Pierre Labauge

Colony-stimulating factor receptor 1-related disorder (CSF1R-RD) is an underrecognized, adult-onset genetic leukodystrophy with a devastating clinical course. Disease monitoring is critical as patients with CSF1R-RD can benefit from hematopoietic stem cell transplantation. Here, we aimed to compare blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels between patients with CSF1R-RD and those with alternative diagnoses and to correlate blood biomarkers values with clinical severity. We analyzed 22 patients with CSF1R-RD and patients with fronto-temporal lobar degeneration due to GRN pathogenic variants (GRN-FTLD, n = 22), CADASIL (N = 9), cerebral adrenoleukodystrophy (13), and primary progressive multiple sclerosis (n = 14). NfL and GFAP were elevated in CSF1R-RD and GRN-FTLD as compared with the other groups. After adjusting for age, GFAP was higher in patients with CSF1R-RD compared with those with GRN-FTLD (p = 0.035). Among CSF1R-RD patients, both NfL (p = 0.0054) and GFAP (p = 0.0065) correlated with Expanded Disability Status Scale scores. For a subset of patients with cognitive testing, GFAP correlated with the processing speed index of the Wechsler adult intelligence scale (p = 0.025) and state anxiety (p = 0.0088). Our results show that blood NfL and GFAP are promising biomarkers of disease progression in patients with CSF1R-RD.

Children with multiple sclerosis (MS) are increasingly treated with high-efficacy monoclonal antibody therapies; however, treatment approaches vary widely, largely because of regulatory restrictions that often delay access until adulthood. We hypothesized that initiating these therapies during childhood confers greater benefits than their initiation in adulthood. This study, therefore, evaluated long-term disability in patients with pediatric-onset MS treated with monoclonal antibodies before age 18 compared with those who initiated these therapies in adulthood. In this retrospective cohort study, patients younger than 18 years at the onset of MS symptoms were identified across 3 MS registries: MSBase, Observatoire Français de la Sclérose en Plaques, and the Italian MS Register. We categorized patients who commenced natalizumab, ocrelizumab, or rituximab between ages 12 and 17 into the pediatric high-efficacy therapy (HET) initiation group and those who began treatment between ages 20 and 22 into the adult HET initiation group. A landmark study design was used, with age 18 designated as the baseline and the outcome period spanning ages 23-27 years. The primary outcome was the change in Expanded Disability Status Scale (EDSS) scores, evaluated using a Bayesian weighted generalized linear mixed model. We included 277 patients (72% female), with a mean (SD) age at onset of MS symptoms of 14.97 (2.23) years. Of these, 108 initiated HET during childhood and 169 during adulthood. The postbaseline increase in EDSS scores was 0.53 steps lower in the pediatric HET initiation group compared with the adult group (β -0.53 [95% credible interval -0.87 to -0.19]). This benefit of pediatric HET initiation was most pronounced within the EDSS range of 4.5-6.0, with up to a 97% reduction in the odds of further disability worsening (odds ratio of EDSS score 5.0 over 4.5: 0.03 [95% credible interval 0.003-0.22]). Commencing high-efficacy monoclonal antibody therapy in childhood is associated with more favorable long-term disability outcomes than delayed initiation in adulthood. Early use of highly effective therapy is crucial for preserving neurologic function in children with MS. This study provides Class II evidence that, in children aged 12-17 years with MS, initiating therapy with monoclonal antibodies before age 18 (vs 20-22) is associated with less disability accrual between the ages of 23 and 27.

