ORCID Profile
0000-0003-3778-1376
Current Organisations
Royal Melbourne Hospital
,
University of Melbourne
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Central Nervous System | Pattern Recognition and Data Mining | Medical Devices | Artificial Intelligence and Image Processing
Expanding Knowledge in the Information and Computing Sciences | Health and Support Services not elsewhere classified |
Publisher: SAGE Publications
Date: 11-07-2016
Abstract: Randomised clinical trials are the primary source of evidence, guiding the use of disease-modifying drugs in multiple sclerosis. However, the spectrum of questions that can be answered in the trial setting is relatively narrow. ‘Real-world’ observational data analysis has always been the major source of evidence for epidemiology, aetiology, outcomes and prognostics, but is now also increasingly used to study treatment effectiveness. While analyses of observational cohorts typically offer superior power, generalisability and duration of follow-up relative to prospective randomised trials, they are also subject to multiple biases. It is the role of researchers to mitigate bias and to ensure the results of observational studies are robust and valid. In this review of observational data research, we provide an overview of the inherent biases, the available mitigation strategies, and the state and direction of contemporary treatment outcomes research. The review will help clinicians critically appraise published results of observational studies.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-10-2019
DOI: 10.1212/WNL.0000000000008319
Abstract: Disease-modifying drugs are changing the natural history of multiple sclerosis (MS). However, currently available clinical trial data are insufficient to develop accurate personalized treatment algorithms to assign the best possible treatment to each person with MS according to disease features, treatment history, and comorbidities. Such accurate algorithms would require the presence of numerous head-to-head trials of long duration, which is virtually impossible, given the economic costs, required time, and difficulties with attrition. Thus, efforts are being made to compare relative treatment efficacy through observational designs, using large multicenter prospective cohorts or “big MS data,” and network meta-analyses. Although such studies can yield useful information, they are liable to biases and their results should be confirmed in other study populations, including smaller, single-center cohorts, where some of these biases can be minimized. In this View article, we analyze the potential benefits and biases of all these strategies alternative to head-to-head trials in MS. Finally, we propose the combination of all these types of studies to obtain reliable head-to-head drug comparisons in the absence of randomized designs.
Publisher: Wiley
Date: 14-09-2023
DOI: 10.1111/ENE.16059
Publisher: JMIR Publications Inc.
Date: 12-10-2020
Abstract: ladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied. his study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3. his will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance. his study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021. his will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS. his study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165). ERR1-10.2196/24969
Publisher: SAGE Publications
Date: 24-04-2018
Publisher: Informa UK Limited
Date: 12-2012
Publisher: American Society of Neuroradiology (ASNR)
Date: 12-09-2019
DOI: 10.3174/AJNR.A6195
Publisher: SAGE Publications
Date: 2019
Abstract: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1–3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test–retest reliability and the discriminative ability of MSReactor. A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them ‘very anxious’. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified.
Publisher: BMJ
Date: 27-10-2023
Publisher: Public Library of Science (PLoS)
Date: 21-05-2013
Publisher: SAGE Publications
Date: 05-12-2014
Abstract: 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. We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. 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. Of the 3326 included patients, 345–1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated % 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. 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.
Publisher: Oxford University Press (OUP)
Date: 05-2020
Abstract: 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.
Publisher: SAGE Publications
Date: 21-07-2015
Abstract: 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). 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. 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 .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 .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. 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.
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2019
DOI: 10.1101/671651
Abstract: Alzheimer’s disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of taurelated neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies. We investigated this possibility using data from the National Alzheimer’s Coordinating Center (NACC) database. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment. Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains. These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.
Publisher: Oxford University Press (OUP)
Date: 03-03-2018
DOI: 10.1093/BRAIN/AWY056
Publisher: Wiley
Date: 24-08-2023
DOI: 10.1111/ENE.16046
Abstract: The validity, reliability, and longitudinal performance of the Patient‐Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. We included relapsing–remitting MS patients with an Expanded Disability Status Scale (EDSS) score of less than 4. Validity and test–retest reliability was examined. Longitudinal data were analysed with mixed‐effect modelling and Cohen's kappa for concordance in confirmed disability progression (CDP). We recruited a total of 1093 participants, of whom 904 had complete baseline data. The baseline correlation between PDDS and EDSS was weak ( ρ = 0.45, p 0.001). PDDS had stronger correlations with patient‐reported outcomes (PROs). Conversely, EDSS had stronger correlations with age, disease duration, Kurtzke's functional systems and processing speed test. PDDS test–retest reliability was good to excellent (concordance correlation coefficient = 0.73–0.89). Longitudinally, PDDS was associated with EDSS, age and depression. A higher EDSS score was associated with greater PDSS progression. The magnitude of these associations was small. There was no concordance in CDP as assessed by PDDS and EDSS. The PDDS has greater correlation with other PROs but less correlation with other MS‐related outcome measures compared to the EDSS. There was little correlation between PDDS and EDSS longitudinally. Our findings suggest that the PDDS scale is not interchangeable with the EDSS.
Publisher: SAGE Publications
Date: 27-07-2022
DOI: 10.1177/13524585221111677
Abstract: Patients with relapsing–remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. To determine predictors of relapse hazard when switching to cladribine. Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03–5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01–4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65–14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35–12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91–0.99). Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-10-2022
DOI: 10.1212/WNL.0000000000201029
Abstract: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43–0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08–0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1–2 ARR: 0.80, 0.70–0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, −0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1–10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72–0.81) and disability accumulation (0.73, 0.65–0.80). The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
Publisher: Oxford University Press (OUP)
Date: 18-10-2013
DOI: 10.1093/BRAIN/AWT281
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2017
DOI: 10.1038/NRNEUROL.2016.188
Abstract: The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.
Publisher: Oxford University Press (OUP)
Date: 27-06-2023
Abstract: Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis which is characterised by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate-efficacy immunotherapy in a geographically erse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalised definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate-efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude (median hazard ratio = 1.21, 95% credible interval [1.16, 1.26]), higher national multiple sclerosis prevalence (1.07 [1.03, 1.11]), male sex (1.30 [1.22, 1.39]), older age at onset (1.35 [1.30, 1.39]), higher disability (2.40 [2.34, 2.47]) and frequent relapses (1.18 [1.15, 1.21]) at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate-efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis (0.76 [0.73, 0.79]) and reduced the effect of latitude (interaction: 0.95 [0.92, 0.99]). At the country-level, patients in Oman, Kuwait, and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate-efficacy immunotherapy can mitigate some of this geographically co-determined risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-03-2021
DOI: 10.1212/NXI.0000000000000979
Abstract: To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL. Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models. Age was not associated with the rate of BVL (β = −0.003 Cohen f2 = 0.0005 adjusted p = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = −0.012 Cohen f2 = 0.004 adjusted p = 4 × 10 −5 ). Analysis of association between tissue-specific brain volume changes and age (β = −0.019 to −0.011 adjusted p = 0.028–1.00) or disease duration (β = −0.028 to −0.008 adjusted p = 0.16–0.96) confirmed these results. Although increase in the relapse rate (β = 0.10 adjusted p = 9 × 10 −9 ), Expanded Disability Status Scale (EDSS β = 0.17 adjusted p = 8 × 10 −5 ), and EDSS change (β = 0.15 adjusted p = 2 × 10 −5 ) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = −0.29 Cohen f2 = 0.133 p = 5.5 × 10 −8 ). The rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.
Publisher: Oxford University Press (OUP)
Date: 09-2020
Abstract: In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
Publisher: BMJ
Date: 30-09-2022
Abstract: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. Using the global MSBase registry, we identified patients who were years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15–17) years. Older age at symptom onset (exp(β)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-09-2023
Publisher: SAGE Publications
Date: 06-04-2017
Abstract: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. 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. 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. Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.
Publisher: Wiley
Date: 16-06-2014
DOI: 10.1111/ENE.12479
Abstract: The prevalence of osteopenia and osteoporosis is higher amongst patients with multiple sclerosis in comparison with the general population. In addition to the general determinants of bone health, two factors may contribute to reduced bone mineral density in multiple sclerosis: physical disability and corticosteroid therapy. The aim of this study was to examine the effect of physical disability and steroid exposure on bone health in weight-bearing bones and spine and on the incidence of low-trauma fractures in multiple sclerosis. In this retrospective analysis of prospectively collected data, associations between bone mineral density (at the femoral neck, total femur and the lumbar spine) and its change with disability or cumulative steroid dose were evaluated with random-effect models adjusted for demographic and clinical determinants of bone health. The incidence of low-trauma fractures during the study follow-up was evaluated with Andersen-Gill models. Overall, 474 and 438 patients were included in cross-sectional and longitudinal analyses (follow-up 2347 patient-years), respectively. The effect of severely impaired gait was more apparent in weight-bearing bones (P ≤ 10(-15) ) than in spine (P = 0.007). The effect of cumulative steroid dose was relatively less pronounced but diffuse (P ≤ 10(-4) ). Risk of low-trauma fractures was associated with disability (P = 0.02) but not with cumulative steroid exposure and was greater amongst patients with severely impaired gait (annual risk 3.5% vs. 3.0%). Synergistic effects were found only between cumulative steroid dose in patients ambulatory without support (P = 0.02). Bone health and the incidence of low-trauma fractures in multiple sclerosis are more related to impaired gait than to extended corticosteroid therapy.
Publisher: American Medical Association (AMA)
Date: 11-2018
Publisher: BMJ
Date: 06-07-2023
Abstract: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.MSARD.2019.01.003
Abstract: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing. To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS. 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. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1007/S00415-018-9126-Y
Abstract: Patients with multiple sclerosis who experience disease breakthrough often switch disease-modifying therapy (DMT). To compare treatment effectiveness of switch to highly effective DMT (heDMT) with switch to moderately effective DMT (meDMT) for patients who switch due to disease breakthrough defined as at least one relapse within 12 months of their treatment switch. We retrieved data from The Danish Multiple Sclerosis Registry on all relapsing-remitting MS patients with expanded disability status scale (EDSS) less than 6 who experienced disease breakthrough. We used propensity score matching to compare annualized relapse rates (ARRs), time to first confirmed relapse, time to first confirmed EDSS worsening and time to first confirmed EDSS improvement. Each matched group comprised 404 patients. Median follow-up time was 3.2 years [interquartile range (IQR) 1.7-5.8]. ARRs were 0.22 (0.19-0.27) with heDMT and 0.32 (IQR 0.28-0.37) with meDMT relapse rate ratio was 0.70 (95% CI 0.56-0.86 p = 0.001). Escalation to heDMT reduced the hazard of reaching a first relapse (HR 0.65 95% CI 0.53-0.80 p < 0.001). We found no evidence of delayed disability worsening (HR 0.83 95% CI 0.62-1.10 p = 0.20) and weak evidence of disability improvement (HR 1.33 95% CI 1.00-1.76 p = 0.05) with heDMT. Switching to heDMT is associated with reduced ARR and delay of first relapse compared with switching to meDMT. Patients on DMT who experience relapses should escalate therapy to heDMT.
Publisher: SAGE Publications
Date: 2021
Abstract: To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features. We retrospectively analysed adult patients at the Royal Melbourne Hospital electronically identified to have ICD codes for MS and seizures and/or epilepsy between 1996 to 2019, utilising paper and electronic-based records. Of the 2,125 MS patients identified, 16 (0.75%) experienced epileptic seizures during a mean follow-up period of 12.9 years. Median age of MS diagnosis (SD) was 38 (9.3) years. Four patients had relapsing remitting MS (25%), 10 secondary progressive MS (63.5%), and 2 primary progressive MS (12.5%). More than two-thirds of patients had seizure onset following the diagnosis of MS, and the majority of these had advanced disease (approximate EDSS ) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures. The estimated prevalence of seizures in our cohort was lower than in previous studies (0.75 vs 2–4%). In most cases, seizures occurred after the diagnosis of MS in the context of advanced disease. Further studies are required to determine if MS disease modifying treatments reduce the risk of seizures in this cohort.
Publisher: American Medical Association (AMA)
Date: 04-2015
DOI: 10.1001/JAMANEUROL.2014.4147
Abstract: 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. 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. 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. Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. 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. 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.
Publisher: Copernicus GmbH
Date: 29-07-2015
Abstract: Abstract. Iron availability in the Southern Ocean controls phytoplankton growth, community composition and the uptake of atmospheric CO2 by the biological pump. The KEOPS-2 (KErguelen Ocean and Plateau compared Study 2) "process study", took place around the Kerguelen Plateau in the Indian sector of the Southern Ocean. This is a region naturally fertilised with iron on the scale of hundreds to thousands of square kilometres, producing a mosaic of spring blooms which show distinct biological and biogeochemical responses to fertilisation. This paper presents biogeochemical iron budgets (incorporating vertical and lateral supply, internal cycling, and sinks) for three contrasting sites: an upstream high-nutrient low-chlorophyll reference, over the plateau and in the offshore plume east of the Kerguelen Islands. These budgets show that distinct regional environments driven by complex circulation and transport pathways are responsible for differences in the mode and strength of iron supply, with vertical supply dominant on the plateau and lateral supply dominant in the plume. Iron supply from "new" sources (diffusion, upwelling, entrainment, lateral advection, atmospheric dust) to the surface waters of the plume was double that above the plateau and 20 times greater than at the reference site, whilst iron demand (measured by cellular uptake) in the plume was similar to that above the plateau but 40 times greater than at the reference site. "Recycled" iron supply by bacterial regeneration and zooplankton grazing was a relatively minor component at all sites ( 8 % of new supply), in contrast to earlier findings from other biogeochemical iron budgets in the Southern Ocean. Over the plateau, a particulate iron dissolution term of 2.5 % was invoked to balance the budget this approximately doubled the standing stock of dissolved iron in the mixed layer. The exchange of iron between dissolved, biogenic particulate and lithogenic particulate pools was highly dynamic in time and space, resulting in a decoupling of the iron supply and carbon export and, importantly, controlling the efficiency of fertilisation.
Publisher: SAGE Publications
Date: 06-10-2021
DOI: 10.1177/13524585211047977
Abstract: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. We analyzed 369 blood s les from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL ( 90th or 90th percentile). In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9% OR = 4.25, 95% CI: [2.02, 8.95] p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36% 95% CI = [−0.60, −0.13] p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2013
DOI: 10.1038/GENE.2013.17
Abstract: It has not yet been established whether genetic predictors of multiple sclerosis (MS) susceptibility also influence disease severity and accumulation of disability. Our aim was to evaluate associations between 16 previously validated genetic susceptibility markers and MS phenotype. Patients with clinically isolated syndrome verified by positive magnetic resonance imaging (MRI) and cerebrospinal fluid findings (n=179) were treated with interferon-β. Disability and volumetric MRI parameters were evaluated regularly for 2 years. Sixteen single-nucleotide polymorphisms (SNPs) previously validated as predictors of MS susceptibility in our cohort and their combined weighted genetic risk score (wGRS) were tested for associations with clinical (conversion to MS, relapses and disability) and MRI disease outcomes (whole brain, grey matter and white matter volumes, corpus callosum cross-sectional area, brain parenchymal fraction, T2 and T1 lesion volumes) 2 years from disease onset using mixed-effect models. We have found no associations between the tested SNPs and the clinical or MRI outcomes. Neither the combined wGRS predicted MS activity and progression over 2-year follow-up period. Power analyses confirmed 90% power to identify clinically relevant changes in all outcome variables. We conclude that the most important MS susceptibility loci do not determine MS phenotype and disease outcomes.
