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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.

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.

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

© 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: 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.

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.

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.

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.

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

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.

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.

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

International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS

Background: methodological challenges limit the use of brain atrophy and lesion burden measures in the followup of multiple sclerosis (MS) patients on clinical routine datasets. Objective: to determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. Methods: a total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. Results: longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). Conclusions: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term., Novartis; Genzyme-Sanofi; Biogen; Merck; Genentech; Abbvie; Bayer AG; Celgene/ BMS; Mallinckrodt Pharmaceuticals, Inc.; WebMD Global; Teva; BioCSL; Almirall; Roche; Generica; Deva; Nerve Research Foundation; Multiple Sclerosis Research Australia; Keystone Heart; Bristol Myers Squibb; EMD Serono; V-WAVE Medical; Mapi Pharma; Protembis

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

PubMed: 32473575 Background: Although studies report a high prevalence rate of restless legs syndrome (RLS) among patients with multiple sclerosis (PwMS) ranging from 13.3 to 65.1%, little is known about the causes of this relationship. Methods: To ascertain the prevalence, features and impact of RLS among PwMS a nation-wide, multicenter, prospective and a cross-sectional survey, designed to reflect all of the PwMS throughout Turkey, was conducted in 13 centers. Exploring the relationship of the two conditions could possibly contribute to the understanding of the causes of the high and wide-ranging prevalence rates and the pathophysiology of both diseases. Results: Of the 1068 participants 173 (16,2%) found to have RLS [RLS(+)] and 895 (83,8%) did not [RLS(-)]. Among the RLS(+) 173, all but 8 patients (4,6%) were underdiagnosed in terms of RLS. More than half of the patients with RLS had ‘severe’ or ‘very severe’ RLS. The onset of RLS was before or synchronous with the onset of MS in about a half of our patients. Conclusion: We conclude that RLS should be meticulously investigated in PwMS and MS can be a direct cause of RLS at least in part of PwMS. Our data about the timing of the onset of MS and RLS, along with the high prevalence of RLS in PwMS suggest that the pathologic changes in the initial phases of MS can possibly trigger RLS symptoms. © 2020 Elsevier B.V.

Altintas, Ayse/0000-0002-8524-5087; Laureys, Guy/0000-0002-1708-4373; Vucic, Steve/0000-0002-8323-873X; patti, francesco/0000-0002-6923-0846; Kister, Ilya/0000-0003-3549-949X; Lugaresi, Alessandra/0000-0003-2902-5589 WOS: 000521648000049 PubMed: 31877445 Background: Aquaporin-4-IgG positive (AQP4-IgG(+)) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG + NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG + NMOSD. Method: This MSBase cohort study of AQP4-IgG + NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. Results: 206 AQP4-IgG + patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p < 0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (beta = 0.45 (per decade), p < 0.001) and disease duration (beta = 0.07 per year, p < 0.001). A slower increase in EDSS was associated with azathioprine (beta = -0.48, p < 0.001), mycophenolate mofetil (beta = -0.69, p = 0.04) and rituximab (beta = -0.35, p = 0.024). Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766, 1080518]; MerckMerck & Company; BiogenBiogen; NovartisNovartis; Bayer-ScheringBayer AG; Sanofi-Genzyme; Teva This study was financially supported by National Health and Medical Research Council of Australia [project grants 1083539 and 1129189, and fellowships 1140766 and 1080518]. The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

[No Abstract Available], Peripheral Nerve Soc, Abdi Ibrahim Pharmaceuticals, This work was funded by Abdi Ibrahim Pharmaceuticals

Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. Methods: This RRMS MSBase cohort study ( n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. Conclusion: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

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.

