Background
Outcomes of coronavirus disease 2019 (COVID‐19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), ...often treated with immunosuppressive therapies, are still unknown.
Methods
We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID‐19 between 1 March 2020 and 30 June 2020. Main outcome was COVID‐19 severity score assessed on a seven‐point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).
Results
Fifteen cases (mean SD age: 39.3 14.3 years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24‐year‐old patient with positive aquaporine‐4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti‐CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean SD age: 37.0 13.4 years), with a longer disease duration (mean SD: 8.3 6.3 years) and had a lower expanded disability severity score (EDSS) score (median range EDSS: 2.5 0–4) relative to patients requiring hospitalization (mean SD age: 44.0 16.4 years, mean SD disease duration: 5.8 5.5 years, median range EDSS: 4 0–6.5).
Conclusions
COVID‐19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID‐19; however, we recommend personal protective measures to reduce risk of SARS‐CoV‐2 infection in this immunocompromised population.
We present a cohort of 15 patients with neuromyelitis optica and associated disorders who had Coronavirus disease 2019 (COVID‐19). COVID‐19 outcome was overall favorable, 5 patients, all on Rituximab, needed hospitalization, and one patient needed mechanical ventilation.
Introduction
Fatty‐acid oxidation disorders (FAODs) are recessive genetic diseases.
Materials and methods
We report here clinical and paraclinical data from a retrospective study of 44 adults with ...muscular FAODs from six French reference centers for neuromuscular or metabolic diseases.
Results
The study cohort consisted of 44 adult patients: 14 with carnitine palmitoyl transferase 2 deficiency (32%), nine with multiple acyl‐CoA deficiency (20%), 13 with very long‐chain acyl‐CoA dehydrogenase deficiency (30%), three with long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (7%), and five with short‐chain acyl‐CoA dehydrogenase deficiency (11%). Disease onset occurred during childhood in the majority of patients (59%), with a mean age at onset of 15 years (range = 0.5–35) and a mean of 12.6 years (range = 0–58) from disease onset to diagnosis. The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L (range = 660–300,000). General metabolic complications were observed in 58% of patients, respiratory manifestations in 18% of cases, and cardiological manifestations in 9% of cases. Fasting acylcarnitine profile was used to orient genetic explorations in 65% of cases. After a mean follow‐up of 10 years, 33% of patients were asymptomatic and 56% continued to display symptoms after exercise. The frequency of rhabdomyolysis decreased after diagnosis in 64% of cases.
Conclusion
A standardized register would complete this cohort description of muscular forms of FAODs with exhaustive data, making it possible to assess the efficacy of therapeutic protocols in real‐life conditions and during the long‐term follow‐up of patients.
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.
The objectives were to determine the proportion of untreated patients with multiple sclerosis (MS) followed in expert centers in France and to determine the predictive factors of non‐treatment. Among the 21,189 patients with MS, 31.3% were not receiving any disease‐modifying treatment and the most important predictive factor for not being treated was the disease course: 14.8% of patients with a relapsing‐remitting course were untreated, while 50.4% of those with secondary and 64.2% of those with primary progressive MS were untreated. 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 and lower Expanded Disability Status Scale score.
Background:
In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression.
Objective:
We aimed to develop and validate a dynamic ...score to guide the early decision to switch from first- to second-line therapy.
Methods:
Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs).
Results:
From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09–0.22) for the waiting group and 0.40 (95% CI 0.32–0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30–0.46) and 0.44 (95% CI 0.37–0.52), respectively.
Conclusions:
By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.
Abstract Background and Purpose Small‐fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin ( TTR ) gene, but ...not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337‐18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. Methods In this retrospective single‐center study, we analyzed the frequency of the c.76G>A and c.337‐18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. Results We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337‐18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. Conclusions The c.76G>A and c.337‐18G>C TTR gene variants are not associated with SFN.
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).
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).
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.
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.
Background
HTLV1-associated myelitis (HAM) is a slowly progressive myelopathy in which spinal cord MRI demonstrates no lesion or atrophy.
Objective
We examined the overlap between NMOSD features and ...HTLV1 infection.