The therapeutic strategy for late-onset multiple sclerosis (LOMS) with a relapsing-remitting onset remains unclear, potentially leading to underexposure to disease-modifying therapies (DMTs) compared with adult-onset multiple sclerosis (AOMS). We investigated the differences in DMT use between LOMS and AOMS within the French MS registry at comparable levels of disease severity. This retrospective cohort study used data extracted in December 2024 from the French MS registry on patients with relapsing-remitting onset MS between 1997 and 2023. The primary outcome was the annual probability of receiving a DMT according to age at MS onset, adjusted for disease severity. Secondary outcomes included the annual probability of receiving a highly effective DMT (HEDMT), each DMT separately, having ≥1 EDSS measurement, having ≥1 brain MRI, and DMT initiations and discontinuations. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. A total of 36,148 were included patients; 26,540 (73.4%) were female, mean age was 33.5 years (SD, 9.7), and 2,308 (6.4%) were aged ≥50 at disease onset. Median follow-up was 10.8 years (interquartile range, 5.6-17.0). Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with AOMS (73.7% vs 83.1%; odds ratio [OR], 0.57 [95% CI 0.52-0.62]). The difference was greater for HEDMT (24.6% vs 44.4%; OR, 0.41 [95% CI 0.36-0.46]). Patients with LOMS were more likely to receive teriflunomide and less likely to receive fumarates, S1PR modulators, natalizumab, or anti-CD20. Clinical and radiologic follow-up did not differ significantly between patients with LOMS and AOMS. The rate of DMT initiation was lower in patients with LOMS (0.13 vs 0.17 initiation per patient-year). Although the proportions of DMT discontinuation were similar (59.7% vs 60.4%, excluding pregnancy-related discontinuations), these discontinuations were more often attributed to a complete discontinuation strategy (27.9% vs 22.3%) and less often to an escalation strategy (9.2% vs 13.8%) in patients with LOMS. At comparable levels of disease severity, patients with LOMS were less likely to be treated with DMTs, particularly HEDMT, than patients with AOMS. This gap was driven both by fewer DMT initiations and more frequent complete discontinuations.

The most common cause of convexity subarachnoid hemorrhage (cSAH) in younger patients (younger than 60 years) is reversible cerebral vasoconstriction syndrome (RCVS). Evidence on the long-term outcomes of future vascular events and functional outcome after cSAH due to RCVS is limited. We aimed to assess the rates and baseline predictors of our primary outcomes (cSAH, intracerebral hemorrhage (ICH), and ischemic stroke), functional outcome, and mortality after cSAH attributed to RCVS. Individual patient data pooled analysis in patients with cSAH attributed to RCVS. A systematic literature search was conducted in PubMed and EMBASE. Two independent reviewers screened studies and extracted data. Quality assessment was assessed using the Newcastle-Ottawa Scale. Early events during the accepted time frame of an RCVS episode (<3 months) were classified as progression rather than recurrence. Follow-up was truncated at 5 years. Primary outcomes were recurrent cSAH, ICH, and ischemic stroke. Secondary outcomes were mortality and functional status measured by modified Rankin Score (mRS). We identified 21 eligible cohorts finally including 138 patients from 9 collaborative centers, which provided individual patient data. The mean age was 49.3 ± 12.1 years, and 110 (79.7%) were female. During a mean follow-up of 1.8 years, annual rates were cSAH recurrence 0.81% (95% CI 0.1-2.91), ICH 0.81% (95% CI 0.1-2.91), and ischemic stroke 0.81% (95% CI 0.1-2.91). Progression during the initial episode (shortly after admission) occurred in 10 patients for cSAH, 2 for ICH, and 8 for ischemic stroke, respectively. Of 106 patients (76.8%) with available outcome data, 100 (94.3%) achieve a mRS of ≤1 at follow-up, indicating no significant disability. Two patients died (annual rate 0.5%, 95% CI 0.09-2.9): one within 10 days and the other within 2 months of the cSAH. Our data suggest a favorable prognosis for most patients after RCVS-associated cSAH with low rates of recurrent events and a high proportion achieving functional independence. Major limitations include retrospective data collection and potential selection bias from centers providing individual patient data. Nevertheless, these findings provide prognostic information to inform clinical practice.

In women with multiple sclerosis (MS), the therapeutic strategy may be influenced by the anticipation of future pregnancies, leading to underexposure to disease-modifying therapies (DMTs) and highly effective DMTs (HEDMTs) compared with men. We aimed to evaluate potential therapeutic inertia in women with MS and explore its causes. We performed a retrospective cohort study based on data extracted on June 2023 from the Observatoire Français de la Sclérose en Plaques for all patients with a relapsing-remitting MS onset between 18 and 40 years. The primary outcome was the annual probability of receiving a DMT, accounting for sex, disease severity, and pregnancy/postpartum periods. Secondary outcomes were the annual probability of receiving a HEDMT, each DMT separately, and interaction of the effect of sex with calendar year, patient age, and disease duration. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. We included 22,657 patients with MS; 16,857 (74.4%) were female, mean (SD) age at onset was 29.0 (6.0) years, and median (interquartile range) follow-up duration was 11.6 (6.6-17.3) years. Women were significantly less likely to receive a DMT (odds ratio [OR] 0.92, 95% CI 0.87-0.97) or a HEDMT (OR 0.80, 95% CI 0.74-0.86). This difference appeared 2 years after disease onset for DMTs and 1 year for HEDMTs, and did not differ significantly according to patient's age. Teriflunomide, sphingosine-1-phosphate receptor modulators, and anti-CD20s were significantly underused in women throughout their entire period of availability; interferons β (IFN-β) and natalizumab were initially less used and then equally after some time; glatiramer acetate and fumarates were first used equally, then more frequently in women. The proportion of treated women, analyzed from the first childbirth of 5,268 women, began to decline 18 months before childbirth, from 42.6% to 27.9% at the estimated time of conception. Women with MS were significantly less exposed to DMTs compared with men. Anticipation of pregnancy was probably an important factor underlying this difference, but also sex-specific therapeutic inertia. Neurologists and patients should be educated on the most recent recommendations on the use of DMTs in the context of pregnancy to avoid deleterious therapeutic inertia.

