Background

Ependyma forms the epithelial interface boarding the ventricular walls and the spinal cord’s central canal, maintaining crucial central nervous system functions such as the regulation of cerebrospinal fluid (CSF) circulation by synchronous ciliary beating and the monitoring of molecular exchanges between CSF and parenchyma. These functions are dependent of the cellular coupling via gap junction channels.

Neuromyelitis Optica (NMO) is associated with autoantibodies (NMO-IgG), directed against aquaporin 4 (AQP4). NMO-IgG are present in patient’s serum and CSF during attacks, and are known to trigger astrocyte dysfunction leading to demyelination and axonal loss. Interestingly, ependymal cells also express AQP4 and evidences of ependymal alteration have been reported in NMO. Indeed, MRI abnormalities of the ventricles have been reported, and pathological analyses showed AQP4 loss in the ventricular walls of NMO patients.

Objectives

Our aim is to evaluate if NMO-IgG target ependymal cells, and lead to ependymal morphological changes and dysfunctions.

Methods

We used purified NMO-IgG from AQP4 antibodies positive patients’ plasma (NMO-IgG AQP4⁺). IgG from healthy donors (CTRL-IgG) and IgG from AQP4-antibodies negative patients (NMO-IgG AQP4^-) were used as controls. We evaluated ependymal cells on two models: primary ependymal cell cultures and cultured wholemount dissections (“en-face” view of the entire ependyma) of adult rat lateral ventricular walls. We first looked at the effect of different IgGs on the expression of AQP4 and Connexin43, the main gap junction channel expressed by ependymal cells. Then, we assessed the ciliary beating of ependymal cells by analyzing the diffusion of india ink deposited on wholemount preparations. Coupling of ependymal cells in culture was evaluated by measuring the diffusion of Lucifer Yellow (LY), a gap junction specific dye incorporated in cells by scrape loading.

Results

We showed that NMO-IgG AQP4⁺ exposure induced: 1) the delocalization of AQP4 membrane expression and morphological changes of ependymal cells from primary cultures and wholemounts, by contrast different IgG controls had no effect; 2) morphological changes of cilia in primary cultures and alteration of the ciliary dynamic; 3) the alteration of Connexin43 expression and function, demonstrated by the decrease of LY spreading after scrape loading.

Conclusions

These results suggest that NMO-IgG directly induce dysfunctions of ependymal cells, through the perturbation of AQP4 and Cx43 expression and functions.

Background

Glial fibrillar acidic protein (GFAP) autoimmunity is a recently identified disease, at the frontier of auto-immune encephalitis and gliopathies. Clinical features associated to this new entity are still not fully evaluated; especially the risk of relapse and the disability outcome.

Objectives

To report the clinical, biological, imaging features, and the clinical course of a French cohort of patients with GFAP autoantibodies.

Methods

We retrospectively included all patients tested positive for GFAP antibodies since 2017, from two French referral centers (auto-immune encephalitis and rare inflammatory disorders of the brain and the spinal cord). GFAP autoantibodies were detected exclusively in the CSF, by immunohistochemistry and their specificity confirmed by cell-based assay using cells expressing human GFAPα.

Results

We identified 46 patients with GFAP antibodies. Median age at onset was 43 years and men were more affected (30/46). Infectious prodromal symptoms were found in 82% of cases. Other autoimmune diseases were found in 22% of cases and coexisting neural autoantibodies in 11% of cases, including MOG-IgG and AQP4-IgG positive cases. Tumors were present in 24%, and T cell dysfunction in 23% of cases, respectively. The most frequent presentation was acute/subacute menigoencephalitis (85%) with cerebellar dysfunction in 57% of cases. Other/associated clinical presentation included: myelitis (30%), visual tract involvement (35%) and peripheral nervous system involvement (28%). CSF showed pleocytosis (98%), oligoclonal bands (77%) and low glucose level (15%). MRI findings were heterogeneous: radial enhancement was found in 26%, periventricular diffuse T2 hyperintensity in 39%, brainstem involvement in 33%, leptomeningeal enhancement in 23%, and reversible splenial lesions in 4 cases.

39/46 patients have a monophasic course, associated to a good outcome at last follow-up (Rankin Score≤2: 89% at 15,5 months), despite a frequently severe clinical presentation (intensive care unit hospitalization: 42%). Seventy patients were treated with immunotherapy. 11/22 patients showed negativation of GFAP antibodies (median time: 2 months).

Conclusions

GFAP autoimmunity was generally associated to a good outcome and a low risk of relapse. Identification of factors associated to risk of relapse or disability, to monitor immunotherapy, is needed.

Background

Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.

Objectives

The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.

Methods

Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.

Results

We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.

Conclusions

AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.

Background

To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.

Objectives

We aimed to 1) compare clinical features and disease course, and 2) to evaluate the association of MOG-Ab dynamics and relapses, between children and adults with MOGAD.

Methods

Retrospective study evaluating clinical features of 98 children and 266 adults with MOGAD, between January 2014 and September 2019. To analyse relapses over the whole disease course, a Cox regression analysis for recurrent time-to-event data was performed, introducing treatment as time-dependent covariate. To evaluate dynamics, delta mean fluorescence intensity ratio signal (ΔMFIratio) of MOG-Ab was measured in patients with a minimum time elapsed between two samples of 4 months.

Results

Median age at onset of symptoms was 10.9 (interquartile range 5.4-14.3) years in children and 36.2 (27.7-47.6) in adults. Isolated optic neuritis was the most frequent clinical presentation both in children (40.8%) and adults (55.9%), p=0.013, and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs. 5.6%; p<0.001). Compared to adults, children displayed a better recovery (EDSS ≥3.0 at last follow-up reached only by 10 of 97 [10.3%] vs. 66/247 [26.7%], p<0.001).

In the multivariate analysis, adults were at higher risk of relapse than children (Hazard ratio 1.41, 95%Confidence interval [CI] 1.12-1.78; p=0.003). Among the 124 participants evaluated for MOG-Ab dynamics, 36.3% became seronegative, 60.5% decrease and 3.2% increase the ΔMFIratio. At two years, 64.2% (95%CI 40.9-86.5) of non-relapsing children became MOG-Ab negative compared to 14.1% (95%CI 4.7-38.3) of relapsing ones, log-rank p<0.001, with no differences observed between non-relapsing and relapsing adults, log-rank p=0.280.

Conclusions

MOGAD differs in its clinical presentation at onset, showing a progressive shift in the clinical features across age-groups. Compared to children, adults have a higher risk of relapses and a worse functional recovery. Finally, children with monophasic disease became MOG-Ab negative earlier than relapsing ones, but not in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults.