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Background: 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. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: 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. Results: 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. Conclusions: 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.

Background/aim: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. Materials and methods: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients’ database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. Results: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. Conclusion: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Background: COVID-19 vaccines are recommended for people with multiple sclerosis (pwMS). Adequate humoral responses are obtained in pwMS receiving disease-modifying therapies (DMTs) after vaccination, with the exception of those receiving B-cell-depleting therapies and non-selective S1P modulators. However, most of the reported studies on the immunity of COVID-19 vaccinations have included mRNA vaccines, and information on inactivated virus vaccine responses, long-term protectivity, and comparative studies with mRNA vaccines are very limited. Here, we aimed to investigate the association between humoral vaccine responses and COVID-19 infection outcomes following mRNA and inactivated virus vaccines in a large national cohort of pwMS receiving DMTs. Methods: This is a cross-sectional and prospective multicenter study on COVID-19-vaccinated pwMS. Blood samples of pwMS with or without DMTs and healthy controls were collected after two doses of inactivated virus (Sinovac) or mRNA (Pfizer-BioNTech) vaccines. PwMS were sub-grouped according to the mode of action of the DMTs that they were receiving. SARS-CoV-2 IgG titers were evaluated by chemiluminescent microparticle immunoassay. A representative sample of this study cohort was followed up for a year. COVID-19 infection status and clinical outcomes were compared between the mRNA and inactivated virus groups as well as among pwMS subgroups. Results: A total of 1484 pwMS (1387 treated, 97 untreated) and 185 healthy controls were included in the analyses (male/female: 544/1125). Of those, 852 (51.05%) received BioNTech, and 817 (48.95%) received Sinovac. mRNA and inactivated virus vaccines result in similar seropositivity; however, the BioNTech vaccination group had significantly higher antibody titers (7.175±10.074) compared with the Sinovac vaccination group (823±1.774) (p

Objective: We aimed to evaluate the demographic, clinical, and immunological features of myasthenia gravis (MG) in adults according to the age of onset and to investigate the effect on prognosis. Methods: A total of 332 patients with MG were included in the study. Patients were classified into three age subgroups: early-onset MG (EOMG), late-onset MG (LOMG), and very late-onset MG. Complete stable remission, pharmacological remission, and minimal manifestations for 1 year were assessed as a good prognosis on the MGFA-PIS scale. Improved, unchanged, worse, exacerbation and death due to MG were assessed as having a poor prognosis. Results: There were 177 (53.3%) female and 155 male (46.7%) patients with a mean age of 55.3 ± 17.4. A total of 176 patients (53%) were classified as EOMG, 94 patients (28.3%) as LOMG, 62 (18.7%) as very late-onset MG, 282 patients (84.9%) as anti-AChR positive, 21 patients (6.3%) as anti-MuSK positive, and two patients (0.6%) as anti- AChR and anti-MuSK double-positive. While 95.6% of patients with a good prognosis had MGFA-1 at the onset of the disease, 40.3% of patients with a poor prognosis had MGFA-2B. At the end of the clinical follow-up, the MGFA-PIS score was evaluated, 55.1% of the patients had a good prognosis, while 44.9% had a poor prognosis. Conclusions: Age at disease onset was not associated with prognosis. Presence of generalized MG subtype and thymoma, anti-MuSK positivity, hospitalization in the intensive care unit, myasthenic crisis, IVIG administration, plasmapheresis, comorbidity, 2 or more comorbidities were found to have significant association with poor prognosis.

© 2022Background: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, “BRACETD”) often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. Methods: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. Results: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59–0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60–0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03–1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. Conclusions: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod.

Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: 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.Results: 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.Conclusions: 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. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Background Coronavirus disease 2019 (COVID-19) can affect the neurological as well as the respiratory system. Neurological manifestations may involve the central or peripheral nervous systems, or musculoskeletal system. Findings can range from mild presentations, such as headache and anosmia, to severe complications, such as stroke and seizure. Objectives To evaluate the neurological findings and to determine etiological risk factors for mortality in patients hospitalized for COVID-19. Methods Medical records of patients with COVID-19 who were hospitalized and sought neurological consultation between March 2020 and March 2021 at a reference pandemic hospital in Turkey were reviewed retrospectively in a cross-sectional study design. Result We included data from 150 (94 male) patients. Their mean age ± standard deviation was 68.56 ± 16.02 (range 21–97) years. The patients were categorized into 2 groups according to any acute neurological event or progression of neurological disease. Ischemic cerebrovascular events, seizures, and encephalopathy were the most common acute neurological events, while deterioration in consciousness, epileptic seizures, and Parkinson disease were observed in those with progression of neurological disease. Abnormal neurological findings were found at a mean of 7.8 ± 9.7 days following COVID-19 diagnosis and 50 (a third of) patients died. A logistic regression model found that advanced age, increased Modified Charlson Comorbidity Index (MCCI) score, and prolonged duration of hospitalization were factors significantly associated with increased mortality; however, sex and day of abnormal neurological findings after COVID-19 diagnosis were not. Common conditions accompanying neurological events were hypertension, coronary artery disease–heart failure, and diabetes mellitus. Conclusion COVID-19 may present with neurological symptoms in our Turkish patients and comorbidities are often present.

Background: The role of inflammation in the prognosis of cerebral venous sinus thrombosis (CVST) has been demonstrated in a small number of studies. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII) have been studied as prognostic inflammatory biomarkers in numerous thrombo-embolic diseases. However, the number of studies evaluating the relationship between these parameters and CVST is very low. Objectives: The purpose of this retrospective study was to investigate the relationship between PLR, NLR, and SII values on admission and long-term prognosis in patients with CVST in the acute-subacute period. Methods: Fifty-one patients diagnosed with CVST and 51 healthy controls were included in the study. The patient and control groups were compared in terms of NLR, PLR, and SII values. Patients were classified into good and poor prognosis groups based on sixth-month modified Rankin scale scores (mRS) (0-2: good prognosis, 3-6: poor prognosis). Clinical and radiological features and PLR, NLR, and SII values were compared between the good and poor prognosis groups. Multivariate logistic regression analysis was used to identify independent prognostic factors for poor prognosis. The Receiver Operating Curve (ROC) was used to demonstrate the predictive power of PLR, NLR, and SII. Results: Higher NLR and SII emerged as independent factors for poor prognosis in patients with CVST. NLR was the strongest parameter in predicting poor prognosis in CVST (AUC: 0.817, 95% CI: 0.63-1.00, sensitivity 70%, specificity 92.7%, p:0.002). Conclusion: Higher NLR and SII on admission may be a predictor of long-term poor prognosis in patients with acute-subacute CVST.

Background: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). Objective: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. Methods: 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. Results: 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 Conclusion: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Background and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses and reach irreversible disability at a younger age than adult-onset patients. There have been few randomized placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry.MethodsThis retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021 (N=1218). The primary outcome was the time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years post baseline; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement.ResultsPatients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMT (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29–0.83;P=0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMT (HR, 0.15; 95% CI, 0.07–0.31;PP=0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting–adjusted patient populations were confirmed in multiple sensitivity analyses.DiscussionOur results suggest that natalizumab and fingolimod have broadly equivalent therapeutic efficacies in patients with POMS, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. However, analyses of relapse outcomes suggest natalizumab is superior to fingolimod in the control of relapses in this population with high rates of new inflammatory activity.Classification of EvidenceThis study provides Class III evidence that natalizumab may provide better disease control than fingolimod in patients with POMS.

Management of treatment-resistant patients with myasthenia gravis (MG) remains an important issue. This study aimed to evaluate the effects of rituximab (RTX) treatment on the prognosis of patients with acetylcholine receptor autoantibody-positive (AChR-Ab+), muscle-specific kinase autoantibody-positive (MuSK-Ab+), or seronegative or double seropositive MG.Nineteen patients treated with RTX between 2015 and 2020 were included in this study. Demographic and clinical characteristics, prognosis, and prognostic predictors of MG were evaluated retrospectively. The Myas-thenia Gravis Foundation of America Post-Inter-vention Status (MGFA-PIS) before RTX treatment (pre-RTX) and after RTX treatment (post-RTX) were recorded.A total of 10 patients (52.6%) were AchR Ab+, 6 patients (31.6%) were MuSK Ab+, 1 patient (5.3%) was seronegative, and 2 patients (10.5%) were double seropositive. Steroid dose was pre-RTX 38.9±5.7 (25-45), it was post-RTX 10.5±10.3 (0-30) (p0.001). Post-RTX steroid treatment was discontinued in 6 of 19 patients (p=0.041). Only three patients received intravenous immunoglobulin at the post-RTX follow-up (p0.001). In post-RTX 12th month, the MGFA-PIS score was as minimally manifestation or better in 9 patients (47.3%) and improved or was better in 18 patients (94.7%) (p-value 0.004;0.001, respectively).The improvement in MGFA-PIS scores post-RTX was similar in MuSK-Ab+ and AChR-Ab+ patients. The data are insufficient in seronegative and double seropositive patients and RTX must be considered in the treatment of suitable patients with MuSK-Ab+ and AChR-Ab+ refractory MG.A terápiára nem reagáló myasthenia gravis- (MG-) betegek kezelése fontos problémát jelent. Vizsgálatunk célja az volt, hogy megvizsgáljuk a rituxi­mab- (RTX-) kezelés hatását az acetilkolin-receptor-ellenes autoantitest-pozitív (AChR-Ab+), az izomspecifikus kináz-ellenes autoantitest-pozitív (MuSK-Ab+), a szeronegatív és a dupla szeropozitív MG-ben szenvedő betegek esetében.A vizsgálatba 19 olyan MG-beteget vontunk be, akiket 2015 és 2020 között RTX-szel kezeltek. Retrospektív módon összegyűjtöttük a betegek demográfiai és klinikai adatait, valamint értékeltük az MG prognosztikus prediktorait. Feljegyeztük az RTX-kezelés előtti (pre-RTX) és utáni (post-RTX) MGFA-PIS-értékeket (MGFA-PIS: Myasthenia Gravis Foundation of America Post-Intervention Status).10 beteg (52,6%) volt AChR-Ab+, hat beteg (31,6%) volt MuSK-Ab+, egy beteg (5,3%) volt szeronegatív, és két beteg (10,5%) volt dupla szeropozitív. A pre-RTX szteroiddózis 38,9 ± 5,7 (25–45) volt, a post-RTX szteroiddózis pedig 10,5 ± 10,3 (0–30) (p0,001). A post-RTX szteroid-kezelés a 19 betegből hat esetében vált szükségtelenné (p = 0,041). A post-RTX-utánkövetés során mindössze három beteg kapott intravénás immunglobulint (p0,001). Az RTX-kezelés utáni 12. hónapban az MGFA-PIS-pontszám kilenc beteg (47,3%) esetében minimális vagy jobb értékeket mutatott, 18 beteg (94,7%) esetében pedig javuló vagy jobb manifesztációt (p-érték: 0,004;0,001).Következtetés – Az RTX-kezelés utáni MGFA-PIS-pontszám-javulás hasonló volt a MuSK-Ab+ és az AChR-Ab+ betegek körében. A szeronegatív és a dupla szero­pozitív MG-betegek esetében elégtelen mennyiségű adat keletkezett. Az RTX-kezelés megfontolandó a megfelelően kiválasztott, terápiarezisztens MuSK-Ab+ és AChR-Ab+ MG-betegek esetében.

IntroductionCarpal tunnel syndrome (CTS) is the most common entrapment neuropathy in society. Based on the data obtained from basic conventional CTS studies, patients can be staged, and the changes in CTS severity can be followed according to the electrophysiological parameters derived from the data. This study aimed to assess the electrophysiological findings of CTS patients using the Bland and Padua grading systems and median terminal latency index (mTLI) and to evaluate the findings that may indicate the transition to the advanced stage.Material and methodsThe study included 822 patients. After electrophysiological examination, both hands of the patients were staged according to the grading systems proposed by Padua and Bland. Additionally, mTLI was calculated for each hand.ResultsWith the increase in stages, a significant decrease was found in mTLI, median sensory nerve conduction velocity (mSNCV), median sensory amplitude (mSA), median motor nerve conduction velocity (mMNCV), and median motor amplitude (mMA), whereas a significant increase was observed in median sensory distal latency (mSDL) and median motor distal latency (mMDL) (pConclusionsOur results showed that with a cut-off value of 40.5 m/s, mSNCV is an accurate sensitive and specific parameter regarding the indication of transition to the advanced stage.

Background and purpose 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. Methods 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. Results 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 >88% likely to be sustained (events with score >1.5). Conclusions 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. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries

Interferon-β, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS.Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs.In comparison to other DMTs, we did not find evidence of protective effects of interferon-β on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-β. This study does not support the use of interferon-β as a treatment to reduce COVID-19 severity in MS.

Background: Among the comorbidities that accompany multiple sclerosis (MS), restless legs syndrome (RLS) is one of the most common. Anxiety and depression are common psychological comorbidities that impact the quality of life of patients with MS (PwMS), as well as patients with RLS. Objective: To investigate the psychiatric burden of MS and RLS coexistence, we conducted a nationwide, multicenter and cross-sectional survey. Methods: Participants were assessed by using demographic and clinical parameters along with the Hamilton Anxiety and Hamilton Depression Scales (HAM-A and HAM-D). Results: Out of the 1,068 participants, 173 (16.2%) were found to have RLS [RLS(+)] and 895 (83.8%) did not [RLS(-)]. The mean scores for HAM-A and HAM-D were significantly higher among RLS(+) subjects than among RLS(-) subjects (p

The incidence of early onset multiple sclerosis (EOMS) is increasing. We therefore aimed to compare the demographic, clinical, and magnetic resonance imaging features of early onset and adult onset multiple sclerosis patients. Furthermore, the effects of age of onset were evaluated for patients who reached an expanded disability status scale (EDSS) scores of six.This was a retrospective study of MS patient medical charts between 1977 and 2021, which were registered in the MS database. Only patients with relapsing remitting MS longer than 1 year were included in the study. The patients included in the study were divided into the EOMS and adult onset MS (AOMS) groups. General demographic datas, clinical datas such as the characteristics of the first clinical period, the time between the first two attacks, the attack rate in the first 2 and 3 years, the treatment status, the EDSS at the first evaluation, the EDSS score at 6 month intervals, the time to reach an EDSS score of six, and magnetic resonance imaging features such brain and spinal T2 lesions were recorded.Total of 3477 including 353 (10.2 %) EOMS and 3124 (89.8 %) AOMS patients were analyzed. There was no statistically significant difference in symptom patterns between the EOMS and AOMS groups ( p = 0.649). Supratentorial clinical features at first attack were more common in AOMS patients, while optic neuropathy at first attack was more common in EOMS patients. Using univariable analysis, clinical supratentorial features at first attack, clinical optic neuropathy at first attack, clinical spinal cord at fist attack, spinal cord lesions, first EDSS score, relapse in the first 3 years, and onset patterns in terms of age were found to be statistically significant risk factors. In multivariable-adjusted analysis, clinical supratentorial features at first attack, clinical spinal cord lesions at first attack, first EDSS scores relapses in the first 3 years, and onset patterns in terms of age were found to be independent risk factors for EDSS in reaching a score of six. Early treatment start was associated with reduced hazard rate of reaching an EDSS score of 6.Onset pattern in terms of age was an independent prognostic factor for neurological disabilities in MS patients.

Background and Objectives Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed.Methods Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab.Results Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1–7] and 7% [95% CI 4–11]), ICU/artificial ventilation (2% [95% CI 0–4] and 4% [95% CI 2–6]), and death (1% [95% CI 0–2] and 2% [95% CI 1–4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2–8), 3% (95% CI 1–5), and 1% (95% CI 0–3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19.Discussion Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19. BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

The majority of disease-modifying drugs (DMDs) available for the management of active relapsing–remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but this invasive and intensive therapy has challenging side-effects. A short treatment course of a pharmacologic agent hypothesized to act as an IRT, such as Cladribine Tablets 3.5 mg/kg or alemtuzumab, can provide long-term suppression of MS disease activity, without need for continuous treatment (the anti-CD20 mechanism of ocrelizumab has the potential to act as an IRT, but is administered continuously, at 6-monthly intervals). Cladribine Tablets 3.5 mg/kg shows some selectivity in targeting adaptive immunity with a lesser effect on innate immunity. The introduction of IRT-like disease-modifying drugs (DMDs) challenges the traditional maintenance/escalation mode of treatment and raises new questions about how disease activity is measured. In this review, we consider a modern classification of DMDs for MS and its implications for the care of patients in the IRT era.

Purpose: The aim of present study was to evaluate clinical and morphometric differences and to determine the improvement in facial movements in pre- and post- acupuncture treatments of patients with Bell’s palsy sequelae.Materials and Methods: A total of 40 patients with Bell’s palsy sequeale (20 acupuncture group-20 control group) were included in this study. The acupuncture group consisted of Bell’s palsy sequelae and scheduled for acupuncture theraphy (12 sessions). The control group consisted of Bell’s palsy sequelae, being kept on the waiting list. The deatiled medical histories were obtained from all patients. Morphometric measurements were performed based on determined anatomical points on both affected and unaffected sides of the faces in resting and smiling positions. At the end of the study clinical evaluations and morphometric measurements were repeated and results were analyzed statistically.Results: The significant difference was observed in the headache symptoms of the acupuncture group patients in terms of clinical evaluations. In acupuncture group, there was statistically significant difference in pre- and post-treatment values of the affected side in the resting and smiling positions. There were significant changes in clinical symptoms and facial movements in the affected side of the face in the acupuncture group patients. Conclusion: Acupuncture therapy may be considered to have a significant therapeutic effect on changes in facial movements especially in clinical and morphometric aspects of Bell’s palsy sequelae.

Background The multiple sclerosis (MS) landscape has changed over the past two decades across the world and in the Middle East. The Middle East is an ethnically diverse region located between 12 degrees and 42 degrees of latitude and 35 degrees and 54 degrees of longitude and varying altitudes. The magnitude of the shifts observed in the epidemiology and management of MS differ in each region and from country to country. Objectives The aim of this study was to provide a clinicodemographic overview of the cohorts of patients contributed to MSBase, a large international MS registry, in the Middle East and describe disease-modifying treatment (DMT) utilization in the different countries within the region. Understanding the differences between these cohorts is integral to interpretation of the studies conducted using registry data and provides insight into clinical practice in these cohorts. Methods The MSBase registry was searched for patients with MS or clinically isolated syndrome from the Middle Eastern countries with data captured between 2009 and 2018. In 2-year epochs, and with special focus on the most recent epoch (2017-2018), we explored the demographic, clinical characteristics and treatment exposures of the studied cohorts and reported the results using standard descriptive statistics. Results Over the 10-year study period, 13,356 patients from 17 centers in 8 Middle Eastern countries fulfilled the inclusion criteria. The represented countries were Egypt, Iran, Kuwait, Lebanon, Oman, Saudi Arabia, Turkey and the United Arab Emirates. Overall, the represented cohort was young (median 36 years, quartiles 29-45) and captured relatively early after the onset of MS (median disease duration < 10 years, quartiles 3-12). The relapsing-remitting phenotype was the most prevalent phenotype in all countries (73-97%) and the highest proportion of progressive MS was reported in Saudi Arabia (12%). Median Expanded Disability Status Scale (EDSS) ranged from 0 to 3, depicting a mildly disabled cohort, with the exception of Saudi Arabia where the median EDSS was 4 (quartiles 1.5-6.5). The median relapse frequency was highest in Lebanon (median 1.03, 95% CI 0.94-1.16) followed by Egypt (median 1.02, 95% CI 0.89-1.24) and lowest in Saudi Arabia (median 0.70, 95% CI 0.58-0.95) and Kuwait (median 0.75, 95% CI 0.71-0.80). The treatment landscape greatly varied between different countries. Platform injectable therapies were mostly utilized in Egypt, Iran and Turkey (86%, 79% and 53%, respectively), while oral therapies and monoclonal antibodies were more commonly used in Kuwait, Lebanon and the United Arab Emirates (87.2%, 67.3% and 58.7%, respectively). Conclusion Patients in the Middle East enrolled in a large multinational registry are representative of the general MS population. The spectrum of therapies used in the individual countries, however, is highly variable. Further studies that include rural and non-academic practices are needed to enhance our understanding of the MS cohorts in the Middle East.