The therapeutic strategy in patients with late-onset MS (LOMS) remains poorly defined. In this study, we aimed to evaluate both clinical and MRI outcomes between 2 cohorts of patients with relapsing-remitting LOMS treated or not yet treated. Patients with relapsing-remitting MS were included for the analysis if disease onset occurred after 55 years and if they had at least one follow-up visit. The primary outcome was time to first relapse between 2 matched groups of patients with LOMS (treated and not yet treated). Secondary outcomes were as follows: (1) time to first confirmed disability progression (CDP), (2) time to first progression independent of relapse activity (PIRA) event, (3) time to secondary progression (SPMS), (4) time to first MRI activity, and (5) serious infection incidence rates (IIRs). For the comparative analyses, we adopted a time-dependent propensity score matching approach. A total of 881 patients fulfilled the inclusion criteria. The mean (SD) age at onset was 59.9 (4.43) years. After applying propensity score matching, 436 patients were matched. The mean (SD) follow-up duration was 5.2 (4.27) years in the treated group and 5.0 (3.86) years in the not-yet-treated group. Mean (SD) time to first relapse was significantly longer in the treated group compared with the not-yet-treated group (7.0 years [0.33] vs 5.4 years [0.33]; p = 0.001). Mean (SD) time to first MRI activity was significantly longer in the treated group (5.9 years [0.33] vs 5.0 years [0.33]; p = 0.049). However, the mean time to CDP, PIRA, or SPMS was not different between the 2 groups (difference = 0.32 years; p = 0.585 for CDP; difference = 0.40 years; p = 0.442 for PIRA; difference = -0.02 years; p = 0.952 for SPMS). No increase in serious IIRs was observed with an incidence rate ratio of 0.38 (95% CI 0.07-2.10, p = 0.265) in the never-treated group compared with the treated one. This study demonstrates a beneficial effect of disease-modifying therapy (DMT) on disease activity in patients with LOMS but without significant impact on disability progression. Main limitations are linked to the challenge of data collection and to the baseline imbalances between the 2 groups. This study provides Class III evidence that in patients with LOMS, treatment with DMTs is associated with a longer time to first relapse compared with those not treated with DMTs.

Abnormal brain MRI is associated with poor outcomes in anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). We aimed to characterize the lesions on brain MRI in NMDARE and to assess the clinical and prognostic associations. This retrospective cohort study included patients with NMDARE identified at the French Reference Center for Autoimmune Encephalitis, with at least a one-year follow-up, and with available brain MRI results. In case of brain extralimbic lesion, the image files were reviewed when available. Clinical data were collected from medical records. Multivariable logistic regression analysis was used to study the outcomes at 2-year follow-up; recovery was defined as modified Rankin Scale score ≤1. Among the 255 patients included, 37 (14.5%) had limbic hyperintensities and 41 (16.1%) had extralimbic lesions that included multiple sclerosis (MS)-like lesions (14/41, 34.1%); extensive lesions (5/41, 12.2%); and poorly demarcated fluffy lesions, either multifocal (10/41, 24.4%) or involving the cerebral cortex or cerebellum (6/41 each, 14.6%). Extralimbic lesions coexisting with limbic lesions (19/41 patients, 46.3%) were mostly fluffy lesions (11/19, 57.9%). Ten patients had overlapping demyelinating syndromes: 4 with MS, 4 with myelin oligodendrocyte glycoprotein-associated disorder, and 2 with neuromyelitis optica spectrum disorder; all had MS-like (7/10 patients) or extensive (3/10 patients) lesions, and none had fluffy lesions. Extralimbic lesions were associated with symptoms nontypical for NMDARE (23/41, 56.1%, p < 0.001), especially cerebellar ataxia (17/41, 41.5%) and motor impairment (12/41, 29.3%). At 2 years, patients with MS-like or extensive lesions had a lower recovery rate (5/12, 41.7%, and 1/4, 25%, respectively) compared with the patients without extralimbic lesions (124/162, 76.5%; p = 0.014 and p = 0.047, respectively). In multivariable analysis, MS-like lesions, but not hippocampal nor fluffy lesions, were associated with absence of recovery at 2 years (adjusted OR 0.1, 95% CI 0.03-0.42, p = 0.002; extensive lesions [n = 4] not included in the analysis). Brain MRI lesions in NMDARE include limbic hyperintensities and 3 patterns of extralimbic lesions, which are associated with nontypical NMDARE symptoms. Moreover, MS-like and extensive lesions, but not fluffy nor hippocampal lesions, are associated with overlapping demyelinating syndromes and poor clinical outcomes at 2 years. These findings can have practical implications on the monitoring of patients with NMDARE.

