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IMPORTANCE: Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development. OBJECTIVE: To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection. EXPOSURES: Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise. MAIN OUTCOMES AND MEASURES: Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated. RESULTS: Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs. CONCLUSIONS AND RELEVANCE: The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

IMPORTANCE: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. OBJECTIVE: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. EXPOSURES: Natalizumab, fingolimod, rituximab, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Time to first relapse. RESULTS: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. CONCLUSION AND RELEVANCE: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

IMPORTANCE: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. OBJECTIVE: To assess the real-world association of HET as an index treatment compared with MET with disease activity. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. EXPOSURE: HET or MET at treatment initiation. MAIN OUTCOMES AND MEASURES: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. RESULTS: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

Purpose: The efficacy of noninvasive ventilation (NIV) during procedures that require sedation and analgesia has not been established. We evaluated whether NIV reduces the incidence of respiratory events. Methods: In this randomized controlled trial, we included 195 patients with an American Society of Anesthesiologists Physical Status of III or IV during electrophysiology laboratory procedures. We compared NIV with face mask oxygen therapy for patients under sedation. The primary outcome was the incidence of respiratory events determined by a computer-driven blinded analysis and defined by hypoxemia (peripheral oxygen saturation < 90%) or apnea/hypopnea (absence of breathing for 20 sec on capnography). Secondary outcomes included hemodynamic variables, sedation, patient safety (composite scores of major or minor adverse events), and adverse outcomes at day 7. Results: A respiratory event occurred in 89/98 (95%) patients in the NIV group and in 69/97 (73%) patients with face masks (risk ratio [RR], 1.29; 95% confidence interval [CI], 1.13 to 1.47; P< 0.001). Hypoxemia occurred in 40 (42%) patients in the NIV group and in 33 (34%) patients with face masks (RR, 1.21; 95% CI, 0.84 to 1.74; P= 0.30). Apnea/hypopnea occurred in 83 patients (92%) in the NIV group vs65 patients (70%) with face masks (RR, 1.32; 95% CI, 1.14 to 1.53; P< 0.001). Hemodynamic variables, sedation, major or minor safety events, and patient outcomes were not different between the groups. Conclusions: Respiratory events were more frequent among patients receiving NIV without any safety or outcome impairment. These results do not support the routine use of NIV intraoperatively. Study registration: ClinicalTrials.gov (NCT02779998); registered 4 November 2015.

Viral, bacterial, or fungal infections are suspected of triggering multiple sclerosis (MS) and promoting relapses of the disease and are likely to be promoted by immune-active treatments. This raises questions about the infectious workup and preventive treatment of these infections prior to their initiation.

ObjectiveTo assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis.MethodsThe French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change.ResultsOf the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17–40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14–49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%.ConclusionTNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory.Classification of evidenceThis study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.

Establish recommendations for the management of UTIs in MS patients.

New multiple sclerosis (MS) disease-modifying therapies (DMTs), which exert beneficial effects through prevention of relapse, limitation of disability progression, and improvement of patients’ quality of life, have recently emerged. Nonetheless, these DMTs are not without associated complications (severe adverse events like. progressive multifocal leukoencephalopathy). Patient follow-up requires regular clinical evaluations and close monitoring with magnetic resonance imaging (MRI). Detection of new T2 lesions and potential brain atrophy measurements contribute to the evaluation of treatment effectiveness. Current MRI protocols for MS recommend the acquisition of an annual gadolinium (Gd) enhanced MRI, resulting in administration of high volume of contrast agents over time and Gd accumulation in the brain.

Les troubles vésico-sphinctériens dans l’hydrocéphalie chronique de l’adulte ont jusqu’à ce jour été l’objet de peu de publications et n’ont jamais fait l’objet de recommandations. L’objectif de cet article de revue était de réaliser une mise au point sur le diagnostic et la prise en charge des troubles vésico-sphinctériens dans l’hydrocéphalie chronique de l’adulte.

Bronchiolitis obliterans syndrome is the main limitation for long‐term survival after lung transplantation. Some specific B cell populations are associated with long‐term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow‐up. CD24hiCD38hitransitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24hiCD38hitransitional B cells specifically secrete IL‐10 and express CD9. Thus, patients with a total CD9+B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL‐10‐secreting CD24hiCD38hitransitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9‐expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long‐term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival. In lung transplant patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow‐up, IL‐10–secreting CD24hiCD38hi transitional B cells expressing CD9 are associated with better allograft outcome, suggesting CD9‐expressing B cells as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival.

To establish recommendations on immunization for patients with multiple sclerosis (MS).

Although a large range of literature on awareness and metacognition focuses on different neurological populations, little attention has been paid to Multiple Sclerosis (MS). This paper gathers literatures related to studies of anosognosia and the theoretical construct of metacognition which both offer a means to operationalize and measure awareness in MS. We focused on both a clinical concern, regarding the relationship between subjective and objective evolution of cognitive performance, and the theoretical issue of metacognitive processes implicated in disease awareness. We identified 26 papers with findings related to awareness of cognitive impairment in MS using questionnaire-based or performance-based methods. We found support for the idea that the relationship between subjective evaluation and neuropsychological evaluation depends on disease duration and is strongly modulated by other variables, such as mood state. We propose that the metacognitive deficit for memory tasks in this population arises from memory impairment. Finally, we discuss methodological issues, variability in MS patients, and the domain specificity of metacognitive impairment.

Nous rapportons le cas d’un patient souffrant d’une céphalée occipito-auriculaire unilatérale réfractaire aux différents traitements utilisés, chez qui un adénocarcinome pulmonaire a été diagnostiqué neuf mois plus tard. La survenue de douleurs faciales unilatérales au cours d’un cancer pulmonaire en lien avec des mécanismes référés impliquant le nerf vague (dans sa portion thoracique) est rapportée dans de nombreuses observations publiées mais la localisation occipitale n’a jamais été décrite. La présentation clinique, le diagnostic et les mécanismes physiopathologiques de ces douleurs sont discutés à partir d’une analyse de la littérature. Devant une douleur atypique de l’extrémité céphalique pour laquelle le bilan étiologique reste négatif, une exploration thoracique à la recherche d’une pathologie néoplasique semble justifiée.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long‐term survival after lung transplantation. CLADmanifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial‐to‐mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)‐β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)‐9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS,and 16 with RAS. We demonstrated that C‐C motif chemokine 2 secreted by T cells supports TGF‐β–induced MMP‐9 production by BECsafter binding to C‐C chemokine receptor type 2. Longitudinal investigation in LTRsrevealed a rise in plasma MMP‐9 before CLADonset. Multivariate analysis showed that plasma MMP‐9 was independently associated with BOS(odds ratio [OR] =6.19, p = 0.002) or RAS(OR= 3.9, p = 0.024) and predicted the occurrence of CLAD12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP‐9. Plasma MMP‐9 is a potential predictive biomarker of CLAD. The authors investigate the production of matrix metalloproteinase‐9 by primary bronchial epithelial cells after interaction with activated T cells and show that plasma matrix metalloproteinase‐9 can serve as a predictor of chronic lung allograft dysfunction 12 months before clinical diagnosis.

margaux.tiberi@novartis.com(M. Tiberi).

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2inflammatory,3or vascular4stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.

IMPORTANCE The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge. OBJECTIVE To collect data from patients with MS switching from natalizumab to fingolimod. DESIGN, SETTING, AND PARTICIPANTS The Enquête Nationale sur l’Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod. MAIN OUTCOMES AND MEASURES Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod. RESULTS Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). CONCLUSIONS AND RELEVANCE In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. The emergence of disease-modifying therapies (DMTs) has greatly improved disease activity control and progression of disability in MS patients. DMTs differ in their mode of action, route of administration, efficacy, and safety profiles, offering multiple options for clinicians. Personalized medicine aims at tailoring the therapeutic strategy to patients’ characteristics and disease activity but also patients’ needs and preferences. New therapeutic options have already changed treatment paradigms for patients with active relapsing MS (RMS). The traditional approach consists in initiating treatment with moderate-efficacy DMTs and subsequently, escalating to higher-efficacy DMTs when there is evidence of clinical and/or radiological breakthrough activity. Recent real-world studies suggest that initiation of high-efficacy DMTs from disease onset can improve long-term outcomes for RMS patients. In this article, we review different treatment strategies and discuss challenges associated with personalized therapy.