Background

Respiratory disorders (RD) remain incompletely described and understood in multiple sclerosis (MS), although they might play an important role in the burden of MS. RD are the first cause of mortality in MS patients, and could suddenly worsen with acute respiratory failure, for example during an infectious pneumopathy. However, they are underestimated especially due to the motor disability and cognitive disorders.

Objectives

The primary objective was to assess the categories of RD in MS patients:

i) isolated respiratory muscles impairment (decrease of inspiratory maximal pressure or sniff nasal inspiratory pressure < 60%)

ii) diaphragmatic dysfunction (upright vital capacity (VC) - supine VC > 20% of upright VC and/or phasic activation of respiratory muscles during sleep and/or opposition of the thoracic and abdominal respiratory movements during sleep and/or orthopnea and/or respiratory muscles impairment )

iii) nocturne alveolar hypoventilation (PaCO2 > 45 mmHg and/or during the sleep : > 10 min of sleep with PtcCO2 > 55 mmHg or PaCO2 > 50 mmHg if increasing of PaCO2 > 10 mmHg between awake and the sleep).

The secondary objectives were to evaluate the correlation between RD and i) disability scores, including fatigue and cognitive evaluation, and ii) MRI encephalic and spinal lesion load.

Methods

Patients with severe MS (EDSS ≥ 6.5), with or without respiratory complaint, were included in this prospective monocentric study. Comprehensive pulmonary function tests, polysomnography with specific electromyography of accessory respiratory muscles, cognitive tests, brain and cervical spinal cord MRI were performed within 24 hours.

Results

71 patients (39 F/32 M) were included: median age 53,9 years (IQR: 48.40-60.95), median EDSS 7.5 (IQR: 6.5 - 8), median disease duration 21.4 years (IQR: 16-31.35). 46 patients (65%) had diaphragmatic dysfunction, including 36 patients (50%) with isolated respiratory muscles impairment. 9 patients (13%) had nocturnal alveolar hypoventilation. 21 (30 %) patients had no RD. Correlation studies with disability scores and MRI lesion load are on going.

Conclusions

Using specific technics of polysomnography and respiratory muscle testing, this study highlights the frequency of respiratory disorders in MS patients with EDSS ≥ 6.5, but also provides innovative insight into the different types of RD. These findings should lead to specific multidisciplinary care, such as non-invasive ventilation or preventive measures (vaccination against pulmonary infections for patients and families).

Background

Risk factors associated with the severity of COVID-19 in patients with multiple sclerosis (MS) begin to be identified from several cohort studies. Disease modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objectives

The objective was to describe the clinical characteristics and outcomes in patients with COVID-19 and to identify the factors associated with COVID-19 severity.

Methods

This multicenter, retrospective, observational cohort study (COVISEP registry, NCT04355611) included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020 and July 14, 2020. The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1: not hospitalized, no limitations on activities, to 7: death; cutoff at 3: hospitalized, not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Score (EDSS), comorbidities, COVID-19 characteristics and outcome. Univariate and multivariate logistic regression models were used to estimate the influence of collected variables on COVID-19 outcome.

Results

A total of 405 patients (mean age: 44.7 years, female/male: 293/112, mean disease duration: 13.4 years) were analyzed. Seventy-eight patients (19.3%) had a COVID-19 severity score ≥ 3, and 12 patients (3.0%) died from COVID-19. Median EDSS was 2.0 (range: 0-9.5), 326 patients (80.5%) were on DMT. There was a higher proportion of patients with COVID-19 severity score ≥ 3 among patients with no DMT relative to patients on DMTs (39.2% versus 14.4%, p<0.001). Multivariate logistic regression models determined that age (OR for 10 years: 1.8, 95% CI: 1.4-2.4), EDSS (OR for EDSS ≥ 6: 4.5, 95% CI: 2.0-10.0) were independent risk factors for COVID-19 severity score ≥ 3 (hospitalization or higher severity) while immunomodulatory treatment (interferon or glatiramer acetate) was associated with lower risk of COVID-19 severity score ≥ 3 (OR: 0.2, 95% CI: 0.05-0.8). EDSS was associated with the highest variability of COVID-19 severe outcome (R²= 0.18), followed by age (R²= 0.06) and immunomodulatory treatment (R²= 0.02).

Conclusions

EDSS and age were independent risk factors of severe COVID-19, while exposure to immunomodulatory DMTs (interferon and glatiramer acetate) were independently associated with lower COVID-19 severity. We did not find an association between other DMTs exposure (including immunosuppressive therapies) and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of MS patients during the COVID-19 pandemic.

Background

Yellow fever vaccine (YFV) is mandatory for travel in areas where yellow fever is endemic, but is not authorized for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. However, this recommendation is only based on a single study including 7 patients.

Objectives

The aim of the study is to assess the risk of worsening in relapsing remitting (RR) MS after YFV.

The primary objective was to compare the risk of relapse, during the 12 months after the YFV between exposed and non-exposed subjects. The secondary objectives were: (i) to assess the time to first relapse after YFV, using Kaplan-Meier curves. Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for DMT at the time of YFV (ii) to compare the disability progression and the disease form 12 months after YFV, and at the end of the follow-up.

Methods

This is a non-interventional observational retrospective, exposed/non-exposed cohort study, nested in the French national cohort including MS patients. Exposed RR-MS patients received one subcutaneous dose of YFV. Each exposed subject was matched to 3 RR-MS non-exposed to YFV. The matching criteria were: age, sex and annualized relapse rate (ARR) for the year before vaccination. The risk of relapse during the 12 months after the YFV was compared between exposed and non-exposed subjects. The time to first relapse after YFV was assessed using Kaplan Meier curves; Hazard Ratio (HR) was estimated by an adjusted Cox model for EDSS score and for disease modifying therapy at time of YFV. The disability progression 12 months after the YFV was compared between exposed and non-exposed subjects.

Results

128 RR MS according to McDonald Criteria 2017 (32 exposed/96 non-exposed) were included. The ARR the year after YFV did not differ between exposed: 0.233 (0.430) and non-exposed subjects: 0.213 (0.511) (p=0.84). Time to first relapse was not different between the 2 survival curves (adjusted HR, 1.33; 95% CI 0.53-3.30, p=0.54). The disability progression over the year following YFV did not differ between exposed and non-exposed subjects (p=0.83).

Conclusions

YF vaccine, a live attenuated vaccine which is very effective, is required to enter the territory of endemic areas. French and US recommendations for immunization in MS concluded that « There is insufficient data in the literature to conclude on the potential risks related to yellow fever vaccine because studies are either lacking or insufficiently powered ».These results show that YFV doesn’t worsen RR-MS, and suggest that non-immunosuppressed RR-MS patients travelling to endemic areas for professional or personal reasons could be vaccinated against YF.

Background

Siponimod, a potent and highly selective sphingosine 1-phosphate receptor modulator, has recently been approved for treatment of relapsing forms of MS and active SPMS.

Objectives

To assess remyelination and neuroprotective potential of siponimod in a Xenopus remyelination and a mouse optic neuritis (EAEON) model using histological analysis and longitudinal visual system readouts.

Methods

We used a conditional demyelination transgenic Xenopus laevis model (MBP-GFP-NTR), in which oligodendrocyte apoptosis can be induced by metronidazole (MTZ) treatment. After MTZ withdrawal, remyelination was assessed with or without siponimod (0.1nM-1µM). In a pharmacokinetics study, brain siponimod levels were analysed. EAEON was induced in female C57BL/6J mice immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG_35-55) and continuously fed with vehicle- or siponimod-loaded pellets at 10 or 30 mg/kg of food, either prophylactically or therapeutically, over 90 days. Sections of the optic nerve (Xenopus and mouse) were used to detect de- and remyelination, as well as inflammatory infiltrates. In mice, thickness of retinal layers and visual function were assessed by optical coherence tomography and optokinetic response, respectively. Circulating lymphocytes (flow-cytometry) and siponimod blood and brain levels were analysed at the end of the experiment.

Results

Treatment of demyelinated tadpoles with siponimod (1nM in swimming water) improved remyelination by a factor of 2.3±0.2 fold in comparison to control. The dose-response of siponimod efficiency to accelerate remyelination showed a bell-shaped curve with a maximum remyelination effect at concentrations ranging between 70-80 nM in tissues. In the EAEON mouse model, prophylactic siponimod treatments with 10 or 30 mg/kg attenuated the EAEON clinical scores by about 80% and 95%, respectively, and reduced the retinal neurodegeneration and the loss of visual function. Interestingly, therapeutic treatment starting at day 14 of EAEON had no impact on optic nerve immune cell infiltrates but resulted in increased myelin levels and protection of inner retinal layers also in a bell-shaped dose-response curve with significant protective effects only at the lower dose.

Conclusions

Our data suggest that while siponimod strongly impacts immune cells at higher concentrations (classical dose-response), its effects on remyelination and neuroaxonal survival are dose-dependent following the dynamics of a bell-shaped dose-response curve in both animal models.

Abstract

Mechanisms of myelin regeneration

Major progress have been achieved in multiple sclerosis treatment, through the development of immunotherapies reducing central nervous system inflammation and related relapse rate. Prevention of handicap progression, which mostly correlates to irreversible neuronal/axonal damage and loss, is however still an unmet need, notably during the progressive phase of the disease. In this context, promoting remyelination, which results in prevention of neurodegeneration, represents a promising therapeutic strategy to slow or suppress disability progression. Recent years have been fruitful in our understanding of the cellular and molecular mechanisms of the remyelination process, taking advantage of a wide variety of demyelination/remyelination models. One pre-requisite for successful remyelination is the presence of axons (at least without irreversible damage). The other is a sufficient number of remyelinating cells. Aside from oligodendrocyte precursors cells, progenitor cells from the sub-ventricular zone but also mature oligodendrocytes might participate in remyelination, although this is still a matter of debate. Different steps, consisting of cell division, activation, recruitment to the demyelinated area, oligodendroglial maturation and myelin wrapping are needed for remyelination, the relative importance of each step depending on the lesion type. Key molecular pathways have been identified: PDGF and FGF induce cell division, several guidance cues influence OPC recruitment towards the lesion, Semaphorin 3F being attractant, in contrast to the repellent effect of Semaphorin 3A and Netrin 1. Several cues and pathways favoring or inhibiting the oligodendroglial maturation process have been identified. Among the inhibitors of maturation are the Notch signaling pathway , Lingo-1, the Wnt pathway, muscarinic receptor signaling, H3 receptor signaling hyaluronan, chondroitin sulfate proteoglycan, and fibrinogen. The mechano-responsive ion channel PIEZO1 has been identified as an inhibitor of maturation, involved in age- related loss of function of OPC. In contrast, activation of the retinoid X receptor gamma favors oligodendroglial maturation, as well as thyroid hormone and Vitamin D. Furthermore, complementary lines of evidence have highlighted the key role of neuronal electrical activity in myelination onset. From this very active research field, and with the caveat that these mechanisms of remyelination might differ between experimental models and multiple sclerosis, several therapeutic targets have emerged, paving the way to translation.

Abstract

Mechanisms of myelin regeneration

Major progress have been achieved in multiple sclerosis treatment, through the development of immunotherapies reducing central nervous system inflammation and related relapse rate. Prevention of handicap progression, which mostly correlates to irreversible neuronal/axonal damage and loss, is however still an unmet need, notably during the progressive phase of the disease. In this context, promoting remyelination, which results in prevention of neurodegeneration, represents a promising therapeutic strategy to slow or suppress disability progression. Recent years have been fruitful in our understanding of the cellular and molecular mechanisms of the remyelination process, taking advantage of a wide variety of demyelination/remyelination models. One pre-requisite for successful remyelination is the presence of axons (at least without irreversible damage). The other is a sufficient number of remyelinating cells. Aside from oligodendrocyte precursors cells, progenitor cells from the sub-ventricular zone but also mature oligodendrocytes might participate in remyelination, although this is still a matter of debate. Different steps, consisting of cell division, activation, recruitment to the demyelinated area, oligodendroglial maturation and myelin wrapping are needed for remyelination, the relative importance of each step depending on the lesion type. Key molecular pathways have been identified: PDGF and FGF induce cell division, several guidance cues influence OPC recruitment towards the lesion, Semaphorin 3F being attractant, in contrast to the repellent effect of Semaphorin 3A and Netrin 1. Several cues and pathways favoring or inhibiting the oligodendroglial maturation process have been identified. Among the inhibitors of maturation are the Notch signaling pathway , Lingo-1, the Wnt pathway, muscarinic receptor signaling, H3 receptor signaling hyaluronan, chondroitin sulfate proteoglycan, and fibrinogen. The mechano-responsive ion channel PIEZO1 has been identified as an inhibitor of maturation, involved in age- related loss of function of OPC. In contrast, activation of the retinoid X receptor gamma favors oligodendroglial maturation, as well as thyroid hormone and Vitamin D. Furthermore, complementary lines of evidence have highlighted the key role of neuronal electrical activity in myelination onset. From this very active research field, and with the caveat that these mechanisms of remyelination might differ between experimental models and multiple sclerosis, several therapeutic targets have emerged, paving the way to translation.

Abstract

Mechanisms of myelin regeneration

Major progress have been achieved in multiple sclerosis treatment, through the development of immunotherapies reducing central nervous system inflammation and related relapse rate. Prevention of handicap progression, which mostly correlates to irreversible neuronal/axonal damage and loss, is however still an unmet need, notably during the progressive phase of the disease. In this context, promoting remyelination, which results in prevention of neurodegeneration, represents a promising therapeutic strategy to slow or suppress disability progression. Recent years have been fruitful in our understanding of the cellular and molecular mechanisms of the remyelination process, taking advantage of a wide variety of demyelination/remyelination models. One pre-requisite for successful remyelination is the presence of axons (at least without irreversible damage). The other is a sufficient number of remyelinating cells. Aside from oligodendrocyte precursors cells, progenitor cells from the sub-ventricular zone but also mature oligodendrocytes might participate in remyelination, although this is still a matter of debate. Different steps, consisting of cell division, activation, recruitment to the demyelinated area, oligodendroglial maturation and myelin wrapping are needed for remyelination, the relative importance of each step depending on the lesion type. Key molecular pathways have been identified: PDGF and FGF induce cell division, several guidance cues influence OPC recruitment towards the lesion, Semaphorin 3F being attractant, in contrast to the repellent effect of Semaphorin 3A and Netrin 1. Several cues and pathways favoring or inhibiting the oligodendroglial maturation process have been identified. Among the inhibitors of maturation are the Notch signaling pathway , Lingo-1, the Wnt pathway, muscarinic receptor signaling, H3 receptor signaling hyaluronan, chondroitin sulfate proteoglycan, and fibrinogen. The mechano-responsive ion channel PIEZO1 has been identified as an inhibitor of maturation, involved in age- related loss of function of OPC. In contrast, activation of the retinoid X receptor gamma favors oligodendroglial maturation, as well as thyroid hormone and Vitamin D. Furthermore, complementary lines of evidence have highlighted the key role of neuronal electrical activity in myelination onset. From this very active research field, and with the caveat that these mechanisms of remyelination might differ between experimental models and multiple sclerosis, several therapeutic targets have emerged, paving the way to translation.