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1. Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic

Author

Jérôme de Sèze, Elisabeth Maillart, Antoine Gueguen, David A. Laplaud, Laure Michel, Eric Thouvenot, Hélène Zephir, Luc Zimmer, Damien Biotti, and Roland Liblau

Subjects
multiple sclerosis, rituximab, ocrelizumab, ofatumumab, ublituximab, anti-CD20, Immunologic diseases. Allergy, RC581-607
Abstract

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Published
2023
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2. Personalized dietary advices provided by a dietitian increase calcium intake in outpatients with multiple sclerosis—Results from a randomized, controlled, single-blind trial

Author

Sandrine Fiorella, Hanane Agherbi, Emilia El Houjeiry, Giovanni Castelnovo, Dimitri Renard, Pauline Privat, Elodie Santamaria, Virginie Vallayer, Sandrine Alonso, Thierry Chevallier, Candice Bancal, Sabine Laurent-Chabalier, and Eric Thouvenot

Subjects
calcium intake, dietary advice, multiple sclerosis, coaching/accompaniment, personalized medicine, Nutrition. Foods and food supply, TX341-641
Abstract

Background and aimsMultiple sclerosis (MS) is associated with osteoporosis, possibly due to neurological disability and decreased calcium intake. The objective of this study was to evaluate the efficacy of a personalized nutritional advice program by a dietitian compared to the delivery of a standard advice form to optimize dietary calcium intake in outpatients with MS.MethodsWe performed a randomized, controlled, parallel trial comparing the efficacy of a personalized dietary advice (PDA) program to standard advice form (SAF) to increase daily calcium intake in MS patients. The study population was composed by patients with relapsing-remitting MS aged 18–69 years old. PDA program consisted in dietary advice delivered by a dietitian at baseline, 1 month, and 3 months. Calcium and nutrient intake in patients from both groups was evaluated at baseline and 6 months using a dietary survey.ResultsOf the 194 patients screened for inclusion, 182 patients were included (79% female, median age of 42 years, and median EDSS of 2.0), and randomized to SAF (n = 92) or PDA (n = 90). At 6 months, median calcium intake increased by 241 mg/day in the PDA group and decreased by 120 mg/day in the SAF group (p < 0.0001). However, the median calcium intake was 947 mg/day in the SAF group and 778 mg/day in the PDA group at baseline (p = 0.0077), potentially favoring the effect of dietary advice. Complementary analyses focusing on patients with insufficient calcium intakes at baseline revealed comparable values in both groups (p = 0.69). Of those, patients included in the PDA group obtained significantly higher calcium intakes at 6 months than patients from the SAF group (p = 0.0086) independently of EDSS, PASAT, HADS and EQ-5D scores.ConclusionThis work shows the efficacy of dietary management based on personalized advice program over 3 months to durably increase calcium consumption in MS patients with insufficient calcium intake.Clinical trial registrationclinicaltrials.gov, identifier NCT02664623.

Published
2023
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3. Effects of socioeconomic status on excess mortality in patients with multiple sclerosis in France: A retrospective observational cohort studyResearch in context

Author

Sarah Wilson, Floriane Calocer, Fabien Rollot, Mathieu Fauvernier, Laurent Remontet, Laure Tron, Sandra Vukusic, Emmanuelle Le Page, Marc Debouverie, Jonathan Ciron, Aurélie Ruet, Jérôme De Sèze, Hélène Zephir, Thibault Moreau, Christine Lebrun-Frénay, David-Axel Laplaud, Pierre Clavelou, Pierre Labauge, Eric Berger, Jean Pelletier, Olivier Heinzlef, Eric Thouvenot, Jean Philippe Camdessanché, Emmanuelle Leray, Olivier Dejardin, and Gilles Defer

Subjects
Multiple sclerosis, Excess mortality, Net survival, Socio-economic status, Flexible model, Observational cohort study, Public aspects of medicine, RA1-1270
Abstract

Summary: Background: The effects of socio-economic status on mortality in patients with multiple sclerosis is not well known. The objective was to examine mortality due to multiple sclerosis according to socio-economic status. Methods: A retrospective observational cohort design was used with recruitment from 18 French multiple sclerosis expert centers participating in the Observatoire Français de la Sclérose en Plaques. All patients lived in metropolitan France and had a definite or probable diagnosis of multiple sclerosis according to either Poser or McDonald criteria with an onset of disease between 1960 and 2015. Initial phenotype was either relapsing-onset or primary progressive onset. Vital status was updated on January 1st 2016. Socio-economic status was measured by an ecological index, the European Deprivation Index and was attributed to each patient according to their home address. Excess death rates were studied according to socio-economic status using additive excess hazard models with multidimensional penalised splines. The initial hypothesis was a potential socio-economic gradient in excess mortality. Findings: A total of 34,169 multiple sclerosis patients were included (88% relapsing onset (n = 30,083), 12% progressive onset (n = 4086)), female/male sex ratio 2.7 for relapsing-onset and 1.3 for progressive-onset). Mean age at disease onset was 31.6 (SD = 9.8) for relapsing-onset and 42.7 (SD = 10.8) for progressive-onset. At the end of follow-up, 1849 patients had died (4.4% for relapsing-onset (n = 1311) and 13.2% for progressive-onset (n = 538)). A socio-economic gradient was found for relapsing-onset patients; more deprived patients had a greater excess death rate. At thirty years of disease duration and a year of onset of symptoms of 1980, survival probability difference (or deprivation gap) between less deprived relapsing-onset patients (EDI = −6) and more deprived relapsing-onset patients (EDI = 12) was 16.6% (95% confidence interval (CI) [10.3%–22.9%]) for men and 12.3% (95%CI [7.6%–17.0%]) for women. No clear socio-economic mortality gradient was found in progressive-onset patients. Interpretation: Socio-economic status was associated with mortality due to multiple sclerosis in relapsing-onset patients. Improvements in overall care of more socio-economically deprived patients with multiple sclerosis could help reduce these socio-economic inequalities in multiple sclerosis-related mortality. Funding: This study was funded by the ARSEP foundation “Fondation pour l'aide à la recherche sur la Sclérose en Plaques” (Grant Reference Number 1122). Data collection has been supported by a grant provided by the French State and handled by the “Agence Nationale de la Recherche,” within the framework of the “Investments for the Future” programme, under the reference ANR-10-COHO-002, Observatoire Français de la Sclérose en Plaques (OFSEP).

Published
2023
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4. DMTs and Covid‐19 severity in MS: a pooled analysis from Italy and France

Author

Maria Pia Sormani, Marco Salvetti, Pierre Labauge, Irene Schiavetti, Helene Zephir, Luca Carmisciano, Caroline Bensa, Nicola De Rossi, Jean Pelletier, Cinzia Cordioli, Sandra Vukusic, Lucia Moiola, Philippe Kerschen, Marta Radaelli, Marie Théaudin, Paolo Immovilli, Olivier Casez, Marco Capobianco, Jonathan Ciron, Maria Trojano, Bruno Stankoff, Alain Créange, Gioacchino Tedeschi, Pierre Clavelou, Giancarlo Comi, Eric Thouvenot, Mario Alberto Battaglia, Thibault Moreau, Francesco Patti, Jérôme De Sèze, Celine Louapre, the Musc‐, and the Covisep study groups

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p

Published
2021
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6. Comparison of SimoaTM and EllaTM to assess serum neurofilament‐light chain in multiple sclerosis

Author

Audrey Gauthier, Sébastien Viel, Magali Perret, Guillaume Brocard, Romain Casey, Christine Lombard, Sabine Laurent‐Chabalier, Marc Debouverie, Gilles Edan, Sandra Vukusic, Christine Lebrun‐Frénay, Jérôme De Sèze, David Axel Laplaud, Giovanni Castelnovo, Olivier Gout, Aurélie Ruet, Thibault Moreau, Olivier Casez, Pierre Clavelou, Eric Berger, Hélène Zephir, Sophie Trouillet‐Assant, Eric Thouvenot, and OFSEP Investigators

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract We compared SimoaTM and EllaTM immunoassays to assess serum neurofilament‐light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p

Published
2021
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7. Biological Markers in Early Multiple Sclerosis: the Paved Way for Radiologically Isolated Syndrome

Author

Manon Rival, Manon Galoppin, and Eric Thouvenot

Subjects
multiple sclerosis (MS), radiologically isolated syndrome (RIS), prognosis, biomarkers, personalized medicine, Kappa free-light chain index (kFLC index), Immunologic diseases. Allergy, RC581-607
Abstract

Radiologically Isolated Syndrome (RIS) is characterized by MRI-typical brain lesions fulfilling the 2009 Okuda criteria, detected in patients without clinical conditions suggestive of MS. Half of all RIS patients convert to MS within 10 years. The individual course of the disease, however, is highly variable with 12% of RIS converting directly to progressive MS. Demographic and imaging markers have been associated with the risk of clinical MS in RIS: male sex, younger age, infra-tentorial, and spinal cord lesions on the index scan and gadolinium-enhancing lesions on index or follow-up scans. Although not considered as a distinct MS phenotype, RIS certainly shares common pathological features with early active and progressive MS. In this review, we specifically focus on biological markers that may help refine the risk stratification of clinical MS and disability for early treatment. Intrathecal B-cell activation with cerebrospinal fluid (CSF) oligoclonal bands, elevated kappa free light chains, and cytokine production is specific to MS, whereas neurofilament light chain (NfL) levels reflect disease activity associated with neuroaxonal injury. Specific microRNA profiles have been identified in RIS converters in both CSF and blood. CSF levels of chitinases and glial acidic fibrillary protein (GFAP) reflecting astrogliosis might help predict the evolution of RIS to progressive MS. Innovative genomic, proteomic, and metabolomic approaches have provided several new candidate biomarkers to be explored in RIS. Leveraging data from randomized controlled trials and large prospective RIS cohorts with extended follow-up to identify, as early as possible, biomarkers for predicting greater disease severity would be invaluable for counseling patients, managing treatment, and monitoring.

Published
2022
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8. Cerebrospinal fluid A beta 1–40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals

Author

Sylvain Lehmann, Julien Dumurgier, Xavier Ayrignac, Cecilia Marelli, Daniel Alcolea, Juan Fortea Ormaechea, Eric Thouvenot, Constance Delaby, Christophe Hirtz, Jérôme Vialaret, Nelly Ginestet, Elodie Bouaziz-Amar, Jean-Louis Laplanche, Pierre Labauge, Claire Paquet, Alberto Lleo, Audrey Gabelle, and for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Subjects
Alzheimer’s disease, Amyloid peptides, Tau proteins, Biomarkers, Cerebrospinal fluid (CSF), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Amyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1–42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1–40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results. Methods Here, we analyzed the levels of Aβ1–40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1–42 and Aβ1–40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). Results Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1–40 and p-tau (181) in CSF, particularly in control patients. Conclusions These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

Published
2020
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9. Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease

Author

Alvaro Cobo-Calvo, María Sepúlveda, Fabien Rollot, Thais Armangué, Anne Ruiz, Elisabeth Maillart, Caroline Papeix, Bertrand Audoin, Helene Zephir, Damien Biotti, Jonathan Ciron, Francoise Durand-Dubief, Nicolas Collongues, Xavier Ayrignac, Pierre Labauge, Eric Thouvenot, Bertrand Bourre, Alexis Montcuquet, Mikael Cohen, Romain Deschamps, Nuria Solà-Valls, Sara Llufriu, Jerome De Seze, Yolanda Blanco, Sandra Vukusic, Albert Saiz, and Romain Marignier

Subjects
MOG antibodies, Treatment response, Neuromyelitis optica, Multiple sclerosis, Propensity score, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract 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.

Published
2019
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10. Small obliquely oriented cortical cerebellar infarctions are associated with cardioembolic stroke

Author

Adrien Ter Schiphorst, Lavinia Tatu, Vincent Thijs, Christophe Demattei, Eric Thouvenot, and Dimitri Renard

Subjects
Stroke, Infarction, Obliquely, Cerebellar, Cortical, Cardioembolic, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background A revised classification of cerebellar infarctions (CI) may uncover unrecognized associations with etiologic stroke subtypes. We hypothesized that obliquely oriented small cortical cerebellar infarction (SCCI) representing end zone infarctions on MRI would be associated with cardiac embolism. Methods We retrospectively analyzed consecutive stroke patients recruited between January–December 2016 in our center. Analyzed baseline characteristics: sex, age, cardiovascular risk factors, history of stroke or atrial fibrillation (AF). TOAST classification was used for determining stroke subtype. Acute infarction location (anterior/posterior/mixed anterior-posterior circulation), acute uni- or multiterritorial infarction, and acute or chronic CI/SCCI/non-SCCI were assessed by MRI, and vertebrobasilar stenosis/occlusion by vessel imaging. Pre-specified analysis was also performed in patients without known high cardioembolic risk (known AF history or acute multiterritorial infarction). Results We included 452 patients (CI in 154, isolated SCCI in 55, isolated non-SCCI in 50, and mixed SCCI/non-SCCI in 49). Both SCCI and non-SCCI were associated with AF history (SCCI, p = 0.021; non-SCCI, p = 0.004), additional acute posterior circulation infarction (p

Published
2019
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11. Mass Cytometry Identifies Expansion of T-bet+ B Cells and CD206+ Monocytes in Early Multiple Sclerosis

Author

Laura Couloume, Juliette Ferrant, Simon Le Gallou, Marion Mandon, Rachel Jean, Nadège Bescher, Helene Zephir, Gilles Edan, Eric Thouvenot, Aurelie Ruet, Marc Debouverie, Karin Tarte, Patricia Amé, Mikael Roussel, and Laure Michel

Subjects
biomarker, multiple sclerosis, mass cytometry, immunology, B cells, monocytes, Immunologic diseases. Allergy, RC581-607
Abstract

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206+ classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.

Published
2021
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12. AltiKa: a Ka-band Altimetry Payload and System for Operational Altimetry during the GMES Period

Author

Jacques Verron, Eric Thouvenot, Laurent Rey, Laurent Phalippou, Eric Caubetq, Nathalie Steunou, and Patrick Vincent

Subjects
altimeter, radiometer, ocean mesoscale circulation, Ka-band., Chemical technology, TP1-1185
Abstract

This paper describes the Ka-band altimetry payload and system that has beenstudied for several years by CNES, ALCATEL SPACE and some science laboratories.Altimetry is one of the major elements of the ocean observing system to be madesustainable through the GEOSS (Global Earth Observation System of Systems) and GMES(Global Monitoring of the Environment and Security) programs. A short review of somemission objectives to be fulfilled in terms of mesoscale oceanography in the frame of theGEOSS and GMES programs is performed. To answer the corresponding requirements, theapproach consisting in a constellation of nadir altimeter is discussed. A coupled Ka-bandaltimeter-radiometer payload is then described; technical items are detailed to explain howthis payload shall meet the science and operational requirements, and expectedperformances are displayed. The current status of the payload development and flightperspectives are given.

Published
2006
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13. Thalamic Lesions: A Radiological Review

Author

Dimitri Renard, Giovanni Castelnovo, Chantal Campello, Stephane Bouly, Anne Le Floch, Eric Thouvenot, Anne Waconge, and Guillaume Taieb

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background. Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions). Summary. In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations.

Published
2014
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14. Ipsilateral Uveitis and Optic Neuritis in Multiple Sclerosis

Author

Eric Thouvenot, Frédéric Mura, Marie De Verdal, Bertrand Carlander, Mahmoud Charif, Christelle Schneider, Sophie Navarre, and William Camu

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Background. Uveitis is 20 times more frequent in multiple sclerosis (MS) patients than in the general population. Methods. A retrospective study of local multiple sclerosis (n=700) and uveitis cohorts (n=450) described the ophthalmological and neurological characteristics of patients with multiple sclerosis and uveitis. Results. Uveitis and multiple sclerosis were associated in seven patients. The time intervals between diagnoses of MS and uveitis ranged from 6 months to 15 years. Analysis of the patients’ characteristics revealed that multiple sclerosis was associated with an older age of onset than usually expected, that is, 39 years. Uveitis was bilateral in three cases and mainly posterior (5/10). Five patients presented with acute optic neuritis (two in one eye and three in both eyes). All eyes presenting with acute optic neuritis were also affected by uveitis (P=0.02), though not simultaneously. Conclusion. The ipsilateral association between optic neuritis and uveitis in this series of patients with multiple sclerosis may suggest a reciprocal potentiation between optic neuritis and uveitis in multiple sclerosis.

Published
2012
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15. Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy on 1.5T T2*-Weighted Imaging

Author

Dimitri Renard, Sabine Laurent-Chabalier, Adelina Leonte, Marc Hackius, Teodora Parvu, Anne Wacongne, and Eric Thouvenot

Subjects
Neurology, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Cerebellar superficial siderosis (SS) has been recently reported to be present in about 10% of both hereditary and sporadic cerebral amyloid angiopathy (CAA) on 3T MRI using primarily susceptibility-weighted imaging. Objectives: Our aim was to assess cerebellar SS in sporadic CAA patients using 1.5T T2*-weighted MRI and to evaluate possible underlying mechanisms. Method: We retrospectively screened MRI scans of sporadic probable CAA patients initially presenting with intracerebral hemorrhage-, acute subarachnoid hemorrhage- or cortical SS-related symptoms between September 2009 and January 2022 registered in our stroke database. Patients with familial CAA were excluded. On 1.5T T2*-weighted MRI, cerebellar SS (including kappa statistics for interobserver agreement) was assessed together with typical CAA hemorrhagic features and with the presence of supratentorial macrobleed and cortical SS adjacent to the tentorium cerebelli (TC) and TC hemosiderosis. Results: We screened 151 patients and finally included 111 CAA patients (median age 77) with cerebellar SS observed in 6 (5%) patients. Cerebellar SS presence was associated with a higher number of supratentorial macrobleeds (median n = 3 vs. n = 1, p = 0.0012), presence of supratentorial macrobleed adjacent to the TC (p = 0.002), and TC hemosiderosis (p = 0.005). Conclusions: Cerebellar SS in CAA patients can be identified on 1.5T T2*-weighted imaging. Associated MRI characteristics suggest contamination from supratentorial macrobleeds.

Published
2023
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16. Syndecan-1 as specific cerebrospinal fluid biomarker of multiple sclerosis

Author

Geoffrey Hinsinger, Lucile Du Trieu de Terdonck, Serge Urbach, Nicolas Salvetat, Manon Rival, Manon Galoppin, Chantal Ripoll, Renaud Cezar, Sabine Laurent-Chabalier, Christophe Demattei, Hanane Agherbi, Giovanni Castelnovo, Sylvain Lehmann, Valérie Rigau, Philippe Marin, and Eric Thouvenot

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease often characterized by remission and relapse periods occurring at irregular intervals after an initial attack (clinically isolated syndrome) and followed by a gradual progression of disability. Clinical symptoms, magnetic resonance imaging and abnormalities in cerebrospinal fluid (CSF) immunoglobulin profile allow diagnosis with a good sensitivity. However, current biomarkers lack specificity or have poor individual prognostic value. To identify novel candidate biomarkers of MS, we analysed 1) the CSF proteome from symptomatic controls and patients with clinically isolated syndrome or remitting-relapsing multiple sclerosis (n=40), and 2) changes in oligodendrocyte secretome upon proinflammatory or pro-apoptotic treatment. Proteins exhibiting differences in abundance in both studies were combined with previously described MS biomarkers to build a list of 87 proteins that were quantified by parallel reaction monitoring (PRM) in CSF samples from a new cohort comprising symptomatic controls and MS patients at different disease stages (n=60). The eleven proteins that passed this qualification step were subjected to a new PRM assay from a larger cohort (n=158) comprising patients with MS at different disease stages or with other inflammatory or non-inflammatory neurological disorders. Collectively, these studies identified a biomarker signature of MS that might improve MS diagnosis and prognosis. These include the oligodendrocyte precursor cell proteoglycan Syndecan-1, which was more efficient than previously described biomarkers to discriminate MS from other inflammatory and non-inflammatory neurological disorders.

Published
2023
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17. Association between brain metabolism and clinical course of motor functional neurological disorders

Author

Ismael Conejero, Laurent Collombier, Jorge Lopez-Castroman, Thibault Mura, Sandrine Alonso, Emilie Olié, Vincent Boudousq, Fabrice Boulet, Caroline Arquizan, Charlotte Boulet, Anne Wacongne, Camille Heitz, Christel Castelli, Stéphane Mouchabac, Philippe Courtet, Mocrane Abbar, and Eric Thouvenot

Subjects
Stroke, Conversion Disorder, Motor Disorders, Brain, Humans, Disabled Persons, Neurology (clinical), Magnetic Resonance Imaging
Abstract

Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of patients experiencing a first episode of motor functional neurological disorder with recent symptom onset and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from two hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r = −0.75, P = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r = −0.81, P = 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r = −0.65, P = 0.01 and r = −0.75, P = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r = −0.81, P = 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic ‘state markers’ associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.

Published
2022
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18. Brainstem lesions: MRI review of standard morphological sequences

Author

Dimitri Renard, Jean-Sebastien Guillamo, Ioana Ion, and Eric Thouvenot

Subjects
Radiography, Metabolic Diseases, Humans, Neurology (clinical), General Medicine, Nervous System Diseases, Magnetic Resonance Imaging, Brain Stem
Abstract

MRI signal changes in the brainstem are observed in a multitude of disorders including vascular diseases, neoplastic lesions, degenerative diseases, inflammatory disorders, metabolic diseases, infections, and trauma. In some diseases, brainstem involvement is typical and sometimes isolated, while in other diseases, brainstem lesions are only observed occasionally in the presence of other typical extra-brainstem abnormalities. In this review, we will discuss the MRI characteristics of brainstem lesions observed in different disorders associated with frequent and less frequent brainstem involvement. Identification of the origin of the brainstem lesion depends on the exact localisation of the lesion(s) inside the brainstem, the presence and the characteristics of associated lesions seen outside the brainstem, the signal changes on different MRI sequences, the evolution over time of the radiological abnormalities, the history and clinical state of the patient, and other radiological and non-radiological examinations.

Published
2022
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19. Association of symptomatic atherosclerotic carotid arteries with plaque areas showing low densities on computed tomographic angiography

Author

Cassiana Trandafir, Sabine Laurent‐Chabalier, Catalin Cosma, Julien Frandon, Eric Thouvenot, and Dimitri Renard

Subjects
Adult, Endarterectomy, Carotid, Carotid Arteries, Neurology, Angiography, Humans, Carotid Stenosis, Neurology (clinical), Plaque, Atherosclerotic, Retrospective Studies
Abstract

Intraplaque hemorrhage is a key feature of vulnerable carotid atherosclerotic plaque (CAP), associated with low densities (25 Hounsfield units [HU]) on computed tomographic angiography (CTA). This study aimed to analyze CAP on routine CTA performed in patients with symptomatic and asymptomatic carotid stenosis undergoing carotid endarterectomy (CEA) by assessing HU of the CAP area showing the lowest density (CAPALD) using radiological tools available in daily clinical practice, and to compare CAPALD values between symptomatic and asymptomatic carotids.We retrospectively screened preoperative CTA scans of 206 consecutive adult patients undergoing CEA for symptomatic or asymptomatic stenosis. CAPALD values were compared between symptomatic and asymptomatic carotids. Asymptomatic carotids included arteries contralateral to the symptomatic CEA artery, and asymptomatic stenotic arteries undergoing CEA and their contralateral arteries. Carotids were excluded when there was30% stenosis, or when CAP could not be identified or CAPALD could not be measured.In total, 95 symptomatic and 112 asymptomatic carotids (derived from 174 patients) were analyzed. In multivariate analysis, symptomatic arteries showed more severe stenosis (median 70% vs. 67%, p = 0.0228) and lower CAPALD values (median 17 vs. 25 HU, p = 0.049), whereas degree of stenosis and CAPALD values were not correlated (rho = -0.02, p = 0.77). HU values of25 were more frequent in symptomatic than asymptomatic carotids (68% vs. 47%, p = 0.0022).On CTA, symptomatic carotids are associated with CAP areas with low densities. CTA analysis of CAP may be interesting to help identify vulnerable plaques at risk for future stroke, especially in patients lacking strict indications for CEA based on the current guidelines.

Published
2022
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20. Improving the decision to switch from first- to second-line therapy in multiple sclerosis: A dynamic scoring system

Author

Camille Sabathé, Romain Casey, Sandra Vukusic, Emmanuelle Leray, Guillaume Mathey, Jérôme De Sèze, Jonathan Ciron, Sandrine Wiertlewski, Aurélie Ruet, Jean Pelletier, Hélène Zéphir, Laure Michel, Christine Lebrun-Frenay, Xavier Moisset, Eric Thouvenot, Jean-Philippe Camdessanché, Serge Bakchine, Bruno Stankoff, Abdullatif Al Khedr, Philippe Cabre, Elisabeth Maillart, Eric Berger, Olivier Heinzlef, Karolina Hankiewicz, Thibault Moreau, Olivier Gout, Bertrand Bourre, Abir Wahab, Pierre Labauge, Alexis Montcuquet, Gilles Defer, Aude Maurousset, Nicolas Maubeuge, Dalia Dimitri Boulos, Haïfa Ben Nasr, Chantal Nifle, Olivier Casez, David-Axel Laplaud, Yohann Foucher, Université de Nantes, Université de Tours, Inserm, UMR1246 Sphere, Nantes, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Méthodes quantitatives en santé publique (METIS), École des Hautes Études en Santé Publique [EHESP] (EHESP), Recherche sur les services et le management en santé (RSMS), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), and Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)

Subjects
Multiple sclerosis, Neurology, Epidemiology, Second-line treatment, Neurology (clinical), Treatment response, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression. Objective: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy. Methods: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs). Results: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09–0.22) for the waiting group and 0.40 (95% CI 0.32–0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30–0.46) and 0.44 (95% CI 0.37–0.52), respectively. Conclusions: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.

Published
2023
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22. Multiple Paraneoplastic Neurological and Rheumatological Syndromes Revealing an Ovarian Cancer

Author

Ioana Maria Ion, Anca Badoiu, Eric Thouvenot, Morgane Petot, and Vincent Boudousq

Subjects
General Earth and Planetary Sciences, General Environmental Science
Abstract

Multiple paraneoplastic syndromes are a rare clinical manifestation. We describe the case of an 82-year-old woman who presented with neurological (rapidly progressive cerebellar syndrome and combined sensory-motor neuronopathy) and rheumatological (palmar fasciitis and polyarthritis syndrome) paraneoplastic syndromes associated with two onconeural antibodies (anti-Yo and Zic4), that revealed an ovarian cancer. The involvement of multiple organ systems should be a clue to take into consideration a paraneoplastic etiology that could permit early detection of cancer. However, despite the existence of treatments, the prognosis of these conditions remains poor.

