents with acquired brain injury (ABI), causing significant disabilities in daily life. Current paper-and-pencil neuropsychological tests do not capture the complexity of daily life activities, often failing to objectify subtle cognitive impairments. Virtual Reality (VR) simulations might overcome this discrepancy, as it resembles daily life situations. The aim of this study was to evaluate the feasibility, user-experience and preference of a VR simulation with a non-immersive (computer monitor; CM)) and immersive (head mounted display; HMD)) VR setup., Methods: Children and adolescents with ABI (n = 15) and typically developing children and adolescents (n = 21) completed a VR-task with a CM and HMD., Results: Both VR setups were feasible for children and adolescents with ABI. User-experience was enhanced with the HMD compared to CM in both groups. Side effects were low and comparable for both groups, and there were no differences between setups (HMD and CM). The majority of the children and adolescents with ABI preferred the HMD., Conclusion: VR simulations appear feasible to use in paediatric rehabilitation. The preference for a VR setup should be discussed with the child. Further research is needed to develop more sensitive measures to further explore the potential of VR for cognitive assessment.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested., Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis., Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed., Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p  < 0.001), longer disease duration (HR = 1.01, p  = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p  < 0.001), more rapid disability trajectory (HR = 2.82, p  < 0.001) and greater number of relapses in the previous year (HR = 1.07, p  = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p  = 0.039) and disease-modifying therapy exposure (HR = 0.71, p  = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion., Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.

Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing., Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS., Methods: We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed., Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births., Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested., Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes., Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44 449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed., Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse., Main Outcomes and Measures: Cumulative hazard of disability progression., Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P = .003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P = .01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P = .26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P = .16)., Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation., Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time., Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics., Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143; 16.8%), moderate ( n = 378; 44.3%), or severe ( n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively., Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs)., Objective: To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion., Methods: Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices., Results: A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities., Conclusion: This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.

Background: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years., Methods: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models., Findings: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006)., Interpretation: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles., Funding: National Health and Medical Research Council, and the University of Melbourne., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy., Methods: The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6 and 6-6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted., Results: For the EDSS 3-6, 4-6 and 6-6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92-1.11) and postbaseline (2.15-2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58-3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72-0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results., Conclusions: Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis., Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted., Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25-0.29)), cerebellar (β = 0.35 (0.30-0.39)) and bowel/bladder (β = 0.42 (0.35-0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains., Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process., Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression., Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10 -23 ). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10 -17 ). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10 -265 )., Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In a prospective multi-center observational study, we evaluated the frequency, severity, and impact on activities of daily living (ADL) of adverse effects (AEs) of high-dose intravenous methylprednisolone (IVMP) in relapsing remitting multiple sclerosis (MS) patients with a relapse. Online self-report questionnaires stating IVMP's most common AEs were completed at baseline, the 2nd day of treatment, and 1 day and 1 week after treatment. Eighty-five patients were included, 66 completed the baseline questionnaire, and 59 completed at least one post-baseline questionnaire. Patients reported on average 4 (median) AEs; two (3.4 %) reported no AE. Most frequent was change in taste (61 %), facial flushing (61 %), sick/stomach pain (53 %), sleep disturbance (44 %), appetite change (37 %), agitation (36 %), and behavioral changes (36 %). Of all AEs, 34.3 % were severe and 37.9 % impacted on ADL. A 3-day course resulted in 4 (median) AEs and a 5-day course in 7. All patients with high disease impact had two or more AEs, compared with 79 % of those with low impact (p < 0.01). Of patients with high disability, 45 % had severe AEs, compared with 16 % of those with low disability. Severe central nervous system (CNS)-related AEs occurred two times more frequently in patients with high disease impact, and two-and-a-half times more frequently in patients with high disability. Therefore, in virtually all patients, high-dose IVMP leads to AEs, with about one of three AEs being severe with impact on ADL. Patients with high disease impact or high disability may experience more (severe) AEs, due to a higher occurrence of severe CNS-related AEs.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis., Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed., Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009)., Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100., (© 2016 American Neurological Association.)

Objective: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS)., Methods: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence., Results: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation., Conclusion: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications., (© The Author(s), 2015.)

Background: We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries., Methods: The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity., Results: First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) ( p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups., Conclusions: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients., Classification of Evidence: This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA.

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions., Methods: Centers from 18 countries with >20 cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of >1 year and <30 years at time of EDSS measurement were evaluated. The MS Severity Score (MSSS) was used as a measure of disease progression. Comparisons among regions (North America, Europe, Australia and LA), hemispheres and countries were performed., Results: A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%); North America, 1609 (16.7%); Australia, 1119 (11.6%); and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres ( p  = 0.68), regions ( p  = 0.96) or countries ( p  = 0.50)., Conclusions: Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.

Background: The results of head-to-head comparisons of injectable immunomodulators (interferon β, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed., Objective: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators., Methods: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted., Results: Of the 3326 included patients, 345-1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon β-1a relative to intramuscular interferon β-1a and interferon β-1b (p≤0.001). No differences in 12-month confirmed progression of disability were observed., Conclusion: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely., (© The Author(s), 2014.)

Background: Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females., Methods: Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS., Results: In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change., Conclusion: Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.

Objective: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset., Methods: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache., Results: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%)., Conclusions: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting., (© 2015 American Academy of Neurology.)

Objective: To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS)., Methods: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression., Results: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening., Interpretation: This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.

Importance: After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain., Objective: To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS., Design, Setting, and Participants: Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted., Exposures: Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy., Main Outcomes and Measures: Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression., Results: Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P=.009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P=.04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P=.02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P=.005), and lower hazard of treatment discontinuation (HR, 0.55; P=.04) compared with the injectable group., Conclusions and Relevance: Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.

Objective: To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets., Methods: Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group])., Results: Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch., Interpretation: Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.

Objective: In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents., Methods: Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses., Results: Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p < 0.001)., Interpretation: This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden., (© 2014 American Neurological Association.)

Objective: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude., Methods: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak., Results: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028)., Interpretation: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere., (© 2014 American Neurological Association.)

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype., Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis., Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease., Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance., (© The Author(s), 2014.)

Background: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies., Objective: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse., Methods: An observational case-control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses., Results: The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model., Conclusion: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.

Objective: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod., Methods: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod., Results: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001-0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2-4 months compared to no gap (HR 2.10; p = 0.041)., Conclusions: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse., Classification of Evidence: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies.

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Objectives: To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics., Methods: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded., Results: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages., Conclusions: Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Objective: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period., Methods: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria., Results: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets., Conclusions: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) status-for the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power., Methods: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome., Results: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude (p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change (p < 0.001)., Conclusions: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Background: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry., Methods: Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5-year EDSS scores., Results: Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7-12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years; one-point progression risk was greater for EDSS score of >2 than ≤2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4., Conclusions: EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5-year outcome in individuals 4 years after disease onset.

Background: A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out., Objective: In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas., Methods: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births., Results: Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS., Conclusions: Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.

Background: Previously, mainly retrospective and a few important prospective studies postulated the role of sepsis or systemic inflammatory response syndrome (SIRS), multiple organ failure, and the use of medication as causative factors for the development of critical illness polyneuropathy and myopathy (CIPNM). This study aimed to identify the risk factors in the development of CIPNM., Methods: Prospectively, we studied 98 patients who were on artificial respirators for the development of CIPNM. The Acute Physiology and Chronic Health Evaluation (APACHE) III score, presence of SIRS, and sepsis severity score at entry; the dosage of midazolam, vecuronium, and steroids at entry and day 7 of artificial respiration; and the use of aminoglycosides at entry were related with time to CIPNM or time of last follow-up. The Kaplan-Meier method and log-rank test were used., Results: Thirty-two patients (33%) developed CIPNM. After multivariate analysis, it was found that the APACHE III score and the presence of SIRS were significantly related with risk for the development of CIPNM. No significant relation was found for the use of midazolam, vecuronium, or steroids. Based on a risk index from a Cox regression model with APACHE III score and presence of SIRS as outcomes, three groups could be constructed with low-, medium-, and high-risk patients for the development of CIPNM., Conclusions: The APACHE III score, a quantitative index of disease severity based on clinical and laboratory physiologic data, is a valuable predictor for the development of CIPNM in patients in the intensive care unit. Together with the presence of SIRS, it can be used to estimate the risk of developing CIPNM for patients on artificial respirators.

The insulin autoimmune syndrome (IAS) is the third leading cause of spontaneous hypoglycaemia in Japan. Here, we describe the second Dutch case. An 81-year-old man was analysed for collapse and attacks of disorientation, and was found to be hypoglycaemic during such an episode. The performed fasting test appeared to be positive. High levels of insulin and C-peptide postprandially and insulin antibodies were found. IAS was diagnosed.

The Coulter STKS is a fully automated haematology analyser which quantitatively measures and computes haematological quantities including a full "five-part" differential. The aim of this study was to evaluate whether the Coulter STKS can be used for screening purposes in a non-academic clinic. Results from the haemocytometry part of the apparatus correlated very well with those from the Coulter S Plus IV. Reasonable to good correlations were obtained with the standard manual 100-cell differential for neutrophils, lymphocytes, monocytes and eosinophils. Significantly higher percentages of monocytes were found by microscopic observation than by the STKS. Samples from 1080 patients were analysed on the STKS, and manual differentials were also performed. After revision of discrepancies and with the exclusion of neonatal samples, a good numerical agreement for the "five-part" differential was obtained. The STKS gave 1.8% false negatives, and both diagnostic sensitivity (96.3%) and specificity (83.3%) were high. A false negative rate of 1.9% was found for the indication left-shift, with a predictive value of a negative test of 97.4%. The predictive value of a positive test, however, was only 40.3%. An authorization procedure was implemented to reduce false negative samples. The routine laboratory work load for our differentials can be reduced by up to 70%. The Coulter STKS gave a high number of suspect flags for neonatal samples (75%) and is therefore not suitable for screening neonates.

Bovine heart cytochrome c oxidase consists of 12 stoicheiometric polypeptide chains of at least 11 different types. The enzyme contains 14--16 cysteine residues; the distribution of nearly all cysteine residues over the subunits has been established. In native cytochrome c oxidase two thiol groups reacted rapidly and stoicheiometrically with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). These thiol groups are located in subunits I and III, respectively. This implies that subunit I is not fully buried in the hydrophobic core of the enzyme. After dissociation of the enzyme by sodium dodecyl sulphate more thiol groups became available to DTNB, in addition to those in subunits I and III, at least one in subunit II, two in fraction V/VI and one to two in the smallest subunit fraction. It is shown that separation of the subunits of cytochrome c oxidase by gel permeation chromatography in the presence of sodium dodecyl sulphate depends on the pH of the elution medium. The elution volume of subunits I, III and VII is dependent on pH, that of the others independent.