Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to ...multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown.
To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria.
This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021.
Diagnosis of RIS.
Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors.
Among 372 individuals with RIS (mean SD age at index MRI scan, 38.6 12.1 years), 354 individuals were included in the analysis (264 74.6% women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio HR, 4.04 95% CI, 2.00-8.15; P < .001), spinal cord lesions (HR, 5.11 95% CI, 1.99-13.13; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 95% CI, 1.13-3.87; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 95% CI, 9.08-59.96; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%.
This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.
Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in ...patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD.
Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis.
We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (
0.611) and female sex predominance (
0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (
0.716). Median EDSS at sampling was 3.2 (interquartile range IQR 2-7.7) in the AQP4+NMOSD group and 4 (IQR 3-6) in the DS-NMOSD group (
0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL
0.001; median 1.2 vs 0.5 pg/mL,
= 0.001; and median 61.4 vs 35 pg/mL,
0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782,
0.001, AUC GFAP: 0.762,
0.001, AUC UCH-L1: 0.723,
0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD.
Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.
Abstract Background and objective Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous ...side effects. Hence, we aimed to evaluate the effects of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, on such a challenging symptom. Our secondary outcomes included the assessment of tDCS impact on mood and attentional performance. Methods Ten fatigued MS patients were enrolled in a double-blind, sham-controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation over the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. Both cortical targets are key components in the MS fatigue networks. The blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. Results Only active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. Conclusion Our study supports the role of anodal tDCS over the left prefrontal in treating MS fatigue. The lack of tDCS effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the protocol design and duration. Modifying these variables and coupling tDCS with neuroimaging might improve the clinical outcomes and enhance our understanding of the tDCS mechanism of actions.
Abstract Background Although it is recommended that interferon-beta (IFNβ) injections be administered in the evening, it is possible that morning injections could more effectively decrease ...interleukin 6 secretion. Methods This study evaluated the effects of switching from an evening injection of IFNβ to a morning injection on the intensity of flu-like syndrome in patients with multiple sclerosis (MS). We performed an intervention study that consisted of a quantitative evaluation of IFNβ-related flu-like syndrome in a cohort of 105 MS patients. Patients with persistent flu-like reactions who injected IFNβ in the evening were encouraged to switch to morning injections. After one month, we evaluated various quantitative and qualitative changes (e.g., severity of flu-like syndrome, sleep quality, antipyretic drug use). Results Of the 98 patients (93%) who injected IFNβ in the evening, 88 (85%) had a persistent flu-like syndrome (the severity score was 3.92 ± 0.26). A total of 50 (57%) patients switched to morning injections. One month after changing the injection time, 29 patients (58%) reported that their flu-like syndrome was decreased, 11 (24%) thought that it was unchanged and 9 (18%) thought that it was increased ( p = 0.014). In addition, 23 patients (48%) reported improved sleep ( p = 0.001), and 33 (68%) patients chose to continue morning injections, whereas 17 (32%) patients switched back to evening injections ( p = 0.024). Quantitative measures, however, indicated that there was no change in the severity of flu-like syndrome or the number of antipyretic doses taken for its management. Conclusion Morning injections qualitatively improved IFNβ-related flu-like syndrome and sleep. A change in IFNβ injection time from evening to morning could benefit a significant proportion of patients with MS.
Abstract Patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA), non-HBV polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS = ...0)-defined poor-prognosis factors were included in two prospective randomized–controlled trials and were initially treated with corticosteroids (CS) alone. Because some patients required subsequent add-on therapies, inclusion characteristics associated with their use were sought. Add-on treatments (cytotoxic agents, biotherapies, intravenous immunoglobulins and plasma exchanges) were subjected to univariate and multivariate analyses. The study included 193 patients (75 EGPA, 61 MPA and 57 PAN). Mean ± SD follow-up was 97.6 ± 39.6 months. Subsequent add-on treatment(s) were required for 86/193 patients (24 PAN, 32 MPA and 30 EGPA) because of CS failure (37%), relapse (52%) or CS dependence (10%). Seven-year overall survival reached 90% and was comparable for patients given 0 vs ≥ 1 add-on therapies ( P = 0.564). However, the mean Vasculitis Damage Index was significantly higher for the latter: 2.93 vs 1.96 ( P < 0.001), reflecting more frequent sequelae. Initial mononeuritis multiplex was the only factor significantly associated with add-on therapy requirement in univariate ( P = 0.008) and multivariate analyses (hazard ratio = 1.81 95% CI: 1.12–2.93; P = 0.02). Although FFS = 0 predicts good and comparable overall survival of EGPA, PAN or MPA patients, 45% of them required adjunctive treatments for relapse, CS failure or corticodependence, with most having more frequent initial mononeuritis multiplex and sequelae. These findings support prospective evaluation of initial immunosuppressant use combined with CS to prevent treatment failure, relapses and sequelae in FFS = 0 patients with mononeuritis multiplex at diagnosis.
Objectifs La sclérose en plaques (SEP) est une maladie inflammatoire chronique du système nerveux central qui peut se manifester sous différentes formes, la plus fréquente étant la forme rémittente. ...Bien que les corticoïdes à doses élevées soient classiquement utilisés pour traiter les poussées de la SEP, leur impact sur l’excitabilité des réseaux corticaux est rarement abordé. Méthodes Vingt et un patients atteints de SEP rémittente ont terminé l’étude. L’évaluation a eu lieu avant et après trois jours de traitement par méthylprednisolone par voie intraveineuse (1 g par jour). Les mesures de l’excitabilité corticale ont été obtenues par stimulation magnétique transcrânienne. L’évaluation clinique incluait les échelles Expanded Disability Status State (EDSS) et Kurtzke Functional System Scale (KFSS), une échelle de fatigue (FSS) et un test de marche (test de 10 mètres). Résultats Une diminution significative de l’inhibition intracorticale à court intervalle (IIC) et une augmentation de la facilitation intracorticale (FIC) ont été observées suite à l’administration des flashs de méthylprednisolone. Ces derniers ont également entraîné une amélioration significative de la fonction motrice et une tendance à la réduction du score de fatigue et à l’amélioration des fonctions sensitives et cérébelleuses. Aucun changement significatif n’a été retrouvé concernant le handicap ou la marche. Discussion La corticothérapie peut entraîner une amélioration fonctionnelle très rapide de la fonction motrice en induisant des changements « fonctionnels » de l’excitabilité de la membrane axonale, avant que les processus « structurels » de repousse axonale et/ou de remyélinisation puissent avoir lieu. Les corticoïdes semblent moduler la plasticité synaptique intracorticale en améliorant la facilitation glutamatérique et en diminuant l’inhibition GABAérgique. Conclusions Les IIC et FIC semblent être d’une grande utilité dans le suivi des patients atteints de SEP et pourraient servir comme biomarqueurs de cette maladie.
Objectifs La fatigue est un symptôme fréquemment rencontré chez les patients atteints d’une sclérose en plaques (SEP). Malgré son caractère invalidant, sa physiopathologie reste mal définie et semble ...être multifactorielle. La stimulation magnétique transcrânienne est une technique émergente qui permet, grâce à des paradigmes de doubles chocs, l’exploration des mécanismes inhibiteurs et excitateurs corticaux. L’altération de ces derniers pourrait être impliquer dans la génération de divers troubles neuropsychiatriques. Dans le contexte de la fatigue de la SEP, peu d’études se sont intéressées à ces mesures et leurs résultats restent controversés. Méthodes Trente-huit patients atteints de SEP ont été recrutés et répartis en deux groupes : non fatigués ( n = 17) et fatigués ( n = 21), selon le score de l’échelle Modified Fatigue Impact Scale (MFIS). L’évaluation neurophysiologique consistait à tester les paramètres suivants : le seuil moteur au repos, l’amplitude des potentiels évoqués moteurs, l’inhibition intracorticale à court intervalle (IIC), la facilitation intracorticale, la période de silence cortical et l’inhibition interhemisphérique. Résultats L’IIC était significativement plus élevée chez les patients fatigués par rapport à ceux non-fatigués, notamment pour l’intervalle inter-stimuli de 2 ms (35,0 ± 40,8 contre 63,9 ± 20,9 ; p = 0,04). L’IIC à 2 ms était significativement corrélée aux scores de l’échelle MFIS (total : r = 0,4 ; p < 0,01 ; sous-score cognitif : r = 0,4 ; p < 0,01 ; sous-score psychosocial : r = 0,3 ; p = 0,04). Conclusion Les patients SEP fatigués avaient une augmentation de l’inhibition intracorticale par rapport à ceux non fatigués. Ceci pourrait refléter une altération de la balance GABAergique/glutamatergique aux détriments des mécanismes facilitateurs. En d’autres termes, un lien apparent existe entre l’intégrité des mécanismes facilitateurs et la capacité de faire face au déclin fonctionnel, et par la suite à la perception ou la génération de la fatigue chez ces patients.
Objectifs La stimulation magnétique transcrânienne permet de mesurer différents paramètres d’excitabilité corticale, en appliquant divers paradigmes de simple et double choc. Ces mesures ...permettraient de mieux comprendre les mécanismes physiopathologiques de nombreuses maladies et d’évaluer l’efficacité de diverses stratégies thérapeutiques. L’objectif de cette étude était d’évaluer l’excitabilité corticale chez des patients atteints de formes progressives de sclérose en plaques (SEP). Méthodes Trente-quatre patients ont été initialement inclus et répartis en deux groupes selon qu’ils reçoivent ou non des traitements de fond. L’évaluation a eu lieu à l’inclusion (T0), à 6 mois (T6) et à 12 mois (T12). Elle comprenait une détermination du score d’invalidité selon l’échelle Expanded Disability Status Scale (EDSS). En plus, différents paramètres d’excitabilité corticale ont été mesurés, incluant les seuils moteurs actif (SMa) et au repos (SMr), l’amplitude des potentiels évoqués moteurs (PEM) à 120 % du SMr et SMa, la courbe de recrutement, l’inhibition intracorticale à court intervalle (IIC) et la facilitation intracorticale. Résultats Vingt-cinq patients ont terminé l’étude. À T0, les scores EDSS ont été inversement corrélés aux valeurs des SMr/SMa dans les deux groupes ; en plus, les amplitudes des PEM étaient plus élevées chez les patients traités par rapport à ceux non traités. À T12, contrairement aux patients traités qui n’ont montré aucun changement clinique ni neurophysiologique significatif, les patients non-traités présentaient une augmentation du SMr ainsi qu’une réduction de l’IIC. Ces modifications ont été associées à une augmentation des scores EDSS. Conclusion Ces changements témoignent d’une diminution de l’excitabilité des motoneurones et des circuits neuronaux inhibiteurs. Compte tenu de l’implication de ces circuits dans les processus de plasticité cérébrale, ces modifications pourraient refléter la régulation des stratégies d’adaptation corticale. Ces dernières tendent à surmonter le déclin fonctionnel observé au cours de l’évolution de la SEP progressive.
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