Objective To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. Methods A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. Results In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06–1.55; 1.42, 1.10–1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60–0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42–0.83; 0.75, 0.71–0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46–7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. Interpretation This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729–739

The aim of this study was to determine the curative effects of high-dose (100 mg/kg) melatonin on peripheral nerve injury. Forty male Wistar albino rats were randomized into four groups as sham, vehicle, melatonin, and ischemia and their right sciatic nerves were exposed. The process was terminated in the sham group. In the other groups, nerve injury was induced by clip compression. The vehicle group was intraperitoneally administered ethanol 0.1 cc (melatonin solvent), while the melatonin group was intraperitoneally administered a single dose of melatonin (100 mg/kg). Following the surgery, sciatic nerve functional index (SFI) was measured using walking track analysis on days 7, 14, and 21, and latency, amplitude, and muscle action potentials (MAP) field values were measured using electroneuromyography (ENMG) on day 21. Histopathologically, edema, axonal degeneration, myelin damage, and inflammatory response were evaluated in all groups. SFI values were noted to be statistically significantly different among the vehicle, melatonin, and ischemia groups, and the melatonin group showed a faster recovery. In the ENMG evaluations, higher amplitude and field values in the melatonin group indicated that melatonin accelerated peripheral nerve recovery. Histopathologically, although fibers with loss of myelin were identified in the melatonin group, the myelin sheath was preserved in general and the axonal structure was noted to be normal. A single injection of high-dose melatonin was found to preserve myelin sheath, prevent axonal loss, and accelerate functional recovery during the nerve regeneration in peripheral nerve injury.

Turkoglu, Recai/0000-0001-9724-851X; McCombe, Pamela/0000-0003-2704-8517; Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Ramo-Tello, Cristina/0000-0001-8643-5053; Vucic, Steve/0000-0002-8323-873X; Nguyen, Ai-Lan/0000-0003-0378-6005; Kalincik, Tomas/0000-0003-3778-1376; van Pesch, Vincent/0000-0003-2885-9004; Skibina, Olga/0000-0002-6275-8138; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453 WOS: 000459833100045 PubMed: 30623864 Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RAMS) may be increasing. Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RAMS. Methods: We identified all women with RAMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed. Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births. Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month. National Health and Medical Research Council of Australia centre for research excellence grant [1001216]; BiogenBiogen; MerckMerck & Company; NovartisNovartis; RocheRoche Holding; Sanofi-Genzyme This study was financially supported by a National Health and Medical Research Council of Australia centre for research excellence grant [1001216]. The MSBase Foundation is a not-for-profit organisation that receives support from Biogen, Merck, Novartis, Roche and Sanofi-Genzyme. The study was conducted separately and apart from the guidance of the sponsors.

Boz, Cavit/0000-0003-0956-3304 WOS: 000475740000018 PubMed: 31176296 Susac's Syndrome (SS), which was first described in 1979, is a rare and presumably autoimmune disorder characterized by encephalopathy, hearing loss, and visual disturbance resulting from branch retinal artery occlusion (BRAO). This study reports 19 SS patients' clinical characteristics, MRI features, CSF analysis, treatment strategies and outcomes. At initial presentation, only three of 19 patients demonstrated the complete clinical triad. Clinic presentation varied from isolated hemiparesis to the full triad (encephalopathy, hearing loss and visual disturbances). Corpus callosum (CC) involvement was noted in the MRI of 18 patients (97%) and BRAO was detected in 17 (95%) patients. All patients were treated with intravenous methylprednisolone after the initial assessment. This case series is presented to emphasize the differences in clinical presentation of SS and the importance of MRI and FFA in diagnosis.

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.

Objective To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. Methods Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. Results We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0–2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10−22). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = −0.86, p = 1.3 × 10−9). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = −0.36, p = 0.009). Interpretation We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89–100

Background: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. Objective: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Methods: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. Results: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88). Conclusion: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.

Background: Women with multiple sclerosis (MS) experience an increased risk of relapse in the postpartum period. High-dose methylprednisolone is the first-line treatment for acute relapses. Objectives: To determine the transfer of methylprednisolone into human milk in breastfeeding MS patients. Methods: Methylprednisolone therapy was given for postpartum relapse to nine patients for three consecutive days, and seven patients received a daily infusion once a month. Breast milk samples were obtained before infusion and 1, 2, 4, 8, and 12 hours after completion of infusion. Results: Methylprednisolone concentrations in milk were below detection limits immediately before infusion. Cmax was measured at 1, 2, 4, 8, and 12 hours after infusion and levels of 2.100, 1.659, 0.680, 0.174, and 0.102 µg/mL were determined, respectively. The absolute infant dose was 98.98 µg/kg/day, and the relative infant dose (RID) was 0.71% of the weight-adjusted maternal dose. Conclusion: The level of methylprednisolone transfer into breast milk is very low. The RID for methylprednisolone was lower than the generally accepted value. As methylprednisolone therapy is of short duration, infant exposure would be very low should a mother choose to breastfeed 1 hour after infusion. Waiting 2–4 hours after infusion will limit infant exposure still further.

Lugaresi, Alessandra/0000-0003-2902-5589; Ferraro, Diana/0000-0003-4818-3806; patti, francesco/0000-0002-6923-0846; Kister, Ilya/0000-0003-3549-949X; Spelman, Tim/0000-0001-9204-3216 WOS: 000439672500016 PubMed: 30103975 Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age 18 at index DMT start; >= 12 months on index DMT prior to discontinuation; >= 24 months of follow-up post-discontinuation; did not restart DMT for >= 6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for >= 1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFN beta preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option. Bayer ScheringBayer AG; Biogen IdecBiogen; Merck SeronoMerck SeronoMerck & Company; Novartis Pharma; SanofiSanofi-Aventis No targeted funding was provided for this study. MSBase Foundation is a not-for-profit organization that receives support from Bayer Schering, Biogen Idec, Merck Serono, Novartis Pharma, and Sanofi.

Lugaresi, Alessandra/0000-0003-2902-5589; Butzkueven, Helmut/0000-0003-3940-8727; Vucic, Steve/0000-0002-8323-873X WOS: 000433294800035 PubMed: 29807821 …

Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Lugaresi, Alessandra/0000-0003-2902-5589; Vucic, Steve/0000-0002-8323-873X WOS: 000425903700023 PubMed: 29182993 Background: Fingolimod is an efficient and safe drug for treating relapsing-remitting multiple sclerosis (RRMS). In vivo, fingolimod is phosphorylated and binds to "sphingosine-1-phosphate"(S1P) receptors that are expressed in a wide range of cells, including lymphocytes. Under the effect of fingolimod, lymphocytes are retained in lymphoid tissues through the regulation of S1P(1) receptors. The aim of the present study was to assess whether the degree of lymphopenia was correlated to the positive treatment response of RRMS patients with fingolimod. Methods: Data was sourced from the MSBase Registry. Patients were divided into two groups, according to the lymphocyte count on peripheral blood examination. Annualized Relapse Rate (ARR), time to first relapse and time to six-month confirmed disability progression were compared between groups. Results: Group one consisted of 202 patients who reached 750 lymphocytes/mm(3) during treatment while the comparison group two included 101 patients who never reached less than 1000 lymphocytes/mm(3) in peripheral blood during the observation period. There were no differences between groups in ARR, time to first relapse or time to six-month confirmed disability progression. Conclusion: The degree of lymphopenia in peripheral blood was not associated to the positive treatment response of fingolimod in RRMS patients.

Background and purpose Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. Methods An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. Results Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P

Objective In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. Methods Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. Results Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p

Signori, Alessio/0000-0001-6289-9144; Sajedi, Seyed Aidin/0000-0002-6704-9787; Jokubaitis, Vilija G./0000-0002-3942-4340; Shaygannejad, Vahid/0000-0002-6226-0161; Oreja-Guevara, Celia/0000-0002-9221-5716; amato, Maria Pia/0000-0003-3325-3760; Lugaresi, Alessandra/0000-0003-2902-5589; Majdinasab, Nastaran/0000-0001-5163-7210; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; van Pesch, Vincent/0000-0003-2885-9004; pucci, eugenio/0000-0001-7606-7330; Petersen, Thor/0000-0001-5633-2600; Prat, Alexandre/0000-0001-6188-0580; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Slee, Mark/0000-0003-4323-2453; SORMANI, MARIA PIA/0000-0001-6892-104X; Trojano, Maria/0000-0002-6329-8946 WOS: 000432098100013 PubMed: 28382837 Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild (n = 143; 16.8%), moderate (n = 378; 44.3%), or severe (n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis. MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.

OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.

Background and Purpose Restless legs syndrome (RLS) is a common sleep-related movement disorder that is frequently associated with psychological disturbances. Personality traits are of considerable importance with respect to coping with chronic illness and disease vulnerability. This study assessed the temperament and character traits of RLS patients using an approach that involves the psychobiological model of personality. Methods The personality features of 65 newly diagnosed and untreated RLS patients with no neurological or psychiatric diseases and 109 healthy controls were determined using the Temperament and Character Inventory and compared using covariance analyses. The International RLS Study Group Severity Scale was used to assess the severity of the RLS symptoms, and the Beck Depression Inventory was used to assess the presence and severity of depressive symptoms. Results RLS patients scored significantly higher than healthy controls on the temperament dimension of harm avoidance (HA, p=0.02) and significantly lower on self-directedness (SD, p=0.001). No significant difference was observed in terms of the temperament dimension of novelty seeking (p=0.435). HA scores were significantly correlated with the BDI score but not with the RLS severity or duration. Conclusions High HA and low SD scores are the main characterizing personality features of RLS patients. These personality dimensions may be among the factors predisposing patients to development of the depressive symptoms that are frequently associated with RLS.

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Early diagnosis and treatment in acute ischemic stroke are crucial in terms of survival and disability. Many stroke patients remain disabled because of the treatment delay. The purpose of this study was to investigate the factors associated with the early hospital arrival in acute ischemic stroke patients. 113 patients diagnosed with acute ischemic stroke were included in this prospective study performed at the Karadeniz Technical University Medical Faculty Hospital. Patients’ characteristics and patients’ and relatives’ emotional and behavioral reactions were compared between early (within 3 h) and late (after 3 h) arrival groups. 72.6 % of patients arrived at hospital within 3 h from symptoms onset. Univariate analysis revealed that history of atrial fibrillation (p = 0.04) and coronary heart disease (p = 0.02), sudden onset of symptoms (p = 0.001), loss of consciousness (p = 0.03), recognizing symptoms as stroke (p = 0.01), seeking immediate medical attention (p

Boz, Cavit/0000-0003-0956-3304; Altintas, Ayse/0000-0002-8524-5087; YUCEYAR, NUR/0000-0003-4590-6423; Sevim, Serhan/0000-0002-0518-3374; Efendi, Husnu/0000-0002-9143-3893, WOS: 000502098900008, PubMed: 31473488, Background: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. Objectives: the objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. Methods: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. Results: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). Conclusion: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. the two oral therapies exhibited similar effects on disability outcomes.

Background: With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) statusfor the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power. Methods: In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome. Results: A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude ( p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change ( p < 0.001). Conclusions: The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Summary Objectives Cervical vestibular evoked myogenic potentials (cVEMPs) provide assessment of lower-brainstem lesions affecting their neuronal pathways. We aimed to determine whether cVEMPs to air-conducted sound (ACS) are also abnormal in patients with early stages of amyotrophic lateral sclerosis (ALS), with or without bulbar involvement. Methods cVEMPs were recorded in 22 ALS patients and 23 age- and sex-matched healthy volunteers. Their latencies and amplitudes were compared between the ALS patients and the control group. Results cVEMPs were obtained in all ALS patients and controls. P 13 and N 23 latencies and P 13 –N 23 amplitudes did not significantly differ between controls and ALS patients, either with or without bulbar involvement. Conclusions We postulate that the ACS–cVEMP neural pathway is not affected in patients with early stages of ALS, even with clinical findings of bulbar involvement. Therefore, ACS–cVEMP is not a sensitive diagnostic tool for early detection of brainstem involvement in patients with ALS.

Brachial neuritis is characterized by shoulder and arm pain followed by weakness and atrophy of affected muscles and sensory loss in the arm. Isolated sensory involvement of the brachial plexus is very rare. Diagnosis of brachial neuritis is usually based on clinical history and examination, with the confirmation by electrodiagnostic tests. A 72-year-old woman presented with numbness and tingling in the bilateral upper extremities. While nerve conduction examination revealed only sensory abnormalities of the bilateral upper extremities, magnetic resonance imaging (MRI) showed thickening and hyperintensity of the bilateral brachial plexus. We report a case of bilateral brachial neuritis with clinical and electrophysiological pure sensory involvement diagnosed using brachial plexus MRI. Although electrophysiological examination is thought to be the best diagnostic technique in the diagnosis of brachial neuritis, its findings sometimes indicate a distal lesion, while the involvement of the whole brachial plexus can be seen in MRI.

Objective Diagnosis of carpal tunnel syndrome (CTS) is difficult in patients with diabetic polyneuropathy as both conditions may affect median nerve conduction in a similar manner. There is no agreement about which electrodiagnostic tests are more efficient in determining CTS accurately in these patients. In this study, we aimed to define the best electrodiagnostic test in the diagnosis of CTS in diabetic polyneuropathy patients. Methods We prospectively investigated 72 patients with CTS (140 hands), 32 patients with diabetic polyneuropathy without CTS (61 hands), 35 patients with diabetic polyneuropathy with CTS (62 hands) and 43 healthy controls (86 hands). Standard nerve conduction studies, segmental and comparative median nerve conduction tests were performed in all subjects. Cut-off values, sensitivities and specificities of each test for the diagnosis of CTS in diabetic polyneuropathy patients were determined by using receiver operating characteristic (ROC) curve. Results Distoproximal latency ratio (DPLR) with a sensitivity of 90% and specificity of 81% for the cut-off value of 1 and median and ulnar sensory latency difference to digit 4 (MUDD4) with a sensitivity of 90% and specificity of 85% for the cut-off value of 0.35 showed the highest sensitivity and specificity in the diagnosis of CTS in diabetic polyneuropathy patients among all nerve conduction tests. Wrist–palm median sensory conduction velocity (W–P SCV) and median and radial sensory latency difference to digit 1 (MRDD1) also showed high sensitivity and specificity. Conclusions Segmental median nerve conduction studies like DPLR and W–P SCV and sensory comparative tests such as MUDD4 and MRDD1 in combination with standard nerve conduction tests should result in more accurate diagnosis of CTS in diabetic polyneuropathy patients. Significance These results could be helpful to overcome the diagnostic difficulty of CTS in patients with diabetic polyneuropathy.

The purpose of the present study was to assess a group of patients with chronic tension-type headache (CTTH) and control subjects using the personality questionnaire proposed by Cloninger and to determine possible changes in the Temperament and Character Inventory (TCI) patterns of CTTH patients after therapy with serotonergic antidepressants. Forty-five patients with CTTH filled out the TCI and Beck Depression Inventory (BDI) before and after 4-month prophylactic therapy with serotonergic antidepressants. A total of 50 age-, sex- and education level-matched healthy subjects were selected as a control group. During the pretreatment period patients were found to have higher harm avoidance and lower self-directedness scores than healthy comparison subjects. During the post-treatment period, although harm avoidance scores decreased and self-directedness scores increased, harm avoidance scores were still significantly higher and self-directedness scores significantly lower in CTTH patients than in controls. After using BDI score and age as covariates at the post-treatment period, harm avoidance scores were still higher in patients with CTTH while self-directedness scores did not differ between CTTH patients and controls. These findings suggest state and trait dependence of harm avoidance, and strong state dependence of self-directedness scores in CTTH patients. When interpreting data regarding personality measured by the TCI in CTTH patients, the effects of depressive symptomatology should be taken into account.