Pr Romain Marignier
Neurology department – multiple sclerosis, myelin pathologies and neuro-inflammation
The department is specialized in the management of multiple sclerosis (MS) and inflammatory and demyelinating pathologies of the central nervous system (Devic’s neuro-opticomyelitis, leukodystrophies), including in children.
Publications
1. Association of Maintenance Intravenous Immunoglobulin With Prevention of Relapse in Adult Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease
Chen JJ, Huda S, Hacohen Y, Levy M, Lotan I, Wilf-Yarkoni A, Stiebel-Kalish H, Hellmann MA, Sotirchos ES, Henderson AD, Pittock SJ, Bhatti MT, Eggenberger ER, Di Nome M, Kim HJ, Kim SH, Saiz A, Paul F, Dale RC, Ramanathan S, Palace J, Camera V, Leite MI, Lam BL, Bennett JL, Mariotto S, Hodge D, Audoin B, Maillart E, Deschamps R, Pique J, Flanagan EP, Marignier R.
JAMA Neurol (2022) — Abstract
Importance: Recent studies suggest that maintenance intravenous immunoglobulin (IVIG) may be an effective treatment to prevent relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD); however, most of these studies had pediatric cohorts, and few studies have evaluated IVIG in adult patients. Objective: To determine the association of maintenance IVIG with the prevention of disease relapse in a large adult cohort of patients with MOGAD. Design, setting, and participants: This was a retrospective cohort study conducted from January 1, 2010, to October 31, 2021. Patients were recruited from 14 hospitals in 9 countries and were included in the analysis if they (1) had a history of 1 or more central nervous system demyelinating attacks consistent with MOGAD, (2) had MOG-IgG seropositivity tested by cell-based assay, and (3) were age 18 years or older when starting IVIG treatment. These patients were retrospectively evaluated for a history of maintenance IVIG treatment. Exposures: Maintenance IVIG. Main outcomes and measures: Relapse rates while receiving maintenance IVIG compared with before initiation of therapy. Results: Of the 876 adult patients initially identified with MOGAD, 59 (median [range] age, 36 [18-69] years; 33 women [56%]) were treated with maintenance IVIG. IVIG was initiated as first-line immunotherapy in 15 patients (25%) and as second-line therapy in 37 patients (63%) owing to failure of prior immunotherapy and in 7 patients (12%) owing to intolerance to prior immunotherapy. The median (range) annualized relapse rate before IVIG treatment was 1.4 (0-6.1), compared with a median (range) annualized relapse rate while receiving IVIG of 0 (0-3) (t108 = 7.14; P < .001). Twenty patients (34%) had at least 1 relapse while receiving IVIG with a median (range) time to first relapse of 1 (0.03-4.8) years, and 17 patients (29%) were treated with concomitant maintenance immunotherapy. Only 5 of 29 patients (17%) who received 1 g/kg of IVIG every 4 weeks or more experienced disease relapse compared with 15 of 30 patients (50%) treated with lower or less frequent dosing (hazard ratio, 3.31; 95% CI, 1.19-9.09; P = .02). At final follow-up, 52 patients (88%) were still receiving maintenance IVIG with a median (range) duration of 1.7 (0.5-9.9) years of therapy. Seven of 59 patients (12%) discontinued IVIG therapy: 4 (57%) for inefficacy, 2 (29%) for adverse effects, and 1 (14%) for a trial not receiving therapy after a period of disease inactivity. Conclusions and relevance: Results of this retrospective, multicenter, cohort study of adult patients with MOGAD suggest that maintenance IVIG was associated with a reduction in disease relapse. Less frequent and lower dosing of IVIG may be associated with treatment failure. Future prospective randomized clinical trials are warranted to confirm these findings.
2. Astrocytic outer retinal layer thinning is not a feature in AQP4-IgG seropositive neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry
Lu A, Zimmermann HG, Specovius S, Motamedi S, Chien C, Bereuter C, Lana-Peixoto MA, Fontenelle MA, Ashtari F, Kafieh R, Dehghani A, Pourazizi M, Pandit L, D’Cunha A, Kim HJ, Hyun JW, Jung SK, Leocani L, Pisa M, Radaelli M, Siritho S, May EF, Tongco C, De Sèze J, Senger T, Palace J, Roca-Fernández A, Leite MI, Sharma SM, Stiebel-Kalish H, Asgari N, Soelberg KK, Martinez-Lapiscina EH, Havla J, Mao-Draayer Y, Rimler Z, Reid A, Marignier R, Cobo-Calvo A, Altintas A, Tanriverdi U, Yildirim R, Aktas O, Ringelstein M, Albrecht P, Tavares IM, Bichuetti DB, Jacob A, Huda S, Soto de Castillo I, Petzold A, Green AJ, Yeaman MR, Smith TJ, Cook L, Paul F, Brandt AU, Oertel FC; GJCF International Clinical Consortium for NMOSD
J Neurol Neurosurg Psychiatry (2022) — Abstract
Background: Patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort. Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site. Results: No significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere. Conclusion: The results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates
3. Myelin-oligodendrocyte glycoprotein antibody-associated disease
Marignier R, Hacohen Y, Cobo-Calvo A, Pröbstel AK, Aktas O, Alexopoulos H, Amato MP, Asgari N, Banwell B, Bennett J, Brilot F, Capobianco M, Chitnis T, Ciccarelli O, Deiva K, De Sèze J, Fujihara K, Jacob A, Kim HJ, Kleiter I, Lassmann H, Leite MI, Linington C, Meinl E, Palace J, Paul F, Petzold A, Pittock S, Reindl M, Sato DK, Selmaj K, Siva A, Stankoff B, Tintore M, Traboulsee A, Waters P, Waubant E, Weinshenker B, Derfuss T, Vukusic S, Hemmer B
Lancet Neurol (2021) — Abstract
Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.
4. TNF-α inhibitors used as steroid-sparing maintenance monotherapy in parenchymal CNS sarcoidosis
Hilezian F, Maarouf A, Boutiere C, Rico A, Demortiere S, Kerschen P, Sene T, Bensa-Koscher C, Giannesini C, Capron J, Mekinian A, Camdessanché JP, Androdias G, Marignier R, Collongues N, Casez O, Coclitu C, Vaillant M, Mathey G, Ciron J, Pelletier J, Audoin B; Under the aegis of the French Multiple Sclerosis Society
J Neurol Neurosurg Psychiatry (2021) — Abstract
Objective: To assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis. Methods: The French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change. Results: Of the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17-40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14-49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%. Conclusion: TNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory. Classification of evidence: This study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.
5. Serum Glial Fibrillary Acidic Protein: A Neuromyelitis Optica Spectrum Disorder Biomarker
Aktas O, Smith MA, Rees WA, Bennett JL, She D, Katz E, Cree BAC; N-MOmentum scientific group and the N-MOmentum study investigators
Ann neurol (2021) — Abstract
Objective: Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment. Methods: N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis). Results: At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.
6. Antibodies to MOG in CSF only: pathological findings support the diagnostic value
Carta S, Höftberger R, Bolzan A, Bozzetti S, Bonetti B, Scarpelli M, Ottaviani S, Ghimenton C, Alberti D, Schanda K, Reindl M, Marignier R, Ferrari S, Mariotto S
Acta Neuropathol (2021) — Abstract
No abstract available
7. Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO)
Specovius S, Zimmermann HG, Oertel FC, Chien C, Bereuter C, Cook LJ, Lana Peixoto MA, Fontenelle MA, Kim HJ, Hyun JW, Jung SK, Palace J, Roca-Fernandez A, Diaz AR, Leite MI, Sharma SM, Ashtari F, Kafieh R, Dehghani A, Pourazizi M, Pandit L, Dcunha A, Aktas O, Ringelstein M, Albrecht P, May E, Tongco C, Leocani L, Pisa M, Radaelli M, Martinez-Lapiscina EH, Stiebel-Kalish H, Hellmann M, Lotan I, Siritho S, de Seze J, Senger T, Havla J, Marignier R, Tilikete C, Cobo Calvo A, Bichuetti DB, Tavares IM, Asgari N, Soelberg K, Altintas A, Yildirim R, Tanriverdi U, Jacob A, Huda S, Rimler Z, Reid A, Mao-Draayer Y, de Castillo IS, Yeaman MR, Smith TJ, Brandt AU, Paul F; GJCF International Clinical Consortium for NMOSD.
BMJ Open (2020) — Abstract
Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD. Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices. Findings to date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline. Future plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
