Background

Pregnancy management in patients with relapsing-remitting multiple sclerosis (MS) treated by Natalizumab (NTZ) is challenging because of the risk of disease reactivation after treatment discontinuation.

Objectives

To compare clinical disease activity (annual relapse rate) during and after pregnancy among three therapeutic approaches: continuation of NTZ all along the pregnancy and the postpartum, discontinuation of NTZ in the second trimester and discontinuation of NTZ before pregnancy.

Methods

Data were collected from the French MS registry OFSEP (Observatoire Français de la Sclérose en Plaques). We included patients with relapsing-remitting MS who started a pregnancy between 6/2013 and 9/2018 while taking NTZ, or within six months after its suspension. 3 groups were compared : continuation of NTZ throughout pregnancy and postpartum (Group 1), 3 to 6 months of exposure to NTZ during pregnancy (Group 2) and suspension prior to pregnancy (Group 3). Annual relapse rate (ARR) during 2 years (9 months before and 15 months after preganncy onset) was the primaty outcome and effect on EDSS and MRI were secondary end-points.

The main analysis was performed using a negative binomial regression with the follow-up duration as the offset term. Univariate and multivariate anlyses after adjustment for baseline variables (age, EDSS, ARR in the year before starting NTZ, first-line patient on NTZ vs. second-line patient).

Results

117 patients from 27 centers* were included. Baseline mean age was 31,5 y, median EDSS was 2.0 and mean duration of disease was 7,89 y. The mean ARR were respectively 0.078 +/- 0.24 in Group 1, 0.308 +/- 0.43 in Group 2 and 0.456 +/- 0.63 in Group 3 during the observation period and was significantly higher in Groups 2 and 3 as compared with ARR in Group 1 (p=0,007). The risk of relapses was 4 times higher in Group 2 versus Group 1 (p=0,014) and 6 times higher in Group 3 versus Group 1 (p=0,001).

Multivariate analyses did not show any effect of the adjustment variables.

Evaluation of safety outcomes on the mother and the fetus is in progress.

* Investigators: AR, JCO, CD, PB (Bordeaux), SD, BA, AR, AM, CB, JP (Marseille), MD, S Pitton (Nancy), JD (Strasbourg), TM (Dijon), JC, D Biotti (Toulouse), OC, M Vaillant (Grenoble),E Berger (Besançon), D Laplaud (Nantes), G Defer (Caen), I Patry (Corbeil-Essonnes), P Vermersch (Lille), P Labauge (Montpellier), O Bourre (Rouen), B Stankoff (Paris-Saint-Antoine), A Créange (Créteil), P Cabre (Fort-de-France), E Thouvenot (Nîmes), T De Broucker (Saint-Denis), C Papeix (Paris-Salpêtrière), P Clavelou (Clermont-Ferrand), O Gout (Paris-F.Rothschild), A Montcuquet (Limoges), C Lebrun (Nice), O Heinzlef (Poissy) N Maubeuge (Poitiers).

Conclusions

Continuation of Natalizumab during all three trimesters of pregnancy is associated with a lower risk of relapses as compared with discontinuation before the pregnancy or even during the second trimester.

Safety data is being collected.

Background

Multiple sclerosis (MS) is associated with brain dysconnectivity that leads to changes in network organisation. However, given the inconsistent results obtained by studies of structural and functional connectivity, the relationship between the structural and functional deficits in MS is unclear.

Objectives

This study explored structure-function relationships during the early stages of MS and their role in cognitive performance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years. Healthy controls matched for age, sex and level of education were followed-up in parallel.

The evolution of structural and functional brain networks was investigated, and structural-functional coupling was assessed. Clinical and cognitive status was determined at each follow-up visit. The association between brain network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

The study included 32 patients (25 females) and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Both structural and functional reorganisation was observed during the disease course. Structural clustering coefficient was significantly increased after 5 years whereas characteristic path length decreased, indicating strengthened short-distance connections and the loss of long-range connections. By contrast, functional connections and related path lengths were decreased after 5 years, suggesting stronger local short-distance connections. Structural-functional coupling had increased significantly after 5 years, indicating greater constraint of functional connectivity by direct anatomical connections. This structural-functional coupling was the only parameter associated with cognitive and clinical status, with stronger coupling associated with a decline in both domains.

Conclusions

Our findings provide novel biological evidence that MS leads to less dynamic brain function in relation to the underlying anatomy of the brain. The collapse of this network leads to both cognitive impairment and clinical disability.

Background

Multiple sclerosis (MS) is frequently associated with memory impairment. Nevertheless, the pathophysiology of memory impairment in MS is still unclear. Most studies now agree on hippocampal involvement. However, whether functional reorganization could help compensate and mitigate memory deficit is a matter of debate.

Objectives

This study aimed to identify the patterns of functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances at the early stage of MS. We hypothesized that functional reorganization could compensate for structural damage, allowing a delay in memory impairment appearance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS in a prospective longitudinal study, along with matched healthy controls, and followed over 5 years. Verbal and visual memory scores were assessed. We used a multimodal approach, combining in vivo structural measures – i.e. hippocampal volume and connectivity – and functional measures – i.e. rs-fMRI connectivity. The association between network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

This study included 32 patients and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Verbal memory scores decreased significantly over time, whereas visuospatial memory performances were maintained.

Hippocampal volume of patients decreased significantly over time, indicating an increase in tissue alteration with the evolution of the pathology. Structural shortest path length of the hippocampus significantly decreased after 5 years along with an increase in hippocampus’ connections, indicating strengthened short-distance connections.

As for the functional network, the hippocampus showed a significant increase in the number of connections after 5 years, with a decrease of its shortest path length, suggesting stronger local short-distance connections.

Hippocampal volume loss was associated with worse verbal memory, while the hippocampus functional shortest path length significantly explained visual memory performances.

Conclusions

Our study demonstrated an important interplay between hippocampal-related structural and functional networks in explaining cognitive performances in the early stages of MS. As the structural damage increases, functional reorganization is able to maintain visual memory performances with strengthened short-distance connections.