Publications by authors named "Caroline Papeix"

77 Publications

Untreated patients with multiple sclerosis: a study of French expert centers.

Eur J Neurol 2021 Mar 1. Epub 2021 Mar 1.

Université Clermont Auvergne, CHU de Clermont-Ferrand, Inserm, Neuro-Dol, F-63000, Clermont-Ferrand, France.

Background: Disease modifying therapies (DMTs), have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (pwMS) remain untreated. The objective of the present study was to determine the proportion of untreated patients with multiple sclerosis (pwMS) followed in expert centers in France and determine the predictive factors of non-treatment.

Methods: Retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on 12/15/2018 and pwMS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. Results Among the 21,189 pwMS (age 47.1±13.1; EDSS 3.4±2.4), 6,631 (31.3%; 95%CI=30.7-31.9) of the patients were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95%CI = 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among relapsing-remitting pwMS, the main factors explaining never having been treated were not having ≥9 lesions on brain MRI (OR = 0.52 [0.44-0.61]) and lower EDSS (OR = 0.78 [0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, 11.6% for secondary and 34.0% for primary progressive MS had never received any DMT.

Conclusion: A significant proportion of pwMS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of pwMS.
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http://dx.doi.org/10.1111/ene.14790DOI Listing
March 2021

Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination.

Mult Scler 2021 Feb 25:1352458521991433. Epub 2021 Feb 25.

Centre de Ressources et de Compétences Sclérose en plaques. AP-HP, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.

Few cases of human papillomavirus (HPV) diseases have been reported in multiple sclerosis (MS) patients treated with fingolimod. We describe a case series of 16 MS patients (11 women, 5 men) developing HPV lesions after the onset of fingolimod, without previous HPV history. Fingolimod had to be discontinued in six patients. Six patients received vaccination for HPV, with good tolerance. Our report highlights that systematic HPV screening and discussion about HPV vaccination before fingolimod onset are crucial. In case of occurrence of HPV lesions during fingolimod treatment, a comprehensive workup of HPV disease is necessary, with discussion of HPV vaccination to prevent secondary lesions. Prevalence studies of HPV lesions are needed in MS patients with the different disease-modifying therapies.
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http://dx.doi.org/10.1177/1352458521991433DOI Listing
February 2021

Pregnancy in Patients With AQP4-Ab, MOG-Ab or Double-Negative Neuromyelitis Optica Disorder.

Neurology 2021 Feb 24. Epub 2021 Feb 24.

Department of Neurology, CHU de Strasbourg, Strasbourg, France.

Objective: To analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST).

Methods: We performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum (PP). The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy and PP. Events such as miscarriage, abortion and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy.

Results: We included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab and 13 without either Ab) in 58 NMOSD patients. Compared to the pre-pregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the PP period in patients with AQP4-Ab (<0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months PP than untreated patients (26% vs 53%, = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in two (2%) patients who were AQP4-Ab positive.

Conclusion: We found a rebound in the ARR during the first PP trimester that was higher than the pre-pregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.
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http://dx.doi.org/10.1212/WNL.0000000000011744DOI Listing
February 2021

Unexpected REM sleep excess associated with a pontine lesion in multiple sclerosis.

J Clin Sleep Med 2021 Feb 4. Epub 2021 Feb 4.

AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France.

None: Sleep disorders are prevalent in patients with multiple sclerosis. In contrast, a frank increase of REM sleep time is a rare phenomenon, mostly described in the context of REM sleep rebound (after sleep deprivation, abrupt withdrawal of antidepressants or neuroleptics, and during the first night of ventilation for severe sleep apnea), but not in link with specific brain lesions. We incidentally found an isolated, marked increase in REM sleep time (200 min, 40% of total sleep time, normative values: 18.2-20.3%) and in rapid eye movements density during REM sleep in a patient with a secondary progressive multiple sclerosis, associated with an anterior pontine demyelinating lesion on MRI. This result suggests that a network blocking REM sleep in the pons has been damaged.
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http://dx.doi.org/10.5664/jcsm.9114DOI Listing
February 2021

The long-term outcome of MOGAD: An observational national cohort study of 61 patients.