Publisher: BMJ
Date: 28-09-2022
Abstract: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3–4. A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297 35.9%), a moderate (n=1936 53.6%) and a severe (n=380 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-06-2021
DOI: 10.1212/WNL.0000000000012084
Abstract: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Using data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. We included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27–0.32), fell to 0.19 (0.14–0.24) in the third trimester, and increased to 0.59 (0.51–0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28–0.49) and 0.29 (0.22–0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60–0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04–0.32], p 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41–0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.AUTNEU.2016.08.015
Abstract: Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia.
Publisher: Elsevier BV
Date: 03-1995
Publisher: BMJ
Date: 28-09-2017
Abstract: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy. 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. 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. 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.
Publisher: Informa UK Limited
Date: 14-05-2022
DOI: 10.1080/10428194.2022.2074990
Abstract: Chimeric antigen receptor T-cell (CAR-T) therapy is a promising immunotherapy approved for hematological malignancies. Despite its effectiveness, clinically significant rates of toxicity, including immune effector cell associated neurotoxicity syndrome (ICANS), limit its widespread use. In certain contexts, ICANS may occur in up to one-third of patients using commercially available CAR-T therapies. The syndrome presents with a range of neurological signs and symptoms, as well as a variety of neuroimaging manifestations reported in the literature. A systematic review of the literature was performed. The systematic search strategy identified 24 studies discussing the neuroimaging appearances associated with ICANS. Imaging findings are more common in patients with higher grade neurotoxicity. The neuroimaging findings are heterogeneous, but can be grouped either anatomically (white matter, gray matter, brainstem, or leptomeninges) or pathologically (ischemic changes, hemorrhages, or cerebral edema). An understanding of the imaging manifestations of ICANS has the potential to impact the management of patients.
Publisher: Wiley
Date: 05-07-2010
Publisher: Springer Science and Business Media LLC
Date: 18-03-2022
DOI: 10.1007/S40261-022-01129-7
Abstract: There is growing interest in the issue of disease reactivation in multiple sclerosis following fingolimod cessation. Relatively little is known about modifiers of the risk of post-cessation relapse, including the delay to commencement of new therapy and prior disease activity. We aimed to determine the rate of relapse following cessation of fingolimod and to identify predictors of relapse following cessation. Data were extracted from the MSBase registry in March 2019. Inclusion criteria were (a) clinically definite relapsing multiple sclerosis, (b) treatment with fingolimod for ≥ 12 months, (c) follow-up after cessation for ≥ 12 months, and (d) at least one Expanded Disability Status Scale score recorded in the 12 months before cessation. A total of 685 patients were identified who met criteria. The mean annualised relapse rate was 1.71 (95% CI 1.59, 1.85) in the year prior to fingolimod, 0.50 (95% CI 0.44, 0.55) on fingolimod and 0.43 (95% CI 0.38, 0.49) after fingolimod. Of these, 218 (32%) patients experienced a relapse in the first 12 months. Predictors of a higher relapse rate in the first year were: younger age at fingolimod cessation, higher relapse rate in the year prior to cessation, delaying commencement of new therapy and switching to low-efficacy therapy. Disease reactivation following fingolimod cessation is more common in younger patients, those with greater disease activity prior to cessation and in those who switch to a low-efficacy therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-04-2020
DOI: 10.1212/NXI.0000000000000714
Abstract: To determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS). This observational study included 163 patients (405 s les) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 s les) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models. From the sNfL s les ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort s les (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients. Low sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%–36.4%) of visits in clinically stable patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2022
DOI: 10.1101/2022.09.08.22279617
Abstract: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking. Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. TRIPOD guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expended disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated on their area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. A temporal attention model was the best model. It achieved a ROC-AUC of 0·71 ± 0·01, an AUC-PR of 0·26 ± 0·02, a Brier score of 0·1 ± 0·01 and an expected calibration error of 0·07 ± 0·04. The history of disability progression is more predictive for future disability progression than the treatment or relapses. Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This makes these models ready for a clinical impact study. All our preprocessing and model code is available at debrouwer/ms_benchmark , making this task an ideal benchmark for predicting disability progression in MS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2010
Publisher: SAGE Publications
Date: 28-04-2014
Abstract: 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. 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. 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. Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2021
Publisher: SAGE Publications
Date: 30-09-2011
Abstract: Background: Information about cost of multiple sclerosis (MS) is available from a number of European countries, but no data from the Czech Republic have been published so far. Objective: The objective of this study was to establish the cost of MS in the Czech Republic, overall and by level of disease severity. Methods: Data on demographics, disease history, resource consumption and production losses were collected from 909 patients recruited in 7 MS centres in the Czech Republic. Annual costs were estimated in the societal perspective, using 2007 unit costs. To evaluate the relationship between disability and costs, patients were stratified into those with mild (67%), moderate (27%) and severe (10%) disability using the Expanded Disability Status Scale. Results: Mean total annual costs per patient were €12,272, of which 51% were direct medical costs, 4% direct non-medical costs and 45% indirect costs. The average annual costs in patients with mild, moderate and severe disability amounted to €9905, €14,064 and €22,880, respectively. Conclusion: The total costs of MS in the Czech Republic are estimated at €208.6 million per year. Consistent with other studies, the costs increase significantly with the severity of MS.
Publisher: BMJ
Date: 17-04-2023
Abstract: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Included patients comprised 1872 with PPMS (47% men 50% with activity) and 2575 with SPMS (32% men 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2–47.3) vs 43.9 (43.3–44.4) p .001), greater baseline disability, slower disability accrual (HR 0.86 (0.78–0.94) p .001) and similar age at wheelchair dependence. We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
Publisher: BMJ
Date: 28-07-2022
Abstract: Little is known about the comparative effectiveness of multiple sclerosis (MS) disease-modifying therapies (DMTs) on patient-reported outcomes in MS. We compared the effects of natalizumab to other DMTs in relation to MS symptom severity, quality of life, disability, disease progression and employment outcomes using real-world data. We included 2817 observations in 2015, 2016 and 2017 from 1382 participants in the Australian MS Longitudinal Study. Information on treatment, health and employment outcomes was prospectively collected by questionnaires. Marginal structural models with interaction terms for DMT×time were used to compare natalizumab and other comparator treatment groups. Natalizumab was associated with improvements over time, or general trends of improvement, in the severity of many symptoms and work productivity loss. Compared with any other DMTs, natalizumab was associated with superior effects over time for 8 of 23 patient-reported outcomes, with similar directions of effect observed for another 6, demonstrating consistency. There were no differences in effect for spasticity, fatigue, pain, feelings of depression, disability, European quality of life five dimension index, presenteeism and work status. Natalizumab did not perform significantly worse over time compared with any other DMTs for any of the outcomes. Natalizumab was associated with superior outcomes over time for many patient-reported health and employment outcomes when compared with other DMTs in this large prospective cohort study. These findings may influence treatment selection in clinical practice and future treatment cost-effectiveness analyses.