Objective To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Methods Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included (modern cohort). Annualised relapse rates (ARR) were calculated before, during and after pregnancy. Predictors of intrapartum and early postpartum (1st3 months) relapse were determined by clustered logistic and Cox regression analyses, respectively. Results We included 1640 pregnancies from 1452 women. Disease-modifying therapy (DMT) used in the one-year preconception included natalizumab (n=219), fingolimod (n=147), dimethyl fumarate (DMF; n=57) and low-efficacy therapies (n=845). Preconception ARR by DMT class used before conception were: natalizumab, 0.29 (95% CI 0.22-0.37); fingolimod, 0.37 (0.28-0.49); DMF, 0.24 (0.13-0.41); low-efficacy, 0.29 (0.25-0.33); and none, 0.24 (0.19-0.31). Among women who used fingolimod or natalizumab, ARR increased during pregnancy. Intrapartum ARR decreased in preconception DMF, low-efficacy or no DMT groups. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p Conclusion Women with MS prescribed natalizumab or fingolimod preconception had higher rates of intrapartum and postpartum relapse. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 32-34 weeks gestation, with early re-initiation after delivery is an effective option to minimise relapse risks. Strategies of DMT use have to be balanced against potential foetal/neonatal complications.

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Background: Multiple sclerosis (MS) is one of the most common chronic neurological diseases affecting the central nervous system in young adults. Objective: To investigate demographic and clinical factors that are effective in the development of irreversible disability from the onset of MS, and to identify factors that affect the transformation from the relapse-remitting MS (RRMS) phase to the progressive MS (PMS) phase. Methods: Retrospective study on 741 patients who were diagnosed with RRMS and PMS according to the McDonald criteria, and were enrolled into the Turkish MS database of the Department of Neurology MS Polyclinic, at the Faculty of Medicine, Karadeniz Technical University, in Trabzon, Turkey. Kaplan-Meier analysis was used to evaluate the time taken to reach EDSS 4 and EDSS 6 from the onset of disease, and the time taken between EDSS 4 and EDSS 6. Results: Age of onset >40 years; having polysymptomatic-type onset, pyramidal or bladder-intestinal system-related first episode; ≥7 episodes in the first 5 years; and 2 years until start of first treatment; and smoking. Conclusions: Our findings reveal important characteristics of MS patients in our region. However, the associations between these parameters and MS pathophysiology remain to be elucidated. RESUMO Introdução: A esclerose múltipla (EM), uma das doenças neurológicas crônicas mais comuns, afeta o sistema nervoso central em jovens adultos. Objetivo: Investigar fatores demográficos e clínicos que são efetivos no desenvolvimento de deficiência irreversível, desde o início da EM, e identificar fatores que afetam a transformação da fase de EM recorrente-remitente (EMRR) para a fase de EM secundária progressiva (EMSP). Métodos: Estudo retrospectivo de 741 pacientes que foram diagnosticados com EMRR e EMSP, de acordo com os critérios de McDonald, e inscritos no banco de dados turco MSBase, do Departamento de Neurologia da MS Polyclinic, da Universidade Técnica de Karadeniz, Turquia. Análise de Kaplan-Meier foi usada para avaliar o tempo para alcançar EDSS 4 e EDSS 6, desde o início da doença e o tempo entre EDSS 4 e EDSS 6. Resultados: Idade de início>40 anos, início do tipo polissintomático, primeiro ataque relacionado ao sistema piramidal ou bexiga-intestinal, ≥7 recaídas nos primeiros 5 anos e 2 anos até o início do primeiro tratamento e tabagismo. Conclusão: Estudo revelou características importantes dos pacientes com EM em nossa região. No entanto, as associações entre esses parâmetros e a fisiopatologia da EM ainda precisam ser elucidadas.

The multiple sclerosis (MS) landscape has changed over the past two decades across the world and in the Middle East. The Middle East is an ethnically diverse region located between 12° and 42° of latitude and 35° and 54° of longitude and varying altitudes. The magnitude of the shifts observed in the epidemiology and management of MS differ in each region and from country to country.The aim of this study was to provide a clinicodemographic overview of the cohorts of patients contributed to MSBase, a large international MS registry, in the Middle East and describe disease-modifying treatment (DMT) utilization in the different countries within the region. Understanding the differences between these cohorts is integral to interpretation of the studies conducted using registry data and provides insight into clinical practice in these cohorts.The MSBase registry was searched for patients with MS or clinically isolated syndrome from the Middle Eastern countries with data captured between 2009 and 2018. In 2-year epochs, and with special focus on the most recent epoch (2017-2018), we explored the demographic, clinical characteristics and treatment exposures of the studied cohorts and reported the results using standard descriptive statistics.Over the 10-year study period, 13,356 patients from 17 centers in 8 Middle Eastern countries fulfilled the inclusion criteria. The represented countries were Egypt, Iran, Kuwait, Lebanon, Oman, Saudi Arabia, Turkey and the United Arab Emirates. Overall, the represented cohort was young (median 36 years, quartiles 29-45) and captured relatively early after the onset of MS (median disease duration10 years, quartiles 3-12). The relapsing-remitting phenotype was the most prevalent phenotype in all countries (73-97%) and the highest proportion of progressive MS was reported in Saudi Arabia (12%). Median Expanded Disability Status Scale (EDSS) ranged from 0 to 3, depicting a mildly disabled cohort, with the exception of Saudi Arabia where the median EDSS was 4 (quartiles 1.5-6.5). The median relapse frequency was highest in Lebanon (median 1.03, 95% CI 0.94-1.16) followed by Egypt (median 1.02, 95% CI 0.89-1.24) and lowest in Saudi Arabia (median 0.70, 95% CI 0.58-0.95) and Kuwait (median 0.75, 95% CI 0.71-0.80). The treatment landscape greatly varied between different countries. Platform injectable therapies were mostly utilized in Egypt, Iran and Turkey (86%, 79% and 53%, respectively), while oral therapies and monoclonal antibodies were more commonly used in Kuwait, Lebanon and the United Arab Emirates (87.2%, 67.3% and 58.7%, respectively).Patients in the Middle East enrolled in a large multinational registry are representative of the general MS population. The spectrum of therapies used in the individual countries, however, is highly variable. Further studies that include rural and non-academic practices are needed to enhance our understanding of the MS cohorts in the Middle East.

Objective: This study was planned to evaluate the effectiveness of acupuncture treatment for the treatment Bell's palsy sequelae. Methods: In this study, the forty patients with Bell's palsy sequelae were randomly allocated into either the acupuncture or control group. The clinical outcomes in pre- and post- treatment were assessed using the following assays: the facial nerve compound motor action potential (CMAP), House-Brackmann (HB) and Sunnybrook (SB) grading scales. Agreement analysis was performed between the SB and HB grading scales. Results: There was significant difference between pre- and post- treatment CMAP values of the patients within the acupuncture group (p=0.036). In pre- and post- treatment SB and HB scores, significant differences within two groups were observed. However, the significance level in the improvement rate in the acupuncture group was higher than that of the control group. General agreement between the SB and HB scores of groups was an acceptable value, weighted agreement between the scales was a moderate agreement. Conclusion: In this study, we found that acupuncture treatment is effective in improving Bell's palsy sequelae. Acupuncture can be used as a safe method in the treatment of Bell's palsy sequelae. © 2019, Firat University Scientific Research Projects Management Unit

Background: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. Objectives: We sought to develop internationally applicable quality standards for timely, brain health–focused MS care. Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation