Macroglossia: A potentially severe complication of late-onset Pompe disease.

BACKGROUND: Pompe disease is a rare neuromuscular disorder caused by a deficiency of a lysosomal enzyme, acid α-glucosidase. Macroglossia is a classic clinical sign of several inherited myopathies and has also been reported to occur progressively in late-onset Pompe disease (LOPD). METHODS: We describe patients with LOPD and macroglossia included in the French national Pompe disease registry. Clinical, functional, and radiological data were collected during periodic follow-up and analyzed retrospectively. These cases were compared with 15 previously reported cases. RESULTS: Five patients, three females and two males, aged 71-88 years, were included in this study. All but one of the patients suffered from symptoms related to macroglossia before the diagnosis of Pompe disease. Three had localized tongue atrophy and one had significant localized tongue hypertrophy which led to glossectomy 10 years before diagnosis. Two patients had severe dysphagia, one of whom underwent gastrostomy for enteral nutritional support. One patient experienced the persistence of numerous sleep apneas despite nocturnal bilevel positive airway pressure (BiPAP) ventilation. All our patients had dysarthria, and two required speech therapy. Four patients had a tongue hypersignal on magnetic resonance imaging (MRI) T1 sequences. CONCLUSIONS: Detection of macroglossia should be part of the clinical diagnosis and follow-up of patients with LOPD, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole-body MRI with facial sections may facilitate the early diagnosis of Pompe disease with the "bright tongue sign".

Untreated patients with multiple sclerosis: A study of French expert centers.

BACKGROUND AND PURPOSE: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. METHODS: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. RESULTS: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. CONCLUSION: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

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.

Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis.

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.

Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference.

BACKGROUND AND OBJECTIVES: The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). METHODS: We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). RESULTS: We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. DISCUSSION: Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.

Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal.

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions.

Long-term outcomes of refractory neurosarcoidosis treated with infliximab.

Central nervous system localizations of sarcoidosis may be refractory to conventional treatment such as steroids and immunosuppressive drugs. Infliximab, a TNF-α antagonist chimeric antibody, has been shown to be effective for treatment of these localizations. The aim of this study was to evaluate the efficacy and safety, in particular the long-term outcomes, of the use of infliximab for the treatment of neurosarcoidosis. We retrospectively reviewed medical records of patients with neurosarcoidosis who had been treated with infliximab between 2009 and 2015. All patients had histologically proven non-caseating granulomas. Eighteen patients with histologically proven sarcoidosis were included in this study. All had neurological involvement consisting of meningeal (n = 16), cerebral (n = 10), spinal cord (n = 6), and/or optic nerve (n = 5) involvement. Sixteen patients had previously received at least one immunosuppressive drug in addition to corticosteroids, including cyclophosphamide in 11 patients. All patients received treatment with infliximab (3-7.5 mg/kg) associated with corticosteroids (n = 18), low-dose methotrexate (n = 15), azathioprine (n = 2), or mycophenolate (n = 1). Sixteen out of 18 patients improved clinically (initial median modified Rankin scale score of 3, final median score of 1; p < 0.0001). At 6 months after initiation of infliximab, six patients obtained complete remission (33%), ten attained partial remission (56%), and two had stable disease (11%). The median follow-up time was 20 months (range 6-93). Nine patients relapsed during follow-up (50%). Eight patients developed toxic side effects and seven of these side effects were infectious events. Infliximab is an efficacious treatment of refractory neurosarcoidosis. However, relapses frequently occurred during follow-up.

Treatment of neurosarcoidosis: A comparative study of methotrexate and mycophenolate mofetil.

OBJECTIVE: To compare the efficacy of methotrexate (MTX) and mycophenolate mofetil (MMF) in the prevention of relapses in neurosarcoidosis. METHODS: We conducted a retrospective multicenter study including patients who received MTX or MMF for the treatment of histologically proven neurosarcoidosis. The efficacy of the immunosuppressive drug was assessed by determining the time to relapse. RESULTS: Forty patients with a diagnosis of neurosarcoidosis (24 men, 16 women, median age at diagnosis 43.5 years) who received at least 3 months of MTX (n = 32) or MMF (n = 14) were included. The immunosuppressive drug was always associated with steroids. The rate of relapse was 47% in the MTX group (0.2 relapses per year of exposure) and 79% in the MMF group (0.6 relapses per year of exposure) (p = 0.058). The median time to relapse was significantly shorter in the MMF group (11 months) compared with the MTX group (28 months) (p = 0.049). Adverse events occurred in 11 patients during MTX therapy and in 1 patient during MMF therapy (p = 0.12). CONCLUSIONS: Relapses of neurosarcoidosis occur frequently, despite the use of an immunosuppressive drug in addition to corticosteroids. MTX significantly increases the survival time without relapse compared to MMF and should be preferred over MMF for the treatment of neurosarcoidosis. This study provides Class IV evidence that for patients with neurosarcoidosis taking steroids, MTX is superior to MMF in reducing the risk of relapse.