Increase In Expanded Disability Status Scale Research Articles

Phenotyping in vivo chronic inflammation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7T susceptibility-weighted imaging.

11C-PBR28 positron emission tomography (PET), targeting the translocator protein, and paramagnetic rim lesions (PRL) have emerged as promising imaging markers of MS chronic inflammation. No consensus on which is the optimal marker exists. To investigate the ability of 11C-PBR28 PET and PRL assessment to identify chronic inflammation in white matter (WM) MS lesions and their relation to neurological impairment. Based on 11C-PBR28 uptake, brain WM lesions from 30 MS patients were classified as PET active or inactive. The PRL presence was assessed on 7T phase reconstructions, T1/T2 ratio was calculated to measure WM microstructural integrity. Less than half (44%) of non-PRL WM lesions were active on 11C-PBR28 imaging either throughout the lesion (whole active) or at its periphery. PET peripherally active lesions and PRL did not differ in T1/T2 ratio and 11C-PBR28 uptake. A positive correlation was observed between PRL and active PET lesion count. Whole active PET lesion volume was the strongest predictor (β = 0.97, p < 0.001) of increased Expanded Disability Status Scale scores. 11C-PBR28 imaging reveals more active WM lesions than 7T PRL assessment. Although PRL and PET active lesion counts are related, neurological disability is better explained by PET whole active lesion volume.

Hospital-Treated Infections and Risk of Disability Worsening in Multiple Sclerosis.

To investigate the association between infections and disability worsening in people with multiple sclerosis (MS) treated with either B-cell depleting therapy (rituximab) or interferon-beta/glatiramer acetate (IFN/GA). This cohort study spanned from 2000 to 2021, using data from the Swedish MS Registry linked to national health care registries, comprising 8,759 rituximab and 7,561 IFN/GA treatment episodes. The risk of hospital-treated infection was estimated using multivariable Cox models. The association between infections and increase in Expanded Disability Status Scale (EDSS) scores was assessed using a doubly robust generalized estimating equations model. Additionally, a piece-wise exponential model analyzed events of increased disability beyond defined cut-off values, controlling for relapses, and MRI activity. Compared with IFN/GA, rituximab displayed increased risk of both inpatient- and outpatient-treated infections (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.50-2.90 and HR, 1.37; 95% CI, 1.13-1.67, respectively). An inpatient-treated infection was associated with a 0.19-unit increase in EDSS (95% CI, 0.12-0.26). Degree of worsening was greatest for progressive MS, and under IFN/GA treatment, which unlike rituximab, was more commonly associated with MRI activity. After controlling for relapses and MRI activity, inpatient-treated infections were associated with disability worsening in people with relapsing-remitting MS treated with IFN/GA (HR, 2.01; 95% CI, 1.59-2.53), but not in those treated with rituximab. Compared to IFN/GA, rituximab doubled the infection risk, but reduced the risk of subsequent disability worsening. Further, the risk of worsening after hospital-treated infection was greater with progressive MS than with relapsing-remitting MS. Infection risk should be considered to improve long term outcomes. ANN NEUROL 2024.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Paramagnetic rim lesions predict greater long-term relapse rates and clinical progression over 10 years

Background: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression. Objectives: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse. Methods: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models. Results: PRL+ pwMS had greater overall annual relapse rate (β = 0.068; p = 0.010), three times greater overall odds of relapse (exp(β) = 3.472; p = 0.009), and greater rate of yearly EDSS change (β = 0.045; p = 0.010) than PRL− pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(β) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number. Conclusion: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression.

Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

Identification of alemtuzumab-suitable multiple sclerosis patients in Slovakia and sequencing of post-alemtuzumab immunomodulatory treatment.