Eur J Neurol 2021 Feb 2. Epub 2021 Feb 2.

Department of Neurology, Centre de référence des maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

Background And Objective: The prognosis in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a matter of debate. Our aim was to assess the long-term outcomes of patients with MOGAD.

Methods: We retrospectively analysed the clinical and paraclinical data of patients from the French nationwide observatory study NOMADMUS who tested positive for MOG antibodies (MOG-IgG) and who had clinical follow-up of at least 8 years from their first episode.

Results: Sixty-one patients (median [range] age at onset 27 [3-69] years), with a median (mean; range) follow-up of 177 (212.8; 98-657) months, were included. Among 58 patients with a relapsing course, 26.3% relapsed in the first year after onset. Of the 61 patients, 90.2% experienced at least one episode of optic neuritis. At last visit, the median (mean; range) Expanded Disability Status Scale (EDSS) score was 1 (2.12; 0-7.5), 12.5% had an EDSS score ≥6 and 37.5% had an EDSS score ≥3. Of 51 patients with final visual acuity (VA) data available, 15.7% had VA ≤0.1 in at least one eye and 25.5% had VA ≤0.5 in at least one eye. Bilateral blindness (VA ≤0.1) was present in 5.9% of patients. Finally, 12.5% of patients presented bladder dysfunction requiring long-term urinary catheterization. No factor associated significantly with a final EDSS score ≥3 or with final VA ≤0.1 was found.

Conclusion: Overall long-term favourable outcomes were achieved in a majority of our patients, but severe impairment, in particular visual damage, was not uncommon.
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http://dx.doi.org/10.1111/ene.14746DOI Listing
February 2021

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

Eur Radiol 2020 Nov 6. Epub 2020 Nov 6.

Hôpitaux Universitaires de Strasbourg, Service d'imagerie 2, Hôpital de Hautepierre, Strasbourg, France.

Objectives: To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection.

Materials And Methods: In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement.

Results: The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response.

Conclusion: Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML.

Key Points: • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution "the milky way," and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.
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http://dx.doi.org/10.1007/s00330-020-07362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644389PMC
November 2020

Outcomes of coronavirus disease 2019 in patients with neuromyelitis optica and associated disorders.

Eur J Neurol 2020 Oct 26. Epub 2020 Oct 26.

Service de Neurologie and CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.

Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).

Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).

Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.
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http://dx.doi.org/10.1111/ene.14612DOI Listing
October 2020

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Ann Neurol 2021 01 15;89(1):30-41. Epub 2020 Oct 15.

Department of Neurology, Multiple Sclerosis and Neuroinflammation, Pierre Wertheimer Neurological Hospital, Lyon Civil Hospices, Lyon, France.

Objective: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD).

Methods: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives.

Results: Isolated optic neuritis was the most frequent clinical presentation in both 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 better recovery (Expanded Disability Status Scale ≥ 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). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280).

Interpretation: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.
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http://dx.doi.org/10.1002/ana.25909DOI Listing
January 2021

COVID-19 infection in NMO/SD patients: a French survey.

J Neurol 2020 Sep 12. Epub 2020 Sep 12.

Department of Neurology, Pitié Salpêtrière Hospital, APHP, Sorbonne University, 75013, Paris, France.

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http://dx.doi.org/10.1007/s00415-020-10112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486806PMC
September 2020

Beyond COVID-19: DO MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies?

Mult Scler Relat Disord 2020 Nov 3;46:102482. Epub 2020 Sep 3.

AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France; CRC SEP Paris, France; Sorbonne University, Paris Brain Institute, APHP, Inserm, CNRS, CIC neuroscience, Pitié-Salpêtrière Hospital, Paris, France.

Since 2019, a new coronavirus infection (COVID-19) due to an agent called SARS-CoV-2 spread rapidly worldwide. Patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMO-SD) are often treated with immunosuppressants. Beyond their effect on the risk of COVID-19 infection, the consequences on the long-term immune response against the coronavirus remain unknown. Among 13 MS or NMOSD patients with confirmed COVID-19 included, all 5 patients treated with anti-CD20 therapies had a negative SARS-CoV-2 serology. To date, maximal precautions to prevent coronavirus infection should be maintained in MS/NMOSD patients already exposed to COVID-19 during anti-CD20 therapy.
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http://dx.doi.org/10.1016/j.msard.2020.102482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468278PMC
November 2020

Reasons for switching to fingolimod in patients relapsing-remitting multiple sclerosis in France: the ESGILE study.

Mult Scler Relat Disord 2020 Nov 30;46:102433. Epub 2020 Jul 30.

Jennyfer Aboab, Paris; Abdullatif Al Khedr, Amiens; Amer Al Najjar Carpentier, Orsay; Géraldine Androdias, Bron; Rabah Benrabah, Paris; Damien Biotti, Toulouse; Valentin Bohotin, Le Coudray; Mickael Bonnan, Pau; Cecilia Bonnet, Versailles; Jean marc Boulesteix, Cahors; David Brassat, Toulouse; Philippe Busson, Avranches; William Camu, Montpellier; Giovanni Castelnovo, Nîmes; Stéphane Chapuis, Montluçon; Pierre Clavelou, Clermont Ferrand; Philippe Convers, St Priest en Jarez; Marc Coustans, Quimper; Alain Creange, Créteil; Sébastien Delassaux, Epinal; Éric Diot, Vienne; Madjid Djerdi, Bordeaux; Thomas Drouet, St Malo; Sophie Dufour Delalande, Tourcoing; Corinne Dupel Pottier, Pontoise; Didier Ferriby, Tourcoing; Philippe Gaida, La Teste de Buch; Guillaume Gal, Roanne; Pierric Giraud, Metz Tessy; Laurent Guilloton, Mornant; Tijani Hascar, Vienne; Olivier Heinzlef, Poissy; Violaine Jaffrenou Rouaud, Vannes; Alain Jager, Thionville; Christophe Kubler, Altkirch; Patrick Le Coz, Arras; Christine Lebrun Frenay, Nice; Elisabeth Maillart, Paris Marcel Maillet Vioud, Montluçon; Imad Malkoun, Belfort; Éric Manchon, Gonesse; Mikel Martinez, Dax; Dalia Meshaka Dimitri Boulos, Créteil; Alexis Montcuquet, Limoges; Thibault Moreau, Dijon; Antoine Moulignier, Paris; Jean-Philippe Neau, Poitiers; Philippe Neuschwander, Lyon; Ghislain Nokam Talom, Deauville; Jean-Christophe Ouallet, Bordeaux; Ivania Patry, Corbeil Essonne; Stéphane Peysson, Gleize; Fatai Radji, Agen; Viorica Razlog, Montélimar; Christophe Robin, Roanne; Jérôyme Romero, Cagnes-sur-Mer; Nathalie Rosey Dufosse, Boulogne sur Mer; Feras Abdul Samad, Châtellerault; Nicolas Schmidt, Rueil Malmaison; Nicolas Seiller, Sarreguemines; Thierry Soisson, Orléans; Éric Thouvenot, Nîmes; Ayman Tourbah, Reims; Mathieu Vaillant, La Tronche; Anne-Evelyne Vallet Racinoux, Vienne; Nadia Vandenberghe, Lyon; Frédérique Viala, Toulouse; Valery Wattier, St Julien en Genevois; Christophe Zaenker, Colmar; Fabien Zagnoli, Brest; Hatem Zekri, St Brieuc.

Background: Timely treatment switching is an important strategy in optimising management of patients with relapsing remitting multiple sclerosis (RRMS). Patient preferences, as well as clinical benefit, may contribute to the switch decision. Information on reasons determining switching choices and on outcome according to the reason for switching is scarce. Study objectives were to describe the consequences of switching to fingolimod in terms of clinical improvement according to the reasons underlying the switch and to evaluate treatment acceptability from the patient's perspective.

Methods: This prospective observational study was conducted by 71 neurologists in France and included patients with RRMS switching to fingolimod following ≥6 months treatment with a first-line disease modifying treatment (DMT). Reasons for switching were documented. Patients were evaluated at inclusion and 12 months after initiating fingolimod. Physicians documented clinical status by relapse activity, disability (EDSS) at each visit and improvement with the Clinical Global Impression - Change (CGI-C) at Month 12. Patients rated improvement at Month 12 with the Patient Global Impression - Change (PGI-C) and treatment acceptability with the ACCEPT® questionnaire. Adverse events reported during fingolimod treatment were documented.

Results: Overall 232 patients were recruited of whom 190 could be analysed. Multiple reasons for switching were frequently given; 113 patients (59.4%) switched from a first-line injectable DMT. Switching was motivated by disease worsening in 161 patients (84.7%), tolerability in 35 (18.4%) and patient preference in 58 (30.5%). During the follow-up period, 38 patients (20.0%) experienced at least one exacerbation. The mean EDSS score was stable (2.0 ± 1.3 at inclusion; 2.0 ± 1.5 at M12). With the CGI-C, 67 patients (38.7%) were considered improved and 23 (13.3%) worsened. Although no obvious differences in CGI-C ratings were observed as a function of the reason for switching, when patient preferences entered into the decision, the proportion of patients considered minimally improved was somewhat higher (37.7%) and the proportion considered unchanged somewhat lower (41.5%). With the PGI-C, more patients rated themselves improved than were rated as improved by the physician: of 64 patients rated as 'no change' on the CGI-C, 21 (32.8%) rated themselves as 'improved' and 10 (15.6%) as 'worsened'. The overall level of agreement between the two measures was moderate (κ = 0.48 [95% CI: 0.35 - 0.60]). The mean general treatment acceptability score on the ACCEPT® questionnaire was 42.7 [95%CI: 34.5 - 50.9] at inclusion (reflecting acceptability of the previous DMT) and 64.6 [95%CI: 57.6 - 71.6] at M12 (reflecting acceptability of fingolimod). Mean dimension scores ranged from 36.7 for effectiveness to 72.2 for medication inconvenience at inclusion and from 63.4 for effectiveness to 96.8 for medication inconvenience at M12. The frequency and nature of reported adverse events was consistent with the well-characterised safety profile of fingolimod.

Conclusion: Most patients switching from a first DMT to fingolimod do so due to persistent disease activity during the initial treatment, although patient preferences are also important. Switching is followed by a reduction in disease activity, perceived improvement in the clinical state of the patient and improved acceptability of treatment.
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http://dx.doi.org/10.1016/j.msard.2020.102433DOI Listing
November 2020

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

JAMA Neurol 2020 09;77(9):1079-1088

Service de Neurologie, Clinical Investigation Center Institut National de la Santé et de la Recherche Médicale 1434, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France.

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.

Design, Setting, And Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.

Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.

Main Outcomes And Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.

Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).

Conclusions And Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
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http://dx.doi.org/10.1001/jamaneurol.2020.2581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320356PMC
September 2020

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

J Neuroinflammation 2020 Apr 23;17(1):128. Epub 2020 Apr 23.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Lyon/Bron, France.

Background: Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy.

Methods: Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS.

Results: Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%).

Conclusions: A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.
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http://dx.doi.org/10.1186/s12974-020-01773-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178729PMC
April 2020

Multiple cervical dissections after Rituximab.

Mult Scler Relat Disord 2020 Jul 17;42:102105. Epub 2020 Apr 17.

Neurology Department, Pitié-Salpêtrière hospital, Paris, France.

