Response to the Letter to the Editor: “Multiple Sclerosis in Morocco: Impact on Patients' Quality of Life”

The acquisition of a reliable and valid outcome measure in multiple sclerosis (MS) is one of the holy grails for clinician researchers working in the field. The current standard for measuring MS-related disability is the Expanded Disability Status Scale (EDSS), a nonlinear scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) [1]. Widely incorporated into MS clinical trials, the EDSS has provided a critical framework for quantifying the toll that MS takes on those who suffer from it and has been considered the “gold standard” for measuring MS-related disability. Because the science to do so was not advanced enough at the time the EDSS was initially developed, however, its measurement properties were never properly evaluated at the time of its creation [2]. Practitioners who see patients with MS can attest to limitations in the neurologic examination, which essentially serves as the basis for the EDSS, in capturing the current clinical status of a patient. For example, a patient diagnosed by one of the editors with primary progressive MS who had an initial EDSS score of 2.0 due to foot drop returned a few months later with resolution of the foot drop (EDSS 1.0), which brought into question whether the course was truly progressive. However, the patient reported continued progression in difficulty functioning, noting that the disease had eliminated the capacity to jog, a favorite pastime. Further, when confronted with the puzzling improvement in the neurologic exam, the patient revealed that while at the previous visit, they had arrived at the office exhausted after walking several miles to get there; they had been dropped off in front of the clinical building for the follow-up visit. This story illustrates some of the problems with the use of the EDSS as a solitary outcome measure in MS. First, it brings the reliability of the scale into question. That a person with MS, particularly with a progressive course, could have such marked fluctuations and indeed even improvements in the score makes the interpretation of the scores difficult. While the EDSS has been shown to be a valid measure of physical disability in adults, there are problems with its reliability, capacity to discriminate between patients or groups thereof, and responsiveness [2]. Further, while the patient in this illustrative case reported worsening physical functioning that greatly impacted subjective quality of life at the second visit, the EDSS score was 1.0, indicating minimal disability. By design, the EDSS was not intended to be a comprehensive measure of the total impact MS has on the life of someone with the disease [2]. These limitations have prompted the search for better outcome measures for use by regulatory agencies approving new medications and for clinicians caring for patients with MS [3]. In this special edition of Multiple Sclerosis International, we sought to include papers that focused on outcome measures for MS. The articles herein range in scope from evaluations of the measurement properties of currently employed definitions of “sustained progression” using the EDSS to the development of a new relapse assessment measure and to measuring specific aspects of MS-related problems, including imbalance, walking impairment, and reduced quality of life. Studies of paraclinical outcomes, including optical coherence tomography and diffusion tensor imaging, and their relation to disability are also included. The reader will appreciate that no single outcome measure is likely to fulfill all needs. Clinical measures that most closely capture the patient's current level of performance or functioning are subject to fluctuations and may be temporally or physiologically disconnected from the disease pathology targeted by treatment. Imaging outcomes may capture features that are more proximate to the pathophysiology of MS but may not reflect findings that will become clinically meaningful. The body of work featured here adds to the dialogue that will inform the development and refinement of outcome measures that more fully capture and quantify the patient experience of MS. Robert Bermel Amy Waldman Ellen M. Mowry

To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS). Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation. Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007). This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal. Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning.

Disability improvement in the first case treated by Natalizumab in Libya

Retrograde diagnosis of tumifactive multiple sclerosis

To study the relationship between retinal nerve fiber layer (RNFL) thickness and brain atrophy using magnetic resonance imaging (MRI) with bicaudate ratio (BCR) in patients with multiple sclerosis (MS) with different levels of disease severity. We also assessed whether RNFL thickness correlated with Expanded Disability Status Scale (EDSS) score. The participants consisted of 88 patients with MS and 59 age- and sex-matched healthy control subjects. Eleven patients had clinically isolated syndrome (CIS), 68 patients had relapsing-remitting MS (RR-MS), and 9 patients had secondary progressive MS. Patients and controls were evaluated using optical coherence tomography (OCT, Cirrus) and scanning laser polarimetry with variable corneal compensation (GDx VCC). Patients underwent the same brain MRI scanning protocol. Disability was evaluated according to the EDSS. The BCR was calculated by dividing the minimum intercaudate distance by brain width along the same level. The BCR was higher in patients with MS (0.12 ± 0.03) than in controls (0.08 ± 0.009) (P < 0.001). OCT average RNFL thickness in patients with MS was significantly lower (84.51 ± 14.27 μm) than in control subjects (98.44 ± 6.83 μm). BCR was correlated with OCT average RNFL thickness (r = -0.48, P = 0.002) in patients with MS without optic neuritis. Significant correlations were found between average RNFL thickness and EDSS (r = -0.43, P = 0.003). Additionally, there were correlations between BCR with GDx parameters in patients with MS without optic neuritis. This study shows that RNFL thickness correlates with BCR and with MS subtypes. Additionally, our study indicates that OCT is better suited for MS assessment than GDx. We conclude that the damage of retinal axons appears related to brain damage in patients with MS.

Primary progressive multiple sclerosis (PPMS) carries the worst prognosis of the multiple sclerosis (MS) subtypes and is currently untreatable. A previous analysis of the British Columbia MS database challenged the view that disability progression is rapid in PPMS, but identified few predictors of disease progression. Here, we extend previous analyses in an updated PPMS retrospective cohort study of prevalent cases. We used Kaplan-Meier survival analyses and Cox regression models to investigate the influence of gender, age at onset, and onset symptoms on time to and age at Expanded Disability Status Scale (EDSS) 6.0 in patients with PPMS. Of 5,779 patients with definite MS, 552 (10%) had PPMS. Median time to EDSS 6.0 was 14.0 years (95% confidence interval [CI] 11.3-16.7), reached at a median age of 58.6 years (95% CI 56.8-60.3). Sensory onset symptoms were associated with a longer time to and an older age at EDSS 6.0 (multivariable hazard ratios 0.55 [95% CI 0.35-0.87] and 0.54 [0.35-0.85]). Younger age at disease onset was associated with a longer time to but a younger age at EDSS 6.0. Gender and other onset symptoms were not associated with these outcomes. Fifty patients with PPMS (9%) fulfilled criteria for benign MS (EDSS < or =3.0 after 10 years' disease duration). We identified 2 predictors of a slower disease progression in primary progressive multiple sclerosis. Sensory onset symptoms were associated with both a longer time to and a higher age at Expanded Disability Status Scale (EDSS) 6.0. A younger age at disease onset was associated with a longer time to EDSS 6.0, but patients with an early disease onset reached EDSS 6.0 at a younger age.

One of the promising areas in the pathogenetic treatment of multiple sclerosis (MS) is anti-B-cell therapy using ocrelizumab, an anti-CD20 monoclonal antibody. The drug is indicated for primary progressive MS (PPMS), secondary progressive MS (SPMS) and exacerbations, and highly active MS.Objective: to analyze the use of the drug in 32 patients with different types of MS in everyday neurological practice.Patients and methods. The investigation included 32 patients diagnosed with MS using the 2017 McDonald criteria: 12 patients with PPMS, 12 with highly active MS and 8 with SPMS and exacerbations. The median Expanded Disability Status Scale (EDSS) score was 4.0; the most severe course of the disease was observed in patients with SPMS. All the patients received a treatment cycle of 600-mg intravenous ocrelizumab injections (with an infusion pump) every 6 months; the initial dose was by 300 mg every 2 weeks. The follow-up period was 6 to 18 months.Results and discussion. During ocrelizumab therapy, the patients with PPMS showed stabilization of EDSS score; and 6 (50%) had even its slight decrease by 0.5–1.0 scores, which may be caused by compensation for the existing symptoms due to pathogenetic treatment. In highly active MS, only 1 of the 12 ocrelizumab-treated patients had an ongoing exacerbation of the disease. During a subsequent 6–18-month follow-up, magnetic resonance imaging revealed that none of the patients had manifestations of MS activity; the EDSS score decreased in all the patients, indicating their achievement of stable remission. Six (75%) of the 8 patients with SPMS and exacerbations also displayed a decrease in EDSS score in the absence of exacerbations. No adverse events, including infusion reactions, were recorded during drug administration. The drug has a good tolerance and safety profile and ease-to-use.Conclusion. Ocrelizumab therapy with will be able to improve the quality of treatment in patients with different types of MS, which is of great medical and social importance

Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial.

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or ‘transitional’ forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

ObjectiveTo determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS).DesignFrom eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261...

Multiple sclerosis (MS) is an immune-mediated disease of the centralnervous system (CNS) affecting the brain, spinal cord, andoptic nerves. In patients who have MS, the immune system attacks,damages, and strips the myelin sheath, the insulating cover of nervecells responsible for facilitating the conduction of impulses alongaxons. This injury leads to the interruption of nerve impulses travelingthrough the CNS, producing a multitude of symptoms. 1 The diseasecourse of MS may vary between patients, with some experiencing isolatedattacks and others a more progressive disease. 2

Background and ObjectiveUnderstanding the socioeconomic burden of multiple sclerosis (MS) is essential to inform policymakers and payers. Real-world studies have associated increasing costs and worsening quality of life (QoL) with disability progression. This study aims to further evaluate the impact of cognition, fatigue, upper and lower limb function (ULF, LLF) impairments, and disease progression per Expanded Disability Status Scale (EDSS) level, on costs and QoL.MethodsThis was a cross-sectional cohort study including 20,988 patients from the German NeuroTransData MS registry from 2009 to 2019. QoL analyses were based on EQ-5D-5L. Cost analyses included indirect/direct medical and non-medical costs. Eight subgroups, ranging from 439 to 1812 patients were created based on presence of measures for disease progression (EDSS), cognition (Symbol Digit Modalities Test [SDMT]), fatigue (Modified Fatigue Impact 5-Item Scale [MFIS-5]), ULF (Nine-Hole Peg Test [9HPT]), and LLF (Timed 25-Foot Walk [T25FW]). Multivariable linear regression assessed the independent effect of each test’s score on QoL and costs, while adjusting for EDSS and 12 other confounders.ResultsLower QoL was associated with decreasing cognition (p < 0.001), worsening ULF (p = 0.025), and increasing fatigue (p < 0.0001); however, the negative impact of LLF worsening on QoL was not statistically significant (p = 0.54). Higher costs were associated with decreasing cognition (p < 0.001), worsening of ULF (p = 0.0058) and LLF (p = 0.049), and increasing fatigue (p < 0.0001). Each 1-scale-step worsening function of SDMT, MFIS-5, 9HPT, and T25FW scores resulted in €170, €790, €330, and €520 higher costs, respectively. Modeling disability progression based on SDMT, MFIS-5, 9HPT, and T25FW scores as an interaction with EDSS strata found associations with lower QoL and higher costs at variable EDSS ranges.ConclusionsDisease progression in MS measured by 9HPT, SDMT, and MFIS-5 had a significant negative impact on QoL and broad socioeconomic costs independent of EDSS. T25FW had a significant negative association with costs. Cognition, fatigue, ULF, and LLF have stronger impact on costs and QoL in patients with higher EDSS scores. Additional determinants of MS disability status, including SDMT, MFIS-5, 9HPT, and T25FW, should be considered for assessing cost effectiveness of novel therapeutics for MS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-024-00501-x.

Background: Multiple sclerosis (MS) is a disease which has a variable clinical presentation followed by a variable clinical course. Therefore, accuracy of clinical rating scales to measure disability at initial clinical presentation and during follow-up visits is essential to accurately capture the variability inherent in this disease. This is particularly vital when attempting to identify the efficacy of interventions. Objective: This observational study in veterans with MS compared the Kurtkze Expanded Disability Status Scale (EDSS) and the Total Functional Independence Measure (TFIM) scale as measures of MS-related disability. Methods: We retrospectively reviewed the electronic charts of 76 veterans with MS who are regularly followed in our VA MS clinic. Local Institutional Review Board approval was obtained for the protocol. Data were analyzed using SAS (SAS System for Windows, version 9.2, SAS Institute Inc., Cary, NC, USA). Chi-square and Fisher exact tests were used to assess categorical variables. Kruskal–Wallis tests evaluated the relationships between MS types [relapsing–remitting MS (RR), secondary progressive MS (SP), primary progressive MS (PP) and clinical isolated syndrome (CIS)] and the initial TFIM, EDSS and Impairment Index (II) scores. Results: The EDSS score accurately measured MS-related impairment at initial evaluation and follow-up relative to an II. However, the EDSS score did not change over time, compared to the TFIM suggesting reduced sensitivity of the EDSS for detecting change in MS-related disability over time. Conclusions: This suggests TFIM scale is a more sensitive measure of MS-related disability than EDSS for use in future MS clinical trials.Implications for RehabilitationThis study highlights that given the paucity of scales to which EDSS has been compared, TFIM is a valuable adjunct to EDSS in measuring MS-related disability.TFIM is able to accurately measure the severity of MS-related disability and help provide for services patients with MS-related disability would need.TFIM is an easy to administer and a sensitive scale to measure the change in MS-related disability following interventions.

ABSTRACTObjectiveThe cervical spinal cord (cSC) is highly relevant to clinical dysfunction in multiple sclerosis (MS) but remains understudied using quantitative magnetic resonance imaging (MRI). We assessed magnetization transfer ratio (MTR), a semi‐quantitative MRI measure sensitive to MS‐related tissue microstructural changes, in the cSC and its relationship with clinical outcomes in radiologically isolated syndrome (RIS) and MS.MethodsMTR data were acquired from 52 RIS, 201 relapsing–remitting MS (RRMS), 47 primary progressive MS (PPMS), and 43 control (CON) participants across four sites in the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) using 3.0 T MRI systems. Mean MTR was compared between groups in whole cSC and sub‐regions between C2‐C4. Multiple linear regression was used to evaluate relationships between MTR and clinical outcomes, including the expanded disability status scale (EDSS), walking speed test (WST), and manual dexterity test (MDT).ResultsThere were consistent group differences in MTR, which were most pronounced between PPMS and CON (−5.8% to −3.7%, p ≤ 0.01). In PPMS, lower MTR was associated with greater disability as measured by EDSS (β = −0.3 to −0.1, p ≤ 0.03), WST (β = −0.9 to −0.5, p ≤ 0.04), and MDT (β = −0.6 and − 0.5, p = 0.04). In RRMS, MTR was associated with only EDSS (β = −0.1, p ≤ 0.03).InterpretationIn this large sample of RIS and MS, cSC MTR was lowest in PPMS, with associations between MTR and clinical outcomes in MS but not RIS. These findings suggest that MTR provides important information about the underlying tissue microstructural integrity of the cSC relevant to clinical disability in established MS.

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