The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage‐gated sodium channels at nodes of Ranvier. Axo‐glial communication is required for ...assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM‐induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin‐1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin‐R). We show that Contactin‐1 combined with RPTP/Phosphacan or Tenascin‐R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin‐1‐immunodepleted OCM or OCM from Cntn1‐null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin‐1. Altogether, our results identify Contactin‐1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations.
Main Points
Oligodendrocyte secreted factors induce prenode formation on hippocampal GABAergic axons.
Proteomic analysis of OCM to select clustering candidates.
Contactin‐1 in association with Tenascin‐R or Phosphacan is responsible for prenodal clustering.
In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We previously described that node‐like ...clusters can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these clusters prior to myelination. We first demonstrated that their components can partially preassemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Nav for node‐like clustering initiation. We further assessed the fate of these clusters when myelination proceeds. Our results shed light on the intrinsic mechanisms involved in node‐like clustering prior to myelination and unravel a potential role of these clusters in node of Ranvier formation and in guiding myelination onset.
Kinesin‐1 and dynein/dynactin‐1 molecular motors are required for node‐like clustering.
β2Nav is an initiator of node‐like cluster assembly.
Node‐like clusters participate in mature node of Ranvier formation and myelin initiation guidance.
Background:
In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) ...shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed.
Objectives:
To establish recommendations on pregnancy in women with NMOSD.
Methods:
The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence.
Results:
A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments.
Conclusion:
Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.
SARS-CoV-2 seroconversion rate after COVID-19 may be influenced by disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMO-SD).
To ...investigate the seroprevalence and the quantity of SARS-CoV-2 antibodies in a cohort of patients with MS or NMO-SD.
Blood samples were collected in patients diagnosed with COVID-19 between 19 February 2020 and 26 February 2021. SARS-CoV-2 antibody positivity rates and Ig levels (anti-S IgG titre, anti-S IgA index, anti-N IgG index) were compared between DMTs groups. Multivariate logistic and linear regression models were used to estimate the influence of DMTs and other confounding variables on SARS-CoV-2 serological outcomes.
119 patients (115 MS, 4 NMO, mean age: 43.0 years) were analysed. Overall, seroconversion rate was 80.6% within 5.0 (SD 3.4) months after infection. 20/21 (95.2%) patients without DMT and 66/77 (85.7%) patients on DMTs other than anti-CD20 had at least one SARS-CoV-2 Ig positivity, while this rate decreased to only 10/21 (47.6%) for patients on anti-CD20 (p<0.001). Being on anti-CD20 was associated with a decreased odd of positive serology (OR, 0.07 (95% CI 0.01 to 0.69), p=0.02) independently from time to COVID-19, total IgG level, age, sex and COVID-19 severity. Time between last anti-CD20 infusion and COVID-19 was longer (mean (SD), 3.7 (2.0) months) in seropositive patients compared with seronegative patients (mean (SD), 1.9 (1.5) months, p=0.04).
SARS-CoV-2 antibody response was decreased in patients with MS or NMO-SD treated with anti-CD20 therapies. Monitoring long-term risk of reinfection and specific vaccination strategies in this population may be warranted.
NCT04568707.
Background:
Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses.
Objective:
To assess the risk of relapsing-remitting ...multiple sclerosis (RR-MS) worsening after YFV.
Methods:
Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS.
Results:
128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) (p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53–3.30, p = 0.54).
Conclusion:
These results suggest that YFV does not worsen the course of RR-MS.
To evaluate sleepiness and central hypersomnia in multiple sclerosis (MS)-associated fatigue, we performed long-term polysomnography in patients with MS and healthy controls.
Patients with MS and ...healthy controls completed questionnaires on sleep, fatigue, sleepiness, and depression. They underwent nocturnal polysomnography, multiple sleep latency tests, and bed rest 24-hour polysomnography. Patients were divided into 3 groups (fatigue and sleepiness, fatigue and no sleepiness, neither fatigue nor sleepiness).
Among 44 patients with MS, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness. Compared to 24 controls, patients with fatigue and sleepiness had higher REM sleep percentages (median interquartile range 20.5% 19.6-24.7 vs 18.1% 12.6-20.6), lower arousal indexes (12.7 7.5-17.0 vs 22.4 14.3-34.4), and shorter daytime mean sleep latencies (8.6 6.3-14.3 vs 16.6 12.6-19.5 min). Restless leg syndrome, periodic leg movements, and sleep apnea had similar frequencies between groups. Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness (narcolepsy type 2, n = 2), in 2 (13%) patients with fatigue only, and in 3 (30%) patients with neither fatigue nor sleepiness. Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but had similar levels of fatigue, disability, depression, cognitive performance, and frequencies of the human leukocyte antigen DQB1*0602 genotype. The severity of fatigue increased with higher depression scores, higher sleepiness severity, and lower sleep efficacy.
Central hypersomnias are frequent in MS when fatigue and sleepiness are present. Screening them through polysomnography studies is recommended.
Background
Recreational nitrous oxide (N
2
O) use has become more widespread worldwide, leading to an increase in myelopathies and peripheral neuropathies. The aim of this study was to describe ...clinical and socioeconomical characteristics of severe N
2
O-induced (NI) neurological disorders (NI-NDs), to determine its incidence in the Greater Paris area and to compare it with that of similar inflammatory neurological disorders.
Methods
We performed a retrospective multicentric cohort study of all adult patients with severe NI-NDs in the neurology and general internal medicine departments of the Greater Paris area from 2018 to 2021. The incidence was compared with that of non-NI-myelitis and Guillain–Barré syndrome (GBS) using a sample of 91,000 hospitalized patients sourced from health insurance data.
Results
Among 181 patients, 25% had myelopathy, 37% had peripheral neuropathy and 38% had mixed disease. Most were aged between 20 and 25 years, lived in socially disadvantaged urban areas, and exhibited high rates of unemployment (37%). The incidence of NI-NDs increased during 2020 and reached a peak mid-2021. The 2021 incidence in 20–25-year-olds was 6.15 4.72; 8.24 per 100,000 persons for NI-myelopathy and 7.48 5.59; 9.37 for NI-peripheral neuropathy. This was significantly higher than for non-NI-myelitis (0.35 0.02; 2.00) and GBS (2.47 0.64; 4.30). The incidence of NI-NDs was two to three times higher in the most socially disadvantaged areas.
Conclusion
The recent increase in recreational N
2
O use has led to a rise in the incidence of severe NI-NDs, particularly in young adults with low socioeconomic status for whom NI-NDs strongly outweigh similar neurological disorders.
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