Methods
We included all HTLV1-infected patients recruited in French West Indies (FWI) or referred from different centers, and suffering from at least one NMOSD feature. Literature connecting HTLV1-infection and NMOSD was reviewed.
Results
We included six NMOSD-like HAM with acute onset, seronegative against AQP4 and MOG-Abs. All displayed extensive longitudinal myelitis, and the optic nerve was involved in three. We gathered 39 cases of NMOSD-like HAM patients from the literature. Atypical signs of HAM were relapses (15.4%), sensory level (50%), upper limb symptoms (35.9%), optic neuritis (10.2%). Typical lesions involved lateral funiculi and featured a double rope sign (56.3%).
Conclusion
We propose that acute onset of NMOSD-like HAM could be more frequent than expected and should be evoked in high-risk patients. Extensive but often transient cord lesions could be the hallmark of an excessive inflammation of the funiculi targeted by HTLV1 infection. Although usually minor, a few HAM cases demonstrate specific MRI lesions, and the most severe cases may mimic NMOSD attacks.
Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are ...pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group.BACKGROUND AND PURPOSESmall-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group.In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database.METHODSIn this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database.We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database.RESULTSWe included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database.The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.CONCLUSIONSThe c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.
Timely treatment switching is an important strategy in optimising management of patients with relapsing remitting multiple sclerosis (RRMS). Patient preferences, as well as clinical benefit, may ...contribute to the switch decision. Information on reasons determining switching choices and on outcome according to the reason for switching is scarce. Study objectives were to describe the consequences of switching to fingolimod in terms of clinical improvement according to the reasons underlying the switch and to evaluate treatment acceptability from the patient's perspective.
This prospective observational study was conducted by 71 neurologists in France and included patients with RRMS switching to fingolimod following ≥6 months treatment with a first-line disease modifying treatment (DMT). Reasons for switching were documented. Patients were evaluated at inclusion and 12 months after initiating fingolimod. Physicians documented clinical status by relapse activity, disability (EDSS) at each visit and improvement with the Clinical Global Impression - Change (CGI-C) at Month 12. Patients rated improvement at Month 12 with the Patient Global Impression - Change (PGI-C) and treatment acceptability with the ACCEPT® questionnaire. Adverse events reported during fingolimod treatment were documented.
Overall 232 patients were recruited of whom 190 could be analysed. Multiple reasons for switching were frequently given; 113 patients (59.4%) switched from a first-line injectable DMT. Switching was motivated by disease worsening in 161 patients (84.7%), tolerability in 35 (18.4%) and patient preference in 58 (30.5%). During the follow-up period, 38 patients (20.0%) experienced at least one exacerbation. The mean EDSS score was stable (2.0 ± 1.3 at inclusion; 2.0 ± 1.5 at M12). With the CGI-C, 67 patients (38.7%) were considered improved and 23 (13.3%) worsened. Although no obvious differences in CGI-C ratings were observed as a function of the reason for switching, when patient preferences entered into the decision, the proportion of patients considered minimally improved was somewhat higher (37.7%) and the proportion considered unchanged somewhat lower (41.5%). With the PGI-C, more patients rated themselves improved than were rated as improved by the physician: of 64 patients rated as 'no change' on the CGI-C, 21 (32.8%) rated themselves as 'improved' and 10 (15.6%) as 'worsened'. The overall level of agreement between the two measures was moderate (κ = 0.48 95% CI: 0.35 - 0.60). The mean general treatment acceptability score on the ACCEPT® questionnaire was 42.7 95%CI: 34.5 - 50.9 at inclusion (reflecting acceptability of the previous DMT) and 64.6 95%CI: 57.6 - 71.6 at M12 (reflecting acceptability of fingolimod). Mean dimension scores ranged from 36.7 for effectiveness to 72.2 for medication inconvenience at inclusion and from 63.4 for effectiveness to 96.8 for medication inconvenience at M12. The frequency and nature of reported adverse events was consistent with the well-characterised safety profile of fingolimod.
Most patients switching from a first DMT to fingolimod do so due to persistent disease activity during the initial treatment, although patient preferences are also important. Switching is followed by a reduction in disease activity, perceived improvement in the clinical state of the patient and improved acceptability of treatment.
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