Publisher: Cold Spring Harbor Laboratory
Date: 20-07-2019
DOI: 10.1101/19002717
Abstract: The primary aim of the study was to determine whether patients with psychogenic non-epileptic seizures (PNES) have different personality profiles compared to patients with epileptic seizures (ES). The secondary aim was to determine whether any such personality differences could be used to efficiently screen for PNES in clinical settings. PNES and ES are often difficult to differentiate, leading to incorrect or delayed diagnosis. While the current gold-standard investigation is video-EEG monitoring (VEM), it is resource intensive and not universally available. Although some research has investigated the differential psychological profiles of PNES and ES patients, most studies have focused on symptoms of psychopathology. The lack of research using modern personality models in PNES and ES presents a gap in knowledge that this study aimed to address. A retrospective collection of data was conducted on patients who completed the NEO-Five Factor Inventory questionnaire during a VEM admission to the Royal Melbourne Hospital between 2002-2017. Patients were classified as either ES or PNES based on clinical consensus diagnosis. For patients with ES, type of epilepsy and laterality of seizure focus were also recorded. Personality differences were investigated using Bayesian linear mixed effects models. Receiver operating characteristic curve analysis was also performed to generate sensitivities and specificities of in idual personality scores. 305 patients were included in the study. The ‘openness to experience’ domain was the only personality factor demonstrating strong evidence for a group difference (BF 10 = 21.55, d = −0.43 [95% CI −0.71, −0.17]), with patients in the PNES group having higher scores compared to the ES group. Within the openness to experience domain, only the ‘aesthetic interest’ facet showed evidence for a group difference (BF 10 = 7.98, d = −0.39 [95% CI −0.66, −0.12]). ES patients had lower scores on these measures compared to the normal population, while PNES patients did not. Both openness to experience and aesthetic interest, however, showed poor sensitivities (53%, 46% respectively) and specificities (69%, 46% respectively) for classifying PNES and ES patients. There were no differences between personality profiles in Temporal Lobe Epilepsy (TLE) and non-TLE patients, or in laterality in TLE. Patients with ES exhibit lower openness to experience and aesthetic interest compared to patients with PNES and compared to the general population. Despite these differences, the relatively low sensitivity and specificity of these instruments suggests their use is limited in a clinical setting. Nevertheless, these findings open up new avenues of research using modern personality models to further understand patients with epilepsy and related presentations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-01-2020
DOI: 10.1212/CPJ.0000000000000800
Abstract: Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF. Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation. The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 10 9 /L was 2–4 months after discontinuation for patients treated in real-world data sets the median time to reach ALC ≥0.91 × 10 9 /L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 10 9 /L was 12–18 months vs 2–3 months in patients with lymphopenia persisting months. The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2–4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.
Publisher: Wiley
Date: 06-2016
DOI: 10.1002/ANA.24682
Abstract: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. 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. 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). 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 :89-100.
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000382130
Abstract: Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an in idual predisposition to certain phenotypic presentations may imply in idual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies.
Publisher: American Society of Neuroradiology (ASNR)
Date: 11-04-2013
DOI: 10.3174/AJNR.A3503
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-10-2020
DOI: 10.1212/WNL.0000000000010991
Abstract: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25–0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61–1.34), and those in the upper quartile of 1.14 (95% CI 0.59–2.18) (heterogeneity p = 0.012) this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46–0.72), 0.92 (95% CI 0.77–1.09,) and 1.29 (95% CI 0.97–1.71) heterogeneity p 0.0001). We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
Publisher: Cold Spring Harbor Laboratory
Date: 10-02-2021
DOI: 10.1101/2021.02.08.21251316
Abstract: People with multiple sclerosis (MS) are a vulnerable group for severe COVID-19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international s le of people with MS. Data from 12 data-sources in 28 countries were aggregated. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression. 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. Older age, progressive MS-phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.56,95%CI=1.01-2.41 aOR=2.43,95%CI=1.48-4.02) and ICU admission (aOR=2.30,95%CI=0.98-5.39 aOR=3.93,95%CI=1.56-9.89), though only rituximab was associated with higher risk of artificial ventilation (aOR=4.00,95%CI=1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.75,95%CI=1.29-2.38 aOR=2.76,95%CI=1.87-4.07) and ICU admission (aOR=2.55,95%CI=1.49-4.36 aOR=4.32,95%CI=2.27-8.23) but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalisation (aOR=1.86,95%CI=1.13-3.07 aOR=2.88,95%CI=1.68-4.92) and ICU admission (aOR=2.13,95%CI=0.85-5.35 aOR=3.23,95%CI=1.17-8.91), but only rituximab with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission, suggesting their use may be a risk factor for more severe COVID-19.
Publisher: SAGE Publications
Date: 25-11-2016
Abstract: 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). To examine determinants of second attack and validate a prognostic nomogram for in idualised risk assessment of clinical conversion. 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. 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. 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.
Publisher: Wiley
Date: 02-11-2018
DOI: 10.1111/ENE.13824
Abstract: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. Of the 1284 included patients, 533 were matched (treated, n = 195 untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1 95% CI, 0.7-1.6, P = 0.69). Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.
Publisher: SAGE Publications
Date: 02-05-2017
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2023
Publisher: Public Library of Science (PLoS)
Date: 08-01-2013
Publisher: Cold Spring Harbor Laboratory
Date: 09-09-2022
DOI: 10.1101/2022.09.08.22279663
Abstract: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2019
Publisher: SAGE Publications
Date: 08-10-2018
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.AUTREV.2017.04.010
Abstract: Immunotherapy initiated early after first presentation of relapsing-remitting multiple sclerosis is associated with improved long-term outcomes. One can therefore speculate that early initiation of highly effective immunotherapies, with an average efficacy that is superior to the typical first-line therapies, could further improve relapse and disability outcomes. However, the most common treatment strategy is to commence first-line therapies, followed by treatment escalation in patients who continue to experience on-treatment disease activity. While this monitoring approach is logical, the current lack of effective regenerative or remyelinating therapies behoves us to consider high-efficacy treatment strategies from disease onset (including induction therapy) in order to prevent irreversible disability. In this systematic review, we evaluate the effect of high-efficacy immunotherapies at different stages of MS. A systematic review of literature reporting outcomes of treatment with fingolimod, natalizumab or alemtuzumab at different stages of MS was carried out. Twelve publications reporting relevant information were included in the systematic review. The literature suggests that treatment with high-efficacy immunotherapies is more potent in suppressing relapse activity when initiated early vs. with a delay after the MS diagnosis. The evidence reported for disability and MRI outcomes is inconclusive.
Publisher: Oxford University Press (OUP)
Date: 17-08-2023
Abstract: The capacity and power of data from cohorts, registries and randomised trials to provide answers to contemporary clinical questions in neurology has increased considerably over the last two decades. Novel sophisticated statistical methods are enabling us to harness these data to guide treatment decisions, but their complexity is making appraisal of clinical evidence increasingly demanding. In this review, we discuss several methodological aspects of contemporary research of treatment effectiveness in observational data in neurology, aimed at academic neurologists and analysts specialising in outcomes research. The review discusses specifics of the sources of observational data and their key features. It focuses on the limitations of observational data, and study design and statistical approaches aimed to overcome these limitations. Among the ex les of leading clinical themes typically studied with analyses of observational data, the review discusses methodological approaches to comparative treatment effectiveness, development of diagnostic criteria and definitions of clinical outcomes. Finally, this review provides a brief summary of key points that will help clinical audience critically evaluate design and analytical aspects of studies of disease outcomes using observational data.
Publisher: Wiley
Date: 17-01-2015
DOI: 10.1002/ANA.24339
Abstract: 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. 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. 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). 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.
Publisher: Radiological Society of North America (RSNA)
Date: 09-2013
Abstract: To investigate the association between the development of thalamic and cortical atrophy and the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome (CIS). This prospective study was approved by the institutional review board. Informed consent was given by 216 CIS patients, and patients were treated with 30 µg of intramuscular interferon β1a once a week. They were assessed with a magnetic resonance (MR) imaging examination at baseline, 6 months, 1 year, and 2 years. Patients were evaluated within 4 months of an initial demyelinating event, had two or more brain lesions on MR images, and had two or more oligoclonal bands in cerebrospinal fluid. MR imaging measures of progression included cumulative number and volume of contrast agent-enhanced (CE) new and enlarged T2 lesions, and changes in whole-brain, tissue-specific global, and regional gray matter volumes. Regression and mixed-effect model analyses were used. Over 2 years, 92 of 216 patients (42.6%) converted to CDMS 122 (56.5%) CIS patients fulfilled McDonald 2005 criteria and 153 (70.8%) fulfilled McDonald 2010 criteria for MR imaging dissemination in time and space. The mean time to first relapse was 3.1 months, and mean annual relapse rate was 0.46. In mixed-effect model analysis, the lateral ventricle volume (P = .005), accumulation of CE (P = .007), new total T2 (P = .009) and new enlarging T2 lesions (P = .01) increase, and thalamic (P = .009) and whole-brain (P = .019) volume decrease were associated with development of CDMS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes (P = .009) were MR imaging variables associated with the development of CDMS. Measurement of thalamic atrophy and increase in ventricular size in CIS is associated with CDMS development and should be used in addition to the assessment of new T2 and CE lesions.
Publisher: Oxford University Press (OUP)
Date: 10-09-2015
DOI: 10.1093/BRAIN/AWV258
Abstract: 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.
Publisher: Wiley
Date: 25-03-2022
DOI: 10.1111/ENE.15317
Abstract: Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common. This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients. An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5–100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty‐two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain–eye–ear involvement, 14 with brain–ear (44%), six with brain–eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1–9 months) compared to 5.25 months (range 0.5–100 months) for patients with encephalopathy and ocular symptoms at presentation. Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2012
Publisher: JMIR Publications Inc.
Date: 19-10-2021
DOI: 10.2196/24969
Abstract: Cladribine tablets (marketed as Mavenclad) are a new oral therapy, which has recently been listed on the pharmaceutical benefits scheme in Australia for the treatment of relapsing multiple sclerosis (MS). The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS for up to 4 years in 75% of patients (based on annualized relapse rate). However, the reinitiation of therapy after year 4 has not been studied. This study aims to evaluate the safety and efficacy of cladribine tablets over a 6-year period, according to no evidence of disease activity 3. This will be a multicenter, 6-year, phase IV, low interventional, observational study that incorporates clinical, hematological, biochemical, epigenetic, radiological and cognitive biomarkers of disease. Participants considered for treatment with cladribine as part of their routine clinical care will be consented to take part in the study. They will be monitored at regular intervals during the initial course of medication administration in years 1 and 2. After year 3, patients will have the option of redosing, if clinically indicated, or to switch to another disease-modifying therapy. Throughout the duration of the study, we will assess blood-based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation, and RNA analysis as well as magnetic resonance imaging findings (brain volume and/or lesion load) and cognitive performance. This study has been approved by the Hunter New England Local Health District Human Research Ethics Committee. Recruitment began in March of 2019 and was completed by June 2021. This will be the first long-term efficacy trial of cladribine, which offers reinitiation of therapy in the 3rd year, based on disease activity, after the initial 2 courses. We expect that this study will indicate whether any of the assessed biomarkers can be used to predict treatment efficacy or the need for future reinitiation of cladribine in people with MS. This study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12619000257167) with Universal Trial Number (U1111-1228-2165). DERR1-10.2196/24969
Publisher: BMJ
Date: 13-01-2019
Abstract: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring). The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24 p=0.05) and dimethyl fumarate (0.20 vs 0.26 p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22 p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68). The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
Publisher: Elsevier BV
Date: 08-2021
Publisher: SAGE Publications
Date: 08-10-2022
DOI: 10.1177/13524585211049986
Abstract: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
Publisher: SAGE Publications
Date: 19-02-2023
DOI: 10.1177/13524585231151394
Abstract: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80] marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43] marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.
Publisher: Cambridge University Press (CUP)
Date: 28-04-2023
DOI: 10.1017/NEU.2023.25
Abstract: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL 582 pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
Publisher: BMJ
Date: 12-01-2021
Abstract: Switching between first-line disease-modifying therapies in patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) due to reasons other than disease activity is frequent, but evidence on the effect of this practice is limited. We investigated the effect of switching patients with stable RRMS on occurrences of disability accumulation, relapses and future treatment discontinuation. Using the Danish Multiple Sclerosis Registry, we identified patients with RRMS without disease activity who either (1) stayed on injectable platform therapy (interferon-β or glatiramer acetate) or (2) switched to dimethyl fumarate (DMF) or teriflunomide (TFL) and compared treatment outcomes using propensity-score-based methods and marginal structural models (MSM). We included 3206 patients in the study. We found no change in risk of 6-month confirmed Expanded Disability Status Scale score worsening in patients switching to DMF (HR: 1.15, 95% CI 0.88 to 1.50) or TFL (HR: 1.16, 95% CI 0.92 to 1.46). The risk of suffering any relapse tended to decrease when switching to DMF (HR: 0.73, 95% CI 0.51 to 1.04) and tended to increase when switching to TFL (HR: 1.25, 95% CI 0.96 to 1.63). Absolute risk differences were small. MSM analyses showed similar results but did not find an increased relapse risk in TFL switchers. Switching from injectable platform therapies to oral first-line therapies in patients with clinically stable RRMS does not increase the risk of disability accumulation. While the postswitch risk of relapses trended towards marginally higher on TFL, this trend was eliminated by adjustment for time-variant confounders.
Publisher: SAGE Publications
Date: 31-08-2017
Abstract: This propensity score–matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab. We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score–matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results. Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.AUTNEU.2010.05.011
Abstract: Spinal cord transection at T4 results in severe damage of the nervous tissue, with impairment of motor, sensory and autonomic functions. Transplantation of olfactory ensheathing cells (OECs) has the potential to improve these functions through a number of mechanisms, which include facilitation of regeneration and neuroprotection. For cardiovascular functions, we have previously shown that OECs reduce the duration of autonomic dysreflexia, without evidence of regeneration. To further understand the mechanisms underpinning this improvement, we have studied changes in selected morphological features (cavitation, non-cavity tissue loss, morphology of sympathetic preganglionic neurons and primary afferent fibre density) in the T4-transected rat spinal cord over 9 weeks, both in control and OEC-transplanted animals. T4 transection led to a number of structural changes: gradual formation of cavities, non-cavity tissue loss, a long-term increase in soma size of sympathetic preganglionic neurons and a temporary increase in the extent of their dendritic arbours, and an increase in the density of primary afferent fibres caudal to the lesion. OECs decreased the cavitation and normalised soma size of the sympathetic preganglionic neurons below the lesion, while increasing the extent of dendritic arbours in the preganglionic neurons above the lesion. Thus the OECs may contribute to the normalisation of the dysreflexic hypertension through tissue preservation and normalisation of the morphology of the preganglionic neurons caudal to the lesion, while enhancing the input on the rostral preganglionic neurons, whose vasomotor control remains intact. We hypothesise that these changes are mediated through secretion of soluble trophic factors by the transplanted OECs.
Publisher: SAGE Publications
Date: 30-11-2022
DOI: 10.1177/13524585221136036
Abstract: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). We aimed to validate a previously published predictive model of in idual treatment response using a non-overlapping cohort from the Middle East. We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%–96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%–91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.
Publisher: Oxford University Press (OUP)
Date: 30-11-2022
Abstract: Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 in iduals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273 βfemale =0.8289, P = 3.52 × 10-08), the other in males (rs698805 βmale = -1.5395, P = 4.35 × 10-08), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
Publisher: Cold Spring Harbor Laboratory
Date: 06-02-2022
DOI: 10.1101/2022.02.04.22270362
Abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 in iduals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
Publisher: Wiley
Date: 27-03-2015
DOI: 10.1002/ACN3.187
Publisher: SAGE Publications
Date: 27-02-2023
DOI: 10.1177/13524585231151951
Abstract: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. To determine whether early non-disabling relapses predict disability accumulation in RRMS. We redefined mild relapses in MSBase as ‘non-disabling’, and moderate or severe relapses as ‘disabling’. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n = 285 vs 4717 hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00–1.68) or given platform DMTs ( n = 1074 vs 7262 HR = 1.33, 95% CI = 1.15–1.54), but not if given high-efficacy DMTs ( n = 572 vs 3534 HR = 0.90, 95% CI = 0.71–1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.
Publisher: Oxford University Press (OUP)
Date: 11-2020
Publisher: SAGE Publications
Date: 11-07-2016
Abstract: Analyses of observational data have been gaining momentum in the evaluation of ever increasing spectrum of disease modifying therapies for multiple sclerosis. While high cost-effectiveness and generalisability represent their main advantages, these studies are also burdened with high risk of bias that may lead to erroneous conclusions. In this viewpoint, we highlight the key role of rigorous and transparent statistical methodology in the studies of observational data and encourage its thorough editorial scrutiny.
Publisher: SAGE Publications
Date: 11-07-2016
Abstract: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. 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. 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. 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.
Publisher: SAGE Publications
Date: 03-04-2022
DOI: 10.1177/13524585221084577
Abstract: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients’ demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years 72% female disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of in idual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the in idual accuracy of prognostics in MS.
Publisher: BMJ
Date: 19-10-2022
Abstract: To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing-remitting multiple sclerosis switching from fingolimod. Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab. Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation. After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2016
Publisher: Wiley
Date: 19-07-2017
DOI: 10.1002/ANA.24984
Abstract: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly diagnosed nonlesional MTLE actually represents familial MTLE (FMTLE). We identified all consecutive patients presenting to the Austin Health First Seizure Clinic with MTLE and normal magnetic resonance imaging (MRI) or MRI evidence of hippoc al sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by 2 epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE manifestations suspicious for epilepsy or unaffected. Physiological déjà vu was noted. Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9 of 121 relatives versus 0 of 121 controls (p = 0.008). All affected relatives had seizures with intense déjà vu and accompanying features 6 relatives had not been previously diagnosed. Déjà vu experiences that were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives versus none of the controls (p = 0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%). FMTLE accounts for almost one-fifth of newly diagnosed nonlesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena that clinically lie in the "borderland" between epileptic seizures and physiological déjà vu. Ann Neurol 2017 :166-176.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-08-2021
DOI: 10.1212/WNL.0000000000012354
Abstract: To compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag. Patients treated with high-efficacy (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon beta, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP), 2 large observational cohorts. Therapeutic lag was estimated for each patient from their demographic and clinical characteristics. Propensity score was used to match patients treated with high- and low-efficacy therapies. Outcomes after the period of therapeutic lag was disregarded were compared in paired, pairwise-censored analyses. One thousand patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7, p = 0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8, p = 0.39). No evidence for a difference in the risk of disability progression was observed. In treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active but not those with inactive SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group. This study provides Class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS, although we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.
Publisher: Frontiers Media SA
Date: 21-11-2016
Publisher: Wiley
Date: 16-02-2023
DOI: 10.1111/ENE.15706
Abstract: This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
Publisher: SAGE Publications
Date: 08-2016
Abstract: Objective and reproducible evaluation of data quality is of paramount importance for studies of ‘real-world’ observational data. Here, we summarise a standardised data quality, density and generalisability process implemented by MSBase, a global multiple sclerosis (MS) cohort study. Error rate, data density score and generalisability score were developed using all 35,869 patients enrolled in MSBase as of November 2015. The data density score was calculated across six domains (follow-up, demography, visits, MS relapses, paraclinical data and therapy) and emphasised data completeness. The error rate evaluated syntactic accuracy and consistency of data. The generalisability score evaluated believability of the demographic and treatment information. Correlations among the three scores and the number of patients per centre were evaluated. Errors were identified at the median rate of 3 per 100 patient-years. The generalisability score indicated the s les’ representativeness of the known MS epidemiology. Moderate correlation between the density and generalisability scores (ρ = 0.58) and a weak correlation between the error rate and the other two scores (ρ = −0.32 to −0.33) were observed. The generalisability score was strongly correlated with centre size (ρ = 0.79). The implemented scores enable objective evaluation of the quality of observational MS data, with an impact on the design of future analyses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-11-2021
DOI: 10.1212/WNL.0000000000012753
Abstract: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international s le of people with MS. Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1–12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01–2.41 aOR 2.43, 95% CI 1.48–4.02) and ICU admission (aOR 2.30, 95% CI 0.98–5.39 aOR 3.93, 95% CI 1.56–9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54–10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29–2.38 aOR 2.76, 95% CI 1.87–4.07) and ICU admission (aOR 2.55, 95% CI 1.49–4.36 aOR 4.32, 95% CI 2.27–8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09–12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13–3.07 aOR 2.88, 95% CI 1.68–4.92) and ICU admission (aOR 2.13, 95% CI 0.85–5.35 aOR 3.23, 95% CI 1.17–8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71–17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.
Publisher: American Medical Association (AMA)
Date: 15-01-2019
Publisher: Public Library of Science (PLoS)
Date: 15-11-2012
Publisher: SAGE Publications
Date: 20-09-2018
Abstract: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2019
DOI: 10.1101/19002063
Abstract: Patients with the ‘aggressive’ form of MS accrue disability at an accelerated rate, typically reaching EDSS = 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive MS, 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 MS is essential to optimise treatment in this MS subtype. We evaluated whether patients who will develop aggressive MS can be identified based on early clinical markers, and to replicate this analysis in an independent cohort. Patient data were obtained from MSBase. Inclusion criteria were (a) first recorded disability score (EDSS) within 12 months of symptom onset, (b) at least 2 recorded EDSS scores, and (c) at least 10 years of observation time. Patients were classified as having ‘aggressive MS’ if they: (a) reached EDSS = 6 within 10 years of symptom onset, (b) EDSS =6 was confirmed and sustained over =6 months, and (c) EDSS =6 was 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, hospitalisation). Predictors were evaluated using Bayesian Model Averaging (BMA). Independent validation was performed using data from the Swedish MS Registry. Of the 2,403 patients identified, 145 were classified as having aggressive MS (6%). BMA 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 MS (AUC = .80, 95% CIs = .75, .84). 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 MS Registry cohort, 34 (6%) met criteria for aggressive MS. The combination of all three signs was also predictive in this cohort (AUC = .75, 95% CIs = .66, .84). 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 MS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-08-2017
DOI: 10.1212/WNL.0000000000004330
Abstract: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS). Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates. Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2–3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7–1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4–1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8–1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = −0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results. Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years. This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
Publisher: SAGE Publications
Date: 13-08-2021
DOI: 10.1177/13524585211035948
Abstract: Disease-modifying therapies (DMTs) are used to treat people with relapsing-onset multiple sclerosis (ROMS), but our knowledge is largely limited to their short-term effects. To determine (1) the impact of national-level DMT subsidy policy on DMT use and health outcomes in people with MS (PwMS) and (2) the long-term effects of DMT on disability and quality of life (QoL 5-level EQ-5D version (EQ-5D-5L) utility value). This observational cohort study compared Australian and New Zealand populations with different levels of DMT availability 10–20 years post-ROMS diagnosis. Between-country differences were assessed using standardised differences. Associations were assessed with multivariable linear regression models. We recruited 328 Australians and 256 New Zealanders. The Australian cohort had longer DMT treatment duration, greater proportion of disease course treated and shorter duration between diagnosis and starting DMT. The Australian cohort had lower median Expanded Disability Status Scale (EDSS) (3.5 vs 4.0) and Multiple Sclerosis Severity Score (MSSS) (3.05 vs 3.71) and higher QoL (0.71 vs 0.65). In multivariable models, between-country differences in disability and QoL were largely attributed to differential use of DMT. This study provides evidence for the impact of national-level DMT policy on disability outcomes in PwMS. Where DMTs are more accessible, PwMS experienced less disability progression and improved QoL 10–20 years post-diagnosis.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.CLINEURO.2012.02.014
Abstract: To evaluate long-term effects of 2-year treatment with interferon beta combined with low-dose azathioprine and prednisone in multiple sclerosis. In the original 2-year ASA study, 181 patients with early relapsing-remitting multiple sclerosis were randomised into 3 treatment arms: those treated with interferon beta (n=60), with interferon beta and low-dose azathioprine (n=58), and interferon beta, azathioprine and low-dose prednisone (n=63). Of these, 172 were included in this 4-year non-study extension. Three monthly clinical controls and annual MRI scans were carried out. The primary endpoint was annual relapse activity. The secondary endpoints were disability and quantitative MRI parameters. Nine patients were lost to follow-up and 172 were included in the analyses. None of relapse activity, disability accumulation or MRI parameters differed significantly between the groups over 6 years. Only 5.5% and 0.6% of patients were free from disease activity at year 2 and year 6 of the treatment initiation. The tested combined therapeutic regimen does not improve long-term outcomes in patients with multiple sclerosis. Furthermore, interferon is not able to completely abolish disease activity.
Publisher: SAGE Publications
Date: 19-02-2023
DOI: 10.1177/13524585231151400
Abstract: Multiple sclerosis patients experience 3–6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying therapy recipients remains unknown. The objective of this study was to compare seizure risk in multiple sclerosis patients receiving disease-modifying therapy versus placebo. MEDLINE(OVID), Embase, CINAHL, and ClinicalTrials.gov were searched from database inception until August 2021. Phase 2–3 randomized, placebo-controlled trials reporting efficacy and safety data for disease-modifying therapies were included. Network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using Bayesian random effects model for in idual and pooled (by drug target) therapies. Main outcome was log e seizure risk ratios [95% credible intervals]. Sensitivity analysis included meta-analysis of non-zero-event studies. A total of 1993 citations and 331 full-texts were screened. Fifty-six included studies (29,388 patients—disease-modifying therapy = 18,909 placebo = 10,479) reported 60 seizures (therapy = 41 placebo = 19). No in idual therapy was associated with altered seizure risk ratio. Exceptions were daclizumab (−17.90 [−65.31 −0.65]) and rituximab (−24.86 [−82.71 −1.37]) trending toward lower risk ratio cladribine (25.78 [0.94 4.65]) and pegylated interferon-beta-1a (25.40 [0.78 85.47]) trended toward higher risk ratio. Observations had wide credible intervals. Sensitivity analysis of 16 non-zero-event studies revealed no difference in risk ratio for pooled therapies (l0.32 [−0.94 0.29]) No evidence of association was found between disease-modifying therapy and seizure risk—this informs seizure management in multiple sclerosis patients.
Publisher: Wiley
Date: 15-12-2017
DOI: 10.1002/ACN3.512
Publisher: Hindawi Limited
Date: 16-03-2012
DOI: 10.1111/J.1600-0404.2012.01662.X
Abstract: To identify early clinical and MRI predictors of non-response to interferon (IFN) treatment in multiple sclerosis (MS). In 172 patients with relapsing-remitting MS treated with IFNβ, we evaluated prediction of future treatment non-response. Candidate predictors comprised disability and its sustained progression, relapse score (combining frequency and severity of relapses), brain volume change, brain parenchymal fraction, number of new T2 lesions, and T2 and T1 lesion volume within the initial year of treatment. Treatment non-response was evaluated as confirmed disability progression or overall average annual relapse score exceeding 1 over the following 5 years. Logistic regression model was adjusted for patient age, gender, disease duration and changes in treatment. Ninety patients (52%) reached the status of IFN non-responders in years 2-6. Patients with ≥1 new T2 lesion and relapse score ≥2 (odds ratio ≥5.7) or those with ≥3 new T2 lesions regardless of the relapse score (odds ratio = 3) were in a significantly higher risk of future treatment non-response. In patients with MS treated with IFNβ for 1 year, number of new T2 lesions and annualized relapse score predict in idual risk of treatment non-response over the following 5 years.
Publisher: BMJ
Date: 06-07-2023
Abstract: Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy. This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression. 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p .001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p .001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found. Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS. Australian New Zealand Clinical Trials Registry (ACTRN12605000455662).
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.JNS.2011.08.016
Abstract: Visuospatial skills including spatial navigation are known to be impaired in Huntington's disease. Spatial navigation comprises two navigational frameworks, allocentric and egocentric. Several studies have associated the allocentric navigation with the hippoc us and the egocentric navigation with the striatum. The striatum is predominantly impaired from the early stages of Huntington's disease. To find whether spatial navigation impairment is present in the early stages of Huntington's disease and to test the hypothesis that the egocentric navigation is predominantly affected compared to the allocentric navigation. In nineteen patients with Huntington's disease the egocentric and the allocentric navigation skills were tested using the Blue Velvet Arena, a human analog of Morris Water Maze, and compared to nineteen age and gender-matched healthy controls. Cognitive functions, with emphasis on the executive functions, were also assessed. The spatial navigation skills deteriorated with the increasing motor impairment in Huntington's disease. These changes only became apparent in patients with moderate functional impairment. No difference between the egocentric and the allocentric skills was seen. Spatial navigation deficit is not an early marker of the cognitive dysfunction in Huntington's disease. We speculate that the striatal circuitry that is known to degenerate early in the course of Huntington's disease is not directly associated with the spatial navigation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2021
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.03.23290918
Abstract: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a relatively common consequence of chimeric antigen receptor T-cell (CAR-T) therapy, with a wide range of possible cognitive presentations. The aim of this study was to characterise a real-word cognitive and psychological status of patients with advanced haematologic and solid organ malignancies planned for CAR-T. We also aimed to examine utility of two cognitive screening approaches. Patients underwent specialist cognitive assessment, including a self-report questionnaire of psychopathology and subjective cognitive function. A subset of in iduals also completed the Montreal Cognitive Assessment (MoCA). Of 60 patients included, 15-16 (25%-27%) presented with evidence of cognitive impairment, with six unique patterns of dysfunction. Impaired patients were more likely to have B-cell acute lymphoblastic leukaemia ( BF 10 =9.30), be younger ( BF 10 =7.76), have bone marrow involvement ( BF 10 =5.18), report history of anxiety ( BF 10 =4.85), or have evidence of psychopathology ( BF 10 =31.30). Analyses did not support the utility of cognitive screening. Of those patients who completed a self-report measure of psychopathology, nine (15.8%) were elevated on at least one symptom domain. The findings demonstrate a broad spectrum of dysfunction and psychopathology in this cohort, emphasising the importance of baseline evaluation for detecting cognitive neurotoxicity symptoms that might arise after CAR-T infusion.
Publisher: Oxford University Press (OUP)
Date: 03-08-2017
DOI: 10.1093/BRAIN/AWX185
Abstract: Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis however, treatment response varies greatly among patients. Comprehensive predictive models of in idual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for in idual 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 in idual 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 in idual 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 in idual response to disease-modifying therapies at the time of their commencement.
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2019
DOI: 10.1101/735662
Abstract: Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity. 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p=10 -9 ) and worsening of disability (0.81, 0.67-0.99, p=0.043). Continued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.FOODCHEM.2019.125102
Abstract: The chemical compositions and α-glucosidase inhibitory activities of anthocyanins extracted from blueberry, blackcurrant and blue honeysuckle fruits and their acid hydrolysates (anthocyanidins) were analysed. Those anthocyanins were glycosidic anthocyanins that converted to anthocyanidins during acid hydrolysis, leading to increases in their α-glucosidase inhibitory activities (expressed as IC
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000337683
Abstract: b i Aim: /i /b To determine whether corpus callosum atrophy predicts future clinical deterioration in multiple sclerosis. b i Methods: /i /b In 39 multiple sclerosis patients the area of corpus callosum in the sagittal plane, T sub /sub and T sub /sub lesion volumes, brain parenchymal fraction and brain atrophy were determined at baseline and 1 year after treatment initiation. Non-parametric and multiple regression models were built to identify the most reliable predictors of disability and of its changes over 9 years. b i Results: /i /b Corpus callosum atrophy during the first year of treatment was the best predictor of disability (r = –0.56) and of its increase at 9 years (r = 0.65). Corpus callosum atrophy of at least 2% predicted increase in disability with 93% sensitivity and 73% specificity (odds ratio = 35). b i Conclusion: /i /b Corpus callosum atrophy is a simple and accurate predictor of future disability accumulation and is feasible for routine clinical practice.
Publisher: SAGE Publications
Date: 26-11-2022
DOI: 10.1177/13524585221137502
Abstract: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch relapse outcomes included time to first relapse and annualized relapse rate (ARR). Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. In iduals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.AUTNEU.2009.10.001
Abstract: Autonomic dysreflexia is a common complication in high spinal cord injury and can result in serious consequences and death. Here we have examined the effect of acute transplantation of olfactory ensheathing cells on cardiovascular functions in rats. After T4 transection, radio-telemetric recording in conscious animals was used to study blood pressure and heart rate at rest and during autonomic dysreflexia for up to 8 weeks post-injury. Olfactory ensheathing cells from syngeneic rats were transplanted at the injury site control animals received culture medium only. At the study end point, we examined morphometric features of sympathetic preganglionic neurons above and below the injury. T4 transection resulted in a fall in resting mean arterial pressure and an increase in resting heart rate. Colorectal distension, used to trigger autonomic dysreflexia, caused episodic hypertension and bradycardia. Although the cell transplantation had no effect on resting cardiovascular parameters, it led to a significantly faster recovery from hypertension, with the recovery time shortened by approximately 25%. The transection resulted in an increase in soma size of sympathetic preganglionic neurons above and below the injury. OEC transplantation normalised this change below the injury and increased dendritic length of preganglionic neurons above the injury, compared to controls. It has been proposed that changes in sympathetic preganglionic neurons following spinal cord transection may be related to the development of autonomic dysreflexia. Our results suggest that olfactory ensheathing cells may alter the morphology of these neurons, and hence modify their activity in the neuronal networks responsible for the dysreflexic reaction.
Publisher: American Physiological Society
Date: 06-2009
DOI: 10.1152/JAPPLPHYSIOL.00095.2009
Abstract: Subjects with severe chronic spinal cord injury (SCI) are prone to hypothermia when they are exposed to relatively low environmental temperatures that are normally well tolerated by healthy in iduals. This impaired thermoregulation is presumably due to disconnection of territories below the SCI from supraspinal thermoregulatory centers. However, it is not known how these territories respond to low temperatures. Using a complete transection at T 11 in rats, we examined the responses of the tail to cold (6–9°C) by measuring changes in tail blood flow and skin temperature weekly for 8 wk after SCI. Despite no significant change in baseline mean flow or temperature in the tail, the transection effectively removed the sympathetically mediated supraspinal control of the tail vasculature, since the litude of the pulse flow was markedly increased and the natural variations of the mean flow were almost abolished. As expected, the cold challenge before SCI caused a marked drop in mean flow, pulse litude, and temperature of the tail. Surprisingly, the drops in mean blood flow and temperature were observed after SCI, although the decrease in flow was slower and the pulse litude was not reduced. The results suggest that the cutaneous vasculature of the tail is sensitive to cold and will constrict, despite disconnection from supraspinal centers. This local effect is slow but may be sufficient to maintain some level of thermoregulation to cold. Without this vascular reaction, the effects of SCI on temperature regulation to cold would probably be much worse.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-10-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-12-2020
DOI: 10.1212/WNL.0000000000011242
Abstract: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43–0.82, p = 0.0016), worsening of disability (0.56, 0.38–0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19–0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p = 10 −9 ) and worsening of disability (0.81, 0.67–0.99, p = 0.043). Continued treatment with MS immunotherapies reduces disability accrual by 19%–44% (95% CI 1%–62%), the risk of need of a walking aid by 67% (95% CI 41%–81%), and the frequency of relapses by 40–41% (95% CI 18%–57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
Publisher: SAGE Publications
Date: 23-05-2019
Abstract: Over the last decade, clinical registries have significantly contributed to the pool of evidence that supports management decisions in patients with multiple sclerosis. Being the largest international registry of multiple sclerosis and neuroimmunological disorders, MSBase collects demographic, clinical and limited paraclinical information from patients managed in different regions and under various circumstances. In this review, we will provide an overview of its published output, with focus on the information with impact on the management of multiple sclerosis.
Publisher: SAGE Publications
Date: 11-01-2021
Abstract: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) 6 and ARR 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS 6 and ARR 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR 1 54.3 weeks (95% CI = 47.2–61.5). Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
Publisher: Informa UK Limited
Date: 10-2012
DOI: 10.1080/13854046.2012.725101
Abstract: The available instruments for cognitive assessment in multiple sclerosis (MS) require considerable time and resources, and are not readily available in all countries. The study aimed to examine validity of the Czech translation of the Minimal Assessment of Cognitive Function in MS (MACFIMS), to validate the Brief International Cognitive Assessment for MS (BICAMS), and to compare their outcomes. We evaluated 367 MS patients and 134 healthy controls with the MACFIMS battery, which comprises the three tests of the BICAMS (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, second edition). The most accurate BICAMS criterion of cognitive deficit was that of at least one of the overall three tests outside the normal range (sensitivity = 94%, specificity = 86%, p = 10(-28)). Outcomes of the Czech translation of the MACFIMS were comparable to its original. The MACFIMS and the BICAMS identified cognitive deficit in 55% and 58% of the MS patients, respectively. Both batteries predicted patient self-reported vocational status. This is the first study to show that the BICAMS is highly sensitive and specific to cognitive impairment in MS as defined by the MACFIMS. This impairment is associated with vocational status. Czech versions of the studied batteries have now been validated.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-11-2021
DOI: 10.1212/WNL.0000000000012850
Abstract: Longitudinal cognitive trajectories in multiple sclerosis are heterogeneous and difficult to measure. We aimed to identify discrete longitudinal reaction time trajectories in relapsing-remitting multiple sclerosis using a computerized cognitive battery and to assess the association between trajectories of reaction time and disability progression. All participants serially completed computerized reaction time tasks measuring psychomotor speed, visual attention, and working memory. Participants completed at least 3 testing sessions over a minimum of 180 days. Longitudinal reaction times were modeled with latent class mixed models to identify groups of in iduals sharing similar latent characteristics. Optimal models were validated for consistency and baseline associations with class membership tested using multinomial logistic regression. Interclass differences in the probability of reaction time worsening and the probability of 6-month confirmed disability progression were assessed with survival analysis. A total of 460 people with relapsing-remitting multiple sclerosis were included in the analysis. For each task of the MSReactor battery, the optimal model comprised 3 latent classes. All MSReactor tasks could identify a group with high probability of reaction time slowing. The visual attention and working memory tasks could identify a group of participants who were 3.7 and 2.6 times more likely to experience a 6-month confirmed disability progression, respectively. Participants could be classified into predicted cognitive trajectories after just 5 tests with 64% to 89% accuracy. Latent class modeling of longitudinal cognitive data collected by a computerized battery identified patients with worsening reaction times and increased risk of disability progression. Slower baseline reaction time, age, and disability increased assignment into this trajectory. Monitoring of cognition in clinical practice with computerized tests may enable detection of cognitive change trajectories and people with relapsing-remitting multiple sclerosis at risk of disability progression.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1111/ENE.15406
Abstract: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS) however, randomized clinical trials evaluate only short‐term treatment effects on disability. This study aimed to define criteria for 6‐month confirmed disability progression events of MS with a high probability of resulting in sustained long‐term disability worsening. In total, 14,802 6‐month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6‐month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long‐term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52 discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72% 2: 88% 3: 94% 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was % likely to be sustained (events with score ˃1.5). Clinicodemographic characteristics of 6‐month confirmed disability progression events identify those at high risk of sustained long‐term disability. This knowledge will allow future trials to better assess the effect of therapy on long‐term disability accrual.
Start Date: 06-2018
End Date: 12-2024
Amount: $4,133,659.00
Funder: Australian Research Council
View Funded Activity