Older studies reported an increased risk of relapse after in vitro fertilization (IVF) in women with multiple sclerosis (MS), which has not been confirmed by more recent works. All these studies had several limitations, such as small sample sizes, absence of a control population, or lack of neurologic validation of the relapses. The aim of this study was to determine the risk of relapse after IVF in women with MS. This retrospective cohort study included all women with MS who underwent IVF between 2009 and 2019 and a control group of women with MS who did not undergo IVF matched on age, MS duration, number of relapses, and MS-specific treatments in the previous year. Data on MS (disease duration, treatments, and relapses) were from the French MS Registry (OFSEP), whereas data on IVF (number of procedures, stimulation protocol type, and outcomes) were from the French national health insurance database. For this, the 2 databases were linked by indirect matching. In total, 115 women with MS underwent 199 IVF procedures (mean age at first IVF: 33.9 ± 4.0 years; 45.2% had ≥2 IVF procedures), and 175 IVFs (88.0%) could be matched to specific patients. The risk of relapse in the 3 months after index date was the same in both IVF group and control group (0.06 relapse per patient-year), as confirmed also by the before-after analysis in the IVF group (0.06 vs 0.08). This study, using a 10-year clinical and administrative dataset, did not find any increased risk of relapse after IVF. The maintenance of disease-modifying therapies until IVF was a determining factor in reducing the risk of relapse.

Although rituximab failed to demonstrate a significant effect on disability progression in primary progressive multiple sclerosis (PPMS), ocrelizumab succeeded. Our main objective was to analyze confirmed disability progression (CDP) in a cohort of patients with PPMS treated with anti-CD20 therapies compared with a weighted untreated control cohort. This was a retrospective study using data from the French MS registry (Observatoire Français de la Sclérose En Plaques). We included patients with PPMS treated or never treated with anti-CD20 therapies from 2016 to 2021, with an Expanded Disability Status Scale score of ≤6.5 at baseline. The primary outcome was time to first CDP. The secondary outcomes were time to first relapse, MRI activity at 2 years, identification of risk factors associated with CDP, and serious infection incidence rates (IIRs). Each outcome was studied using an inverse probability of treatment weighting method. The outcomes were modeled using a weighted proportional Cox model for the time-to-event outcomes and by a logistic regression regarding the MRI activity. A total of 1,184 patients (426 treated and 758 untreated) fulfilled the inclusion criteria. Median age (Q1-Q3) was 56 years (49.3-63.8), and 52.7% were female. Among treated patients, 295 received rituximab, whereas 131 received ocrelizumab. At baseline, anti-CD20-treated patients were younger (median 51.9 vs 58.6 years, Cohen d = 0.683) and had more active disease (54.5 vs 27.8%, Cohen d = 0.562). 91.6% were drug-naive at inclusion. In time to first CDP analysis, no statistical significance was observed (hazard ratio [HR], 1.13; 95% CI 0.93-1.36, p = 0.2113). In time to first relapse analysis, a nonsignificant trend toward fewer patients relapsing in the treated group was observed (HR 0.83; 95% CI 0.48-1.28, p = 0.0809). For MRI activity, no significant difference was found between the 2 groups. Risk factors associated with CDP in the treated group were male sex and MS duration. IIR was 6.67 (95% CI 3.12-14.25) per 100 person-years in the treated group vs 2.67 (95% CI 0.80-8.86) in the untreated group. Time to first CDP was not different between anti-CD20 treated and untreated patients with PPMS. Although our study is retrospective and mainly included patients treated by rituximab, our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS. This study provides Class III evidence that anti-CD20 therapy of previously untreated patients with PPMS was not superior to no therapy in delaying time to first CDP.

Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.