Alemtuzumab (ALEM) is a humanised monoclonal antibody that depletes circulating lymphocytes by selectively targeting CD52, which is expressed in high levels on T- and B-lymphocytes. This depletion is followed by lymphocyte repopulation and a cytokine expression shift towards a lesser inflammatory profile, both of which may contribute to prolonged efficacy. National recommendations for enrolling and treating multiple sclerosis (MS) patients with ALEM have been established. However, there are no recommendations in place for the treatment of MS reactivation after the ALEM treatment. To evaluate the effectiveness and safety of the use of ALEM and to analyse subsequent disease-modifying treatments (DMTs). A multidimensional prediction model was developed to make a patient-specific prognosis regarding the response to ALEM. A multicentre, prospective, non-controlled, non-interventional, observational cohort study. Relapsing multiple sclerosis patients (RMSp) who received ⩾1 dose of ALEM were enrolled. In each treatment year, the following baseline and prospective data were collected: age, MS history, number, type and duration of previous disease-modifying treatment (PDMT), relapse rate (REL), expanded disability status scale (EDSS), magnetic resonance imaging and serious adverse events (AE). In cases of reactivation of MS, all data about the subsequent DMT were collected. A total of 142 RMSp from 10 MS Slovak Centres fulfilled the inclusion criteria. The average age was 35 years (standard error 8.56). The overall average EDSS was 3.87 (1.46) when ALEM was started. The average duration of PDMT was 6.0 (4.04) years, and the median number of PDMTs was 3 (0-5), while the patients were mostly treated with 2 or 3 DMTs (>65.00%). Post-ALEM treatment was needed in 39 cases (27.46%). The most frequent post-ALEM treatment indicated was ocrelizumab, followed by natalizumab (NAT), siponimod and cladribine. The ocrelizumab and NAT treatment bring little benefit to patients. Siponimod showed less EDSS increase in contrast to ocrelizumab and NAT. Another repopulation therapy, cladribine, may also be an effective option. Statistically significant predictors for the expected EDSS are age (p-value <0.0001), number of ALEM cycles (0.0066), high number of PDMT (0.0459) and the occurrence of relapses (<0.0001). There was no statistically significant effect on the patient's gender (0.6038), duration of disease-modifying treatment before alemtuzumab (0.4466), or the occurrence of AE (0.6668). The study confirms the positive effect of ALEM on clinical and radiological outcomes. We need more data from long-term sequencing studies.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. Association between NfL z scores and CDW. CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Long-term outcome of natalizumab-associated progressive multifocal leukoencephalopathy in Austria: a nationwide retrospective study

Background/objectiveThe use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria.MethodsRetrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome.ResultsAs of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11.ConclusionsThe number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare.

The socioeconomic impact of disability progression in multiple sclerosis: A retrospective cohort study of the German NeuroTransData (NTD) registry.

Multiple sclerosis (MS) is a progressively debilitating neurologic disease that poses significant costs to the healthcare system and workforce. To evaluate the impact of MS disease progression on societal costs and quality of life (QoL) using data from the German NeuroTransData (NTD) MS registry. Cross-sectional cohort study. The cost cohort included patients with MS disability assessed using Expanded Disability Status Scale (EDSS) in 2019 while the QoL cohort included patients assessed using EDSS and EuroQol-5 Dimension 5-Levels between 2009 and 2019. Direct and indirect medical, and non-medical resource use was quantified and costs derived from public sources. Within the QoL cohort (n = 9821), QoL worsened with increasing EDSS. Within the cost cohort (n = 7286), increasing resource use with increasing EDSS was observed. Societal costs per patient, excluding or including disease-modifying therapies, increased from €5694 or €19,315 at EDSS 0 to 3.5 to €25,419 or €36,499 at EDSS 4 to 6.5, and €52,883 or €58,576 at EDSS 7 to 9.5. In multivariate modeling, each 0.5-step increase in EDSS was significantly associated with increasing costs, and worsening QoL. This study confirms the major socioeconomic burden associated with MS disability progression. From a socioeconomic perspective, delaying disability progression may benefit patients and society.

Evaluation of frequency, severity, and independent risk factors for recurrence of disease activity after fingolimod discontinuation in a large real-world cohort of patients with multiple sclerosis.

Clinical and radiological signs of recurring disease activity (RDA) have been described in patients with multiple sclerosis (pwMS) after discontinuation of fingolimod (FGL). To describe frequency, severity and potential risk factors for RDA after FGL discontinuation in a large real-world cohort of pwMS. Post-FGL RDA was defined as evidence of clinical and/or radiological activity within 6 months after FGL discontinuation. Relapses with Expanded Disability Status Scale increase ⩾2 points and/or magnetic resonance imaging (MRI) activity with at least five cerebral gadolinium-enhancing lesions and/or ⩾6 cerebral new T2 lesions were defined as severe recurring disease activity (sRDA). Using a multivariate logistic model, we explored the influence of age, disease duration, sex, clinical, and MRI activity under FGL on the occurrence of RDA. We identified 110 pwMS who discontinued FGL. Thirty-seven (33.6%) developed post-FGL RDA and 13 (11.8%) also fulfilled criteria for sRDA. Younger age at diagnosis [odds ratio (OR) = 1.10, p < 0.01], shorter disease duration (OR = 1.17, p < 0.01), and MRI activity under FGL (OR = 2.92, p = 0.046) were independent risk factors for the occurrence of post-FGL RDA. Individual risk assessment and optimal treatment sequencing can help to minimize the risk of post-FGL RDA. Early switch to highly effective disease-modifying therapy might reduce occurrence of post-FGL RDA.

Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis

Background: Magnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). Objectives: To identify the relationship between SELs and PRLs in MS, and their association with disability. Methods: 61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs. Results: The median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients. Conclusion: SELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.

Can fatigue predict the worsening of multiple sclerosis one year later? An explorative study with participants referred to assess their ability to work

BackgroundMultiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system and is triggered by several environmental factors in genetically predisposed people. ObjectivesTo explore which evaluation battery items used for evaluation of work capacity at baseline can best predict MS progression at 1 year follow-up. MethodsIn this prospective single-centre study, participants with MS were recruited consecutively when visiting a neurologist for referral for the determination work capacity status at the Disability and Working Capacity Assessment Office. At baseline, a neurologist assessed patients using the following evaluation scales: Fatigue self-assessment, Fatigue Descriptive Scale (FDS), Memory self-assessment, Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), Short Form 36 (SF-36), and the Brief International Classification of Functioning and Disability (ICF) core set for MS. The Expanded Disability Status Scale (EDSS) was evaluated by neurologists at baseline and one year later. An increase in EDSS by 0.5 points after one year was defined as MS progression. ResultsDuring the one year period among 72 participants, 21 fulfilled the criteria for MS progression. In more than 75% of these participants, impairments were found in the following ICF subitems at baseline: “energy and drive functions”, “muscle and power functions”, and “moving around”. Greater impairments were identified in progressing participants. Progressing participants scored higher on the FDS and scored lower on the BICAMS and SF-36. Regression analysis indicated that the FDS sum score predicted MS progression one year later. ConclusionsIncreased fatigue might indicate worsening in MS one year later.

Identification of disability status in persons with multiple sclerosis by lower limb neuromuscular function – Emphasis on rate of force development

BackgroundNeurodegeneration is an inevitable consequence of multiple sclerosis (MS) leading to impaired neuromuscular function, especially of the lower extremities. Whilst maximal muscle strength (or force; Fmax) is the most examined feature of neuromuscular function, the ability to rapidly increase muscle force (= rate of force development; RFD) appear to be preferentially sensitive towards neurodegeneration and potentially also of great importance for physical function. The purpose of the present study was to comprehensively examine and compare different outcome measures of neuromuscular function (with specific emphasis given to RFD) across disability status in persons with MS (pwMS), and in comparison, to age- and sex-matched healthy controls (HC). MethodsA total of n=34 HC and n=99 pwMS were enrolled in the study, with the latter being divided into Expanded Disability Status Scale (EDSS) subgroups: MSmild (EDSS 0–2.5, n=51), MSmoderate (EDSS 3.0-4.5, n=33), and MSsevere (EDSS 5-6.5, n=15). Knee extensor neuromuscular function was assessed by Fmax and RFD (RFD50ms and RFD200ms, respectively; calculated in the interval 0–50 ms and 0–200 ms relative to the onset of contraction) with simultaneous electromyography (maximal EMG (EMGFmax) and rate of EMG rise (rEMG50ms and rEMG200ms, respectively)). Voluntary muscle activation derived from the interpolated twitch technique was also determined during additional Fmax trials. Lastly, physical function was assessed by the 5 x sit-to-stand test (5STS), the timed 25-foot walk test (T25FWT), and the 2-min walking test (2MWT). ResultsSubstantial differences (∼deficits) (p<0.05) were observed for all pwMS subgroups compared to HC across all neuromuscular function outcome measures; RFD50ms (MSmild -22%, MSmoderate -36%, MSsevere -66%), RFD200ms (-12%, -21%, -51%), and Fmax (-11%, -14%, -33%). Somewhat comparable differences (∼deficits) (p<0.05) were observed for voluntary muscle activation (rEMG50ms, rEMG200ms, EMGFmax, and activation) and for physical function (5STS, T25FWT, and 2MT). Deficits in neuromuscular function were strongly associated with EDSS (p<0.05) (RFD50ms: slope steepness -13% per 1 point increase in EDSS, r2=0.79; RFD200ms: slope steepness -10%, r2=0.84; Fmax: slope steepness -6%, r2=0.82). Fmax and RFD were associated with physical function outcome measures (p<0.05) to a comparable extent (r2-values ranging from 0.21 to 0.35). ConclusionLower extremity neuromuscular function is impaired in pwMS compared to HC with differences (∼deficits) becoming greater with increasing disability status. RFD was preferentially sensitive in capturing differences (∼deficits) across disability status and by showing strong associations with EDSS. Altogether, knee extensor RFD could serve as a simple objective marker of disability status or even progression in pwMS, that may be helpful to both researchers and clinicians.

Impact of telehealth on health care in a multiple sclerosis outpatient clinic during the COVID-19 pandemic

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has precipitated expansion of telemedicine in outpatient management of chronic diseases including multiple sclerosis (MS). Studies conducted pre-pandemic, when telehealth was an alternative to in-person consultations, represent a different setting to current practice. The aim of this study was to assess the impact of telehealth on MS outpatient care in a tertiary metropolitan hospital in Melbourne, Australia during the COVID-19 pandemic. MethodFrom March-December 2020, patients and clinicians in the MS outpatient clinic were surveyed regarding their attitudes towards telehealth. Scores on the Expanded Disability Status Scale (EDSS) from telehealth and face-to-face appointments during the study period were compared to scores from face-to-face consultations before and after this period. Medical records were reviewed to compare management decisions made during telehealth versus face-to-face consultations. Diagnoses and treatment of MS relapses were compared to 2019. ResultsTelehealth was used in 73% of outpatient appointments. Patient satisfaction was generally high. Patients and clinicians preferred face-to-face consultations but were willing to use telehealth longer term. Overall, there were no significant delays in identifying patients experiencing disability worsening via telehealth, but EDSS increase was recorded in more face-to-face than telehealth appointments particularly for those with lower baseline disability. Disease-modifying therapy commencement rates were similar, but symptomatic therapy initiation and investigation requests occurred more frequently in face-to-face visits. Comparable numbers of MS relapses were diagnosed and treated with corticosteroids in 2019 and 2020. ConclusionsPatient satisfaction with telehealth was high, but both clinicians and patients preferred in-person appointments. Telehealth implementation did not lead to high rates of undetected disability worsening or undiagnosed acute relapses, but telehealth-based EDSS assessment may underestimate lower scores. Treatment inertia may affect some management decisions during telehealth consultations. Telehealth will likely play a role in outpatient settings beyond the COVID-19 pandemic with further studies on its long-term impact on clinical outcomes required.

Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis

ObjectiveTo quantify sex differences in activity and severity of multiple sclerosis (MS) and how it depends on disease duration and time since clinical onset.MethodsAll Danish citizens with onset of relapsing...

Antibodies to neurofilament light as potential biomarkers in multiple sclerosis

Background and objectiveThe concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and blood is widely considered as a quantitative measure of neuro-axonal injury. Immune reactivity to NfL released...

Physical, Emotional, Medical, and Socioeconomic Status of Patients With NMOSD: A Cross-Sectional Survey of 123 Cases From a Single Center in North China.

Objective: This study aimed to assess the physical, emotional, medical, and socioeconomic conditions of patients with neuromyelitis optica spectrum disorder (NMOSD) in North China.Methods: A cross-sectional survey of patients with NMOSD was performed, based on an established questionnaire from the Multiple Sclerosis Patient Survival Report 2018. Logistic regression analysis was conducted to define the significant determinants of certain physical or emotional characteristics of patients. A total of 123 patients were included.Results: A total of 63.4% of participants were initially diagnosed with conditions other than NMOSD, with a median delay of 6 months for accurate diagnosis. An aggregate of 72.2% of patients had one or more relapses, corresponding to an annual relapse rate of 0.8. Paresthesia was the most frequent physical symptom among patients both at disease onset (53.7%) and throughout the duration of the disease (86.2%). Onset in elderly (>50 years) patients was associated with an annual Expanded Disability Status Scale increase ≥1, compared with onset in younger (<30 years) patients (P = 0.001, OR = 7.83). A total of 76.4% of patients had received attack-prevention treatments in the remission phase, and 31.7 and 10.6% of patients had ever been administered rituximab and traditional Chinese medicine, respectively. Additionally, 63.4 and 43.1% of patients reported participating in few or no social activities and being out of work because of the disease. To be noted, 76.4% of patients reported suffering from negative emotions, with the most frequent being worry (60.2%), with 20.3% of patients experiencing suicidal thoughts. The inability to work and participating in few or no social activities due to NMOSD were two determinants of experiencing negative emotions (Pwork = 0.03, ORwork = 3.34; Psocialactivities = 0.02, ORsocialactivities = 3.19).Conclusion: This study reported patient perspectives on NMOSD in North China, whereby demonstrating that the inability to work and participating in few or no social activities due to NMOSD rather than the physical impairment caused by the disease, was directly associated with patients experiencing negative emotions. This insight offers potential ways to manage patients' negative emotions by enhancing family and social support and facilitating active employment.