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http://dx.doi.org/10.1016/j.msard.2020.102105DOI Listing
July 2020

Evaluation of efficacy and tolerability of first-line therapies in NMOSD.

Neurology 2020 04 13;94(15):e1645-e1656. Epub 2020 Mar 13.

From the Department of Neurology (J.P., J.G., O.O., H.Z.) and U995-LIRIC-Lille Inflammation Research International Center, Inserm, Univ Lille (J.G., H.Z.), CHU Lille; Department of Neurology (R.D.), Fondation Ophtalmologique Adolphe de Rothschild, Paris; CNRS, CRMBM UMR 7339 (B.A.), Aix-Marseille Université; Service de Neurologie (B.A.), Pôle de Neurosciences Cliniques, APHM, Hôpital de la Timone, Marseille; Department of Neurology (J.C.), Hôpital Purpan, CHU de Toulouse; Department of Neurology (E.M., C.P.), Hôpital de la Pitié Salpêtrière, AP-HP, Paris; Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (N.C.), INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg; Département de Neurologie (N.C.) and Centre d'Investigation Clinique, INSERM U1434 (N.C.), Centre Hospitalier Universitaire de Strasbourg; Department of Neurology (B.B.), Hôpital Charles Nicolle, CHU Rouen; Centre de Ressources et Compétences Sclérose en Plaques, Neurologie (M.S.), Université Nice Côte d'Azur, CHU Pasteur 2, Nice; Department of Neurology (S.W., D.L.), CHU Nantes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V., R.M.), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (R.M.), Lyon; and INSERM U1028 (R.M.), CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon1 University, France.

Objective: To compare the efficacy and the risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD).

Methods: We retrospectively included patients with NMOSD and a seropositive status for aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies beginning first-line immunosuppressants within 3 years after the disease onset. The main outcome was occurrence of relapse after the initiation of immunosuppressants; the secondary outcome was the annual relapse rate (AAR).

Results: A total of 136 patients were included: 62 (45.6%) were treated with rituximab (RTX), 42 (30.9%) with mycophenolate mofetil (MMF), and 23 (16.9%) with azathioprine (AZA). Compared with RTX-treated patients, the risk of relapse was higher among MMF-treated patients (hazard ratio [HR], 2.74 [1.17-6.40]; = 0.020) after adjusting for age at disease onset, sex, antibody status, disease duration, ARR before treatment, corticosteroid intake, and relapse location. We did not observe any difference between RTX-treated and AZA-treated patients (HR, 2.13 [0.72-6.28]; = 0.17). No interaction was found between the antibody status and immunosuppressive treatments. ARR was lower with RTX than with MMF ( = 0.039), but no difference was observed with AZA. We observed 9 serious infectious events with MMF, 6 with RTX, and none with AZA.

Conclusions: The use of first-line RTX in NMOSD appears more effective than MMF in suppressing clinical activity, independent of the antibody status.

Classification Of Evidence: That study provides Class III evidence that for patients with NMOSD, first-line RTX is superior to MMF to reduce the risk of relapse.
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http://dx.doi.org/10.1212/WNL.0000000000009245DOI Listing
April 2020

Dramatic efficacy of ofatumumab in refractory pediatric-onset AQP4-IgG neuromyelitis optica spectrum disorder.

Neurol Neuroimmunol Neuroinflamm 2020 05 25;7(3). Epub 2020 Feb 25.

From the AP-HP (E.M., C.P.), Pitié-Salpêtrière Hospital, Department of Neurology and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle; Robert Debré Hospital (J.B.F.R., O.B.-T., D.G.), AP-HP Department of Child Neurology; Université de Paris (F.R., O.B.-T., D.G.); Department of Pediatric Neurology (K.D.), National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicetre; Robert Debré Hospital (T.K.), AP-HP Departments of Child Nephrology, Paris; and Service de neurologie (R.M.), sclérose en plaques, pathologies de la myéline et neuro-inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron, France.

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http://dx.doi.org/10.1212/NXI.0000000000000683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051209PMC
May 2020

Secondary hypersomnia as an initial manifestation of neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Feb 25;38:101869. Epub 2019 Nov 25.

Département de neurologie, Hôpital de la pitié salpêtrière, APHP, Sorbonne Université, Paris 75013, France.

The identification of AQP4-IgG, a specific and pathogenic antibody of NMO/SD has led to a broadening of the clinical spectrum of manifestations of NMO/SD including the presence of encephalic symptoms. Lesions are often distributed on peri‑ependymal area and sometimes affected the diencephalon leading to sleep disorders. We report a case of hypersomnia with polysomnographic documentation during the first attack of NMO/SD. Brain MRI revealed bilateral hypothalamic lesions around the third ventricle, whereas optic nerves and spinal cord were intact. The record of the nocturnal video-polysomnography followed by multiple sleep latency tests (MSLT) revealed an abnormal shortened sleep period with a single sleep onset in REM allowing secondary central hypersomnia diagnosis. The recovery of hypersomnia was complete within few months without psychostimulant treatment and the diencephalic lesion disappeared. Thus, diencephalic form of NMO/SD seems to cause narcolepsy or non-narcoleptic central hypersomnia and have a good recovery.
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http://dx.doi.org/10.1016/j.msard.2019.101869DOI Listing
February 2020

Expert opinion: Criteria for second-line treatment failure in patients with multiple sclerosis.

Mult Scler Relat Disord 2019 Nov 19;36:101406. Epub 2019 Sep 19.

CHU de Montpellier, 191 Av. du Doyen Gaston Giraud, Montpellier, France.

Objectives: In the management of multiple sclerosis (MS), defining criteria for identification of suboptimal therapy responses and switching treatment is essential to avoid worsening. Despite the lack of a standardised definition, criteria for first-line treatment are well documented in the literature, based on clinical measures or magnetic resonance imaging (MRI) (gadolinium enhancing [Gd] lesions or new/enlarging T2 lesions) assessed during the first 6-18 months after treatment initiation. However, it is unknown whether the same criteria can be used for second-line treatment failure.

Methods: Five regional boards involving 36 French MS experts were convened to discuss published literature regarding criteria for first- and second-line treatment failure, and to identify differences in local therapeutic practices. A national board of 11 experts was subsequently conducted to identify convergences and differences between regions, and to propose second-line criteria for the definition of therapeutic failure.

Results: Published information is lacking regarding second-line treatment failure criteria. In light of this, regional differences in current therapeutic practices are justifiable. Due to the risk-benefit ratio of these treatments and limited options for third-line treatments, the authors recommend a different therapeutic approach when assessing second-line treatment failure. The treatment switch for second-line treatment should be informed by confirmed disease progression, after 6 months, or combined clinical and MRI outcomes, but only after at least 1 year of treatment.

Conclusions: Experts compared therapeutic attitudes and practices regarding second-line treatment failure between French regions. They identified convergences that were used to propose a national agreement on second-line treatment failure criteria, which should be evaluated in real-life prospective cohorts.
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http://dx.doi.org/10.1016/j.msard.2019.101406DOI Listing
November 2019

Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis.

Neurology 2019 08 12;93(7):e635-e646. Epub 2019 Jul 12.

From INSERM (D.-A.L., L.B.), CIC 0004, Nantes; CRTI-INSERM UMR U1064 (D.-A.L.), Université de Nantes; Service de Neurologie (D.-A.L., S.W., L. Michel), CHU Nantes; Centre des Neurosciences de Lyon (R.C., F.R., S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 and CNRS UMR5292, Lyon; Université Claude Bernard Lyon 1 (R.C., F.R., S.V.), Université de Lyon; Department of Neurology (M.D.), Nancy University Hospital; Université de Lorraine (M.D.), EA 4360 APEMAC, Vandoeuvre-Lès-Nancy; Department of Neurology and Clinical Investigation Center (J.D.S.), CHU de Strasbourg, INSERM 1434; Department of Neurology (D.B.), CHU de Toulouse; Service de Neurologie (B. Brochet), CHU de Bordeaux; Service de Neurologie (J.P.), Hôpital de la Timone, CRMBM, CNRS, APHM, Aix Marseille Univ, Marseille; Univ Lille (P.V.), CHU Lille, LIRIC (Lille Inflammation Research International Center), INSERM UMR995; Service de Neurologie (G.E., L. Michel), CHU de Rennes; CRCSEP Nice (C.L.-F.), Neurologie Pasteur 2, Université Nice Cote d'Azur, Nice; Service de Neurologie (P. Clavelou), CHU de Clermont-Ferrand; Service de Neurologie (E.T.), CHU de Nîmes; Department of Neurology (J.-P.C.), Hôpital Nord, CHU Saint-Étienne; Service de Neurologie et Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; Service de Neurologie (B.S.), CHU Saint-Antoine; Service de Neurologie (A.A.K.), CHU d'Amiens; Service de Neurologie (P. Cabre), CHU de Fort de France; Service de Neurologie (C. Lubetzki, C.P.), CHU Pitié-Salpêtrière; Service de Neurologie (E.B.), CHU de Besançon; Service de Neurologie (O.H.), CH de Poissy; Service de Neurologie (T.D.), CH de Saint-Denis; Service de Neurologie (T.M.), CHU de Dijon; Service de Neurologie (O.G.), Fondation Rothschild; Service de Neurologie (B. Bourre), CHU de Rouen; Department of Neurology (A.W.), Hôpital Henri Mondor, Créteil; Service de Neurologie (P.L.), CHU de Montpellier; Service de Neurologie (L. Magy), CHU de Limoges; Service de Neurologie (G.D.), CHU de Caen; CRC SEP and Department of Neurology (A.-M.G.), CHU Bretonneau, Tours; Department of Neurology (N.M.), CHU La Milétrie, Poitiers; Department of Neurology (C. Labeyrie), CHU Bicêtre, Le Kremlin Bicêtre; Department of Neurology (I.P.), Hôpital Sud Francilien, Corbeil Essonnes; Department of Neurology (C.N.), CHU Versailles; Department of Neurology (O.C.), CHU de Grenoble; Ecole des Hautes Etudes en Santé Publique (E.L.), Rennes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron; and INSERM (Y.F.), UMR 1246-SPHERE, Nantes University, Tours University, Nantes, France.

Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.

Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.

Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, < 0.001).

Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.

Classification Of Evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
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http://dx.doi.org/10.1212/WNL.0000000000007938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715507PMC
August 2019

Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease.

J Neuroinflammation 2019 Jul 2;16(1):134. Epub 2019 Jul 2.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France.

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease.

Methods: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment.

Results: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab.

Conclusion: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD.
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http://dx.doi.org/10.1186/s12974-019-1525-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607517PMC
July 2019

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

Mult Scler 2020 07 31;26(8):936-944. Epub 2019 May 31.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Bron, France; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle and INSERM U1028, CNRS UMR 5292, Lyon 1 University, Center for Research in Neuroscience of Lyon, Lyon, France.

Objectives: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis.

Material And Methods: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0.

Results: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively),  = 0.007 and  = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group,  = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%),  < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)),  = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95,  = 0.046).

Conclusion: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.
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http://dx.doi.org/10.1177/1352458519849511DOI Listing
July 2020

Early radiological features of severe longitudinally extensive transverse myelitis over time.

J Neurol Sci 2019 May 4;400:7-9. Epub 2019 Feb 4.

Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.

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http://dx.doi.org/10.1016/j.jns.2019.01.043DOI Listing
May 2019

Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis.

J Neurol 2019 May 28;266(5):1182-1193. Epub 2019 Feb 28.

Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Objective: The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.

Methods: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions.

Results: The significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs.

Conclusions: The treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.
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http://dx.doi.org/10.1007/s00415-019-09248-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469695PMC
May 2019

Correction to: Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults.

J Neurol 2019 Apr;266(4):816

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, 59 boulevard Pinel, BRON cedex, 69677, Lyon, France.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00415-019-09215-1DOI Listing
April 2019

Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults.

J Neurol 2019 Apr 3;266(4):806-815. Epub 2019 Jan 3.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, 59 boulevard Pinel, BRON cedex, 69677, Lyon, France.

Objective: To analyze whether myelin oligodendrocyte glycoprotein antibody (MOG-Ab) titres at onset of the disease were different according to the clinical phenotype at presentation, and to investigate whether the titres were associated with risk of further relapses or predicted clinical outcome in adult patients. Finally, we assessed an alternative method to the classical measurement of MOG-Ab levels by serial dilutions.

Methods: This is a retrospective study including 79 MOG-Ab-positive adult patients, whose samples were obtained at first episode. MOG-Ab were tested by cell-based assay. HEK293 cells were transfected (tHEK293) with human-MOG plasmid. Non-tHEK293 cells were used as negative controls. Assessment of antibody titres was performed by serial dilution, and delta mean fluorescence intensity ratio signal (MOG-ratio ΔMFI) by flow cytometry. MOG-ratio ΔMFI was calculated as follows: (MFI tHEK293cells- MFI non-tHEK293cells)/MFI non-tHEK293cells. MOG-ratio ΔMFI was calculated from the first serum dilution at 1:320. The association between MOG-Ab titres and risk of relapse was analyzed by Cox regression. The association between MOG-Ab titres and visual or motor disability at last follow-up was performed by binary logistic regression. Poor visual outcome was defined when patients displayed some degree of visual disability (visual acuity [VA] < 20/20) and poor motor outcome when patients displayed some degree of motor disability (Disability Status Scale [DSS] > 1). We also investigated correlations between MOG-Ab titres and MOG-ratio ΔMFI.

Results: MOG-Ab titres were higher in Caucasians than in those with other ethnicities, and in patients with a more severe VA (VA ≤ 20/100) or motor disability (DSS ≥ 3.0) at onset (p = 0.006, 0.034, and 0.058, respectively). MOG-Ab titres were not associated with risk of relapses or with the final clinical outcome. MOG-ratio ΔMFI correlated with MOG-Ab titres in the whole cohort (ρ = 0.90; p < 0.001), and when stratified by initial clinical phenotype.

Conclusion: High MOG-Ab titres at onset are associated with a more severe presentation, but do not predict the future disease course. MOG-ratio ΔMFI is an alternative and straightforward method to determine MOG-Ab levels.
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http://dx.doi.org/10.1007/s00415-018-9160-9DOI Listing
April 2019

False hepatitis B and C viral serologies in patients with multiple sclerosis receiving high-dose biotin.

Mult Scler 2020 02 11;26(2):257-258. Epub 2018 Dec 11.

Department of Neurology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.

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http://dx.doi.org/10.1177/1352458518818294DOI Listing
February 2020

MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study.

CNS Drugs 2018 07;32(7):661-672

Department of Ophthalmology, Faculty of Medicine, CHU de Reims, URCA, Reims, France.

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.

Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.

Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.

Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.

Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.

Trial Registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.
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http://dx.doi.org/10.1007/s40263-018-0528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061426PMC
July 2018

Efficacy of rituximab in refractory RRMS.

Mult Scler 2019 05 3;25(6):828-836. Epub 2018 May 3.

Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France.

Objective: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT).

Methods: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts.

Results: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001).

Conclusion: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
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http://dx.doi.org/10.1177/1352458518772748DOI Listing
May 2019

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Neurology 2018 05 25;90(21):e1858-e1869. Epub 2018 Apr 25.

Objective: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis.

Methods: Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included.

Results: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( = 0.009).

Conclusion: In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.
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http://dx.doi.org/10.1212/WNL.0000000000005560DOI Listing
May 2018