Improved relapse recovery in paediatric compared to adult multiple sclerosis

Abstract Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis.

Download Full-text

Detecting clinically-relevant changes in progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514540969 ◽

2014 ◽

Vol 21 (2) ◽

pp. 171-179 ◽

Cited By ~ 12

Author(s):

LVAE Bosma ◽

JM Sonder ◽

JJ Kragt ◽

CH Polman ◽

BMJ Uitdehaag

Keyword(s):

Multiple Sclerosis ◽

Outcome Measurement ◽

Progressive Multiple Sclerosis ◽

Meaningful Change ◽

Disability Scale ◽

Impact Scale ◽

Disability Status ◽

Disease Impact

Objective: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). Methods: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4–6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy’s Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. Results: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. Conclusion: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.

Download Full-text

Contribution of different relapse phenotypes to disability in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458516643392 ◽

2016 ◽

Vol 23 (2) ◽

pp. 266-276 ◽

Cited By ~ 19

Author(s):

Tamasine Stewart ◽

Tim Spelman ◽

Eva Havrdova ◽

Dana Horakova ◽

Maria Trojano ◽

...

Keyword(s):

Multiple Sclerosis ◽

Functional System ◽

Sensitivity Analyses ◽

Linear Regression Models ◽

Differential Impact ◽

Pronounced Increase ◽

Disease Modifying Therapy ◽

Disability Status ◽

Important Objective

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

Download Full-text

Clinical follow-up of 304 patients with multiple sclerosis three years after mitoxantrone treatment

Multiple Sclerosis Journal ◽

10.1177/1352458506072543 ◽

2007 ◽

Vol 13 (5) ◽

pp. 626-631 ◽

Cited By ~ 15

Author(s):

M. Debouverie ◽

L. Taillandier ◽

S. Pittion-Vouyovitch ◽

S. Louis ◽

H. Vespignani

Keyword(s):

Multiple Sclerosis ◽

Interferon Beta ◽

Progressive Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Disability Status ◽

Relapsing Remitting ◽

Before And After ◽

The Mean ◽

Disease Modifying Treatment

The objectives of this study were to assess the benefits of 1) mitoxantrone after three years of follow-up and 2) disease-modifying treatment (DMT) after stopping mitoxantrone. A retrospective analysis was performed on 304 patients with active relapsing-remitting (RR) or progressive multiple sclerosis (PMS) who were treated with mitoxantrone. After mitoxantrone therapy, some patients received DMT (interferon-beta or glatiramer acetate) while others did not. The disease course of the two groups was evaluated by the Expanded Disability Status Scale (EDSS) before and after mitoxantrone and then every year for three years. The mean EDSS score at starting mitoxantrone and three years after stopping mitoxantrone respectively, were: 3.3 (1.3) and 3.2 (1.7) for the RRMS patients and 5.9 (1.2) and 6.4 (1.4) for the PMS patients. Before starting mitoxantrone, demographic and clinical parameters of predictive disability were not significantly different between patients who received DMT or not. The variation of EDSS between time of stopping mitoxantrone and three years later was significantly different (+0.9 versus +0.3; P=0.03) for patients with RRMS. We found that mitoxantrone treatment induces stable disease up to two years after discontinuation of mitoxantrone therapy. In the third year, patients without DMT deteriorated. Multiple Sclerosis 2007; 13: 626-631. http://msj.sagepub.com

Download Full-text

Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network

Multiple Sclerosis Journal ◽

10.1177/1352458514527862 ◽

2014 ◽

Vol 20 (11) ◽

pp. 1502-1510 ◽

Cited By ~ 46

Author(s):

LE Charvet ◽

EH O’Donnell ◽

AL Belman ◽

T Chitnis ◽

JM Ness ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Functioning ◽

Verbal Memory ◽

Neuropsychological Testing ◽

Visuomotor Integration ◽

Pediatric Multiple Sclerosis ◽

Age Related ◽

The Us ◽

Over Time

Background: Approximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time. Objective: Changes in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers. Methods: A total of 67 individuals with pediatric MS ( n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8–17 years of age (mean age±standard deviation (SD)=14.37±2.02) completed initial and follow-up neuropsychological testing after an average of 1.64±0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning. Results: Rate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure. Conclusion: Findings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

Download Full-text

Decreasing impact of late relapses on disability worsening in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458519848090 ◽

2019 ◽

Vol 26 (8) ◽

pp. 924-935

Author(s):

Kevin Ahrweiller ◽

Chloé Rousseau ◽

Emmanuelle Le Page ◽

Emma Bajeux ◽

Emmanuelle Leray ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Short Term ◽

Secondary Progressive ◽

Increased Risk ◽

Disability Status ◽

Long Term Follow Up

Background: Changes in relapse activity during secondary progressive multiple sclerosis (SPMS) need to be accurately characterized in order to identify patients who might benefit from continuing disease-modifying therapies. Objective: To describe relapse occurrence in patients with SPMS during long-term follow-up and assess its impact on disability worsening. Methods: This retrospective cohort study included 506 patients. We assessed the influence of relapses on time from SPMS onset to an Expanded Disability Status Scale score of 6 (EDSS 6), and on irreversible worsening of EDSS scores across different periods. Results: The annualized relapse rate (ARR) decreased with patient’s age (mean reduction of 43% per decade) and SPMS duration (mean reduction of 46% every 5 years). Post-progression relapses were associated with shorter time from secondary progressive (SP) phase onset to EDSS 6 (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = (1.01, 1.64)). Relapse occurrence during the first 3 years and 3–5 years after SP onset was associated with an increased risk of irreversible EDSS worsening (OR = 3.12 (1.54, 6.31) and 2.04 (1.16, 3.58)). This association was no longer significant after 5 years. Conclusion: The occurrence of relapses was a marker of short-term disability progression during early SPMS, but did not have decisive impact in later SPMS.

Download Full-text

Clinical course of multiple sclerosis: A nationwide cohort study

Multiple Sclerosis Journal ◽

10.1177/1352458516681197 ◽

2016 ◽

Vol 23 (11) ◽

pp. 1488-1495 ◽

Cited By ~ 29

Author(s):

Ali Manouchehrinia ◽

Omid Beiki ◽

Jan Hillert

Keyword(s):

Multiple Sclerosis ◽

Clinical Course ◽

Progressive Multiple Sclerosis ◽

Population Based ◽

Time Of Death ◽

Expanded Disability Status Scale ◽

First Line ◽

Kaplan Meier ◽

Younger Age ◽

Disability Status

Background: The course of multiple sclerosis (MS) has been studied in several cohorts; however, results have varied significantly. Objective: To describe the clinical course of MS in a nationwide cohort of patients. Method: Data from the Swedish MS register (SMSreg) were used to estimate the median time to the sustained Expanded Disability Status Scale (EDSS) scores 3.0, 4.0 and 6.0, onset of secondary progressive multiple sclerosis (SPMS) and death using Kaplan–Meier method. A possible effect of first-line treatments on age at EDSS 6.0 and SPMS was estimated. Results: In all, 12,703 patients were included. Median ages at EDSS scores 3.0, 4.0 and 6.0 were 55.4 (95% confidence interval (CI): 54.8−55.8), 60.7 (95% CI: 60.1−61.2) and 64.3 (95% CI: 63.6−64.7), respectively. Median age at SPMS was 57.4 (95% CI: 56.9−57.9). The median age at the time of death was 80.5 (95% CI: 79.9−81.1). Males and progressive-onset patients showed higher risks of disability worsening. On average, treated patients gained 1.6 years (95% CI: 0.2−3) to EDSS 6.0 as a result of treatment. Conclusion: Ages at disability milestones in this population-based cohort were higher than previously described in clinic- and regional-based samples. Nevertheless, MS patients die at younger age and live at an average almost 20 years with moderate and 30 years with severe disability.

Download Full-text

Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening

Multiple Sclerosis Journal ◽

10.1177/13524585211023365 ◽

2021 ◽

pp. 135245852110233

Author(s):

Emilio Portaccio ◽

Laura Tudisco ◽

Luisa Pastò ◽

Lorenzo Razzolini ◽

Mattia Fonderico ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cox Regression ◽

Multivariable Analysis ◽

Control Group ◽

Treatment Optimization ◽

Younger Age ◽

Disability Status ◽

Clinical Stability

Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06–2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12–1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91–0.99; p = 0.022) and shorter DMD exposure over the follow-up ( p < 0.008). Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.

Download Full-text

Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520981300 ◽

2021 ◽

pp. 135245852098130

Author(s):

Izanne Roos ◽

Emmanuelle Leray ◽

Federico Frascoli ◽

Romain Casey ◽

J William L Brown ◽

...

Keyword(s):

Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Delayed Onset ◽

Disease Characteristics ◽

Disability Status ◽

Male Sex ◽

Pre Treatment ◽

Patient Subgroups

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: 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. Results: 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). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Download Full-text

A Pilot Study of 24-h Motor Activity Patterns in Multiple Sclerosis: Pre-Planned Follow-Up at 2 Years

Clocks & Sleep ◽

10.3390/clockssleep3030023 ◽

2021 ◽

Vol 3 (3) ◽

pp. 366-376

Author(s):

Lorenzo Tonetti ◽

Federico Camilli ◽

Sara Giovagnoli ◽

Vincenzo Natale ◽

Alessandra Lugaresi

Keyword(s):

Multiple Sclerosis ◽

Motor Activity ◽

Activity Pattern ◽

Activity Patterns ◽

Expanded Disability Status Scale ◽

Disability Status ◽

Relapsing Remitting ◽

Edss Score ◽

Activity Prognosis

Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a further prognostic marker. Here we report results collected at T0 and at a 24-month follow-up (T1). Eighteen RRMS patients (11 females, median Expanded Disability Status Scale-EDSS score 1.25, range EDSS score 0–2) were monitored at T0 (mean age 32.33 ± 7.51) and T1 (median EDSS score 1.5, range EDSS score 0–2.5). Patients were grouped into two groups: responders (R, 14 patients) and non-responders (NR, 4 patients) to treatment at T1. Each patient wore an actigraph for one week to record the 24-h motor activity pattern. At T0, NR presented significantly lower motor activity than R between around 9:00 and 13:00. At T1, NR were characterized by significantly lower motor activity than R between around 12:00 and 17:00. Overall, these data suggest that through the 24-h motor activity pattern, we can fairly segregate at T0 patients who will show a therapeutic failure, possibly related to a more active disease, at T1. These patients are characterized by a reduced morning level of motor activation. Further studies on larger populations are needed to confirm these preliminary findings.

Download Full-text

Walking capacities in multiple sclerosis measured by global positioning system odometer

Multiple Sclerosis Journal ◽

10.1177/1352458506070667 ◽

2007 ◽

Vol 13 (2) ◽

pp. 220-223 ◽

Cited By ~ 24

Author(s):

A Créange ◽

I Serre ◽

M Levasseur ◽

D Audry ◽

A Nineb ◽

...

Keyword(s):

Multiple Sclerosis ◽

Global Positioning System ◽

Walking Speed ◽

Walking Distance ◽

Expanded Disability Status Scale ◽

Satellite Technology ◽

Promising Tool ◽

Disability Status ◽

Global Positioning

We used a global positioning satellite technology odometer to determine the maximum objective walking distance capacity (MOWD) of patients with multiple sclerosis (MS). The MOWD correlated with Expanded Disability Status Scale (EDSS) score (r2 =0.41; P < 0.0001), the MSWS-12 scale (r2 = 0.46; P < 0.0001), time to walk 10 m (r2 = 0.51; P < 0.02) and walking speed (r2 =0.75; P < 0.001). Limitation of walking capacities was measurable up to 4550 m, strikingly above the 500-m limit of the EDSS. This objective odometer is a promising tool for evaluation and follow-up of patients with MS. Multiple Sclerosis 2007; 13: 220–223. http://msj.sagepub.com

Download Full-text