Relapses add to permanent disability in relapsing multiple sclerosis patients

ObjectiveWhether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT). MethodsFrom the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke's EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression. ResultsWe included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 – 9.194) and 0.086 in patients without relapses (95% CI 0.074 – 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 – 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 – 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses. ConclusionsOur results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.

Menopause does not modify disability trajectories in a longitudinal cohort of women with clinically isolated syndrome and multiple sclerosis followed from disease onset.

To evaluate the effect of menopause on disability accumulation in women followed from their clinically isolated syndrome (CIS). We examined the longitudinal changes in Expanded Disability Status Scale (EDSS) scores from CIS until the last follow-up in women belonging to the Barcelona CIS prospective cohort, followed through their menopausal transition. The analysis is based on 13,718 EDSS measurements, with an average of 28 EDSS measurements per patient. Differences in EDSS trajectories between menopausal and nonmenopausal women, controlling for age and disease duration, were evaluated. We performed two sensitivity analyses in women with confirmed MS and in those experiencing early menopause. From 764 eligible women, 496 (65%) responded to the questionnaire, and 74 (14.9%) reached menopause over the follow-up. We did not find a significant inflection point in EDSS trajectories around menopause (slope change -0.009; 95% CI -0.066; 0.046). The annual increase in EDSS over the complete course of the disease was significantly higher in menopausal women (0.049; 95% CI, 0.026-0.074) versus nonmenopausal (0.019; 95% CI, 0.008-0.031; interaction p value 0.025). This difference was lost when controlling for age and disease duration (EDSS annual increase of 0.059; 95% CI, 0.025-0.094 vs. 0.038; 95% CI, 0.021-0.057, respectively; interaction p value 0.321). No inflection point was detected when the analysis was restricted to women with confirmed MS or with earlier menopause. Menopause is not associated with an increased risk of disability in a CIS population, considering EDSS trajectories throughout the course of the disease together with age and disease duration.

Clinical and transcriptional recovery profiles in pediatric and adult multiple sclerosis patients.

ObjectiveTo determine whether pediatric‐onset multiple sclerosis (POMS) and adults‐onset multiple sclerosis (AOMS) patients are different in initial disease severity and recovery and to investigate the associations with peripheral blood mononuclear cells (PBMCs) transcriptional profiles.MethodsClinical and radiological severity of first and second relapses and 6‐month recovery were analyzed in 2153 multiple sclerosis (MS) patients and compared between POMS (onset at 8–18years old) and AOMS (onset at 19–40 years old) patients. PBMCs transcriptomes of 15 POMS and 15 gender‐matched AOMS patients were analyzed 6 months after the first relapse and compared to 55 age‐matched healthy controls. Differentially Expressed Genes (DEGs) with a false discovery rate ≤ 10% were evaluated using the Partek software.ResultsPOMS had increased Expanded Disability Status Scale (EDSS) score at first and second relapses, higher brain gadolinium‐enhancing T1‐lesions volume at first relapse, and more complete recovery after both relapses compared to AOMS. POMS patients, who recovered completely from the first relapse, were characterized by 19 DEGs that were mainly related to suppression of antigen presentation. Six upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls. POMS patients, who showed no recovery from the first relapse, were characterized by 28 DEGs that were mainly associated with B‐cell activation. Five upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls.InterpretationPOMS patients may have more severe first and second relapses than AOMS. However, most often, POMS have better recovery that may be attributed to PBMCs age‐related transcriptional profiles associated with antigen presentation and B‐cell activation.