Published
2021
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23. Untreated patients with multiple sclerosis: A study of French expert centers

Author

Xavier Moisset, Bruno Stankoff, Pierre Clavelou, Karolina Hankiewicz, Bruno Brochet, Olivier Casez, Bruno Pereira, Chantal Nifle, Thibault Moreau, Sandra Vukusic, Christine Lebrun-Frenay, Eric Thouvenot, Alain Créange, Olivier Gout, Corinne Pottier, Olivier Heinzlef, Caroline Papeix, Gilles Defer, Eric Berger, David Laplaud, Audrey-Anne Fouchard, S. Bakchine, Alexis Montcuquet, Jean Pelletier, Jérôme De Seze, Dalia Dimitri Boulos, Jean-Philippe Camdessanché, Pierre Labauge, Bertrand Bourre, Philippe Cabre, Abdullatif Al-Khedr, Aude Maurousset, Frederic Taithe, Gilles Edan, Jonathan Ciron, Nicolas Maubeuge, Guillaume Mathey, Patrick Vermersch, Jonchère, Laurent, Cohortes - Observatoire Français de la Sclérose en Plaques - - OFSEP2010 - ANR-10-COHO-0002 - COHO - VALID, CHU Clermont-Ferrand, Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Bordeaux (UB), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Lille, Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Pasteur [Nice] (CHU), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Saint-Antoine [AP-HP], Fondation Ophtalmologique Adolphe de Rotschild, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHI Poissy-Saint-Germain, CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU de la Martinique [Fort de France], CHU Limoges, CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Bicêtre, Centre Hospitalier Versailles, 78000 Le Chesnay, France, parent, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Agence Nationale de la Recherche French National Research Agency (ANR) European Commission [ANR-10-COHO-002], ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Université Paul-Valéry - Montpellier 3 (UPVM), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor [Créteil], and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Adult, medicine.medical_specialty, Multiple Sclerosis, Multivariate analysis, untreated, [SDV]Life Sciences [q-bio], progressive, Unmet needs, Primary progressive, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, 10. No inequality, Retrospective Studies, unmet medical needs, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Retrospective cohort study, Odds ratio, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, relapsing-remitting, Confidence interval, [SDV] Life Sciences [q-bio], Neurology, Neurology (clinical), Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract

International audience; Background and purpose: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. Methods: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. Results: Of the 21,189 patients with MS (age 47.1 +/- 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 +/- 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) 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 patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having >= 9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 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, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. Conclusion: A significant proportion of patients with MS 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 patients with MS.

Published
2021
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24. The long‐term outcome of MOGAD: An observational national cohort study of 61 patients

Author

Valerie Touitou, Bertrand Audoin, Nicolas Collongues, Mikael Cohen, Romain Deschamps, David Laplaud, Nathalie Derache, Jonathan Ciron, Eric Thouvenot, Françoise Durand-Dubief, Caroline Papeix, Jennifer Aboab, Guillaume Mathey, Julie Pique, C. Vignal-Clermont, Aurélie Ruet, Elisabeth Maillart, Romain Marignier, Hélène Zéphir, Bertrand Bourre, Olivier Gout, and Xavier Ayrignac

Subjects
Pediatrics, medicine.medical_specialty, Optic Neuritis, Visual acuity, Bilateral blindness, medicine.medical_treatment, Urinary catheterization, National cohort, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Optic neuritis, 030212 general & internal medicine, Autoantibodies, Retrospective Studies, Aquaporin 4, First episode, Expanded Disability Status Scale, business.industry, medicine.disease, Neurology, Myelin-Oligodendrocyte Glycoprotein, Observational study, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

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.

Published
2021
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25. Full spectrum of vitamin D immunomodulation in multiple sclerosis: mechanisms and therapeutic implications

Author

Manon Galoppin, Saniya Kari, Sasha Soldati, Arindam Pal, Manon Rival, Britta Engelhardt, Anne Astier, Eric Thouvenot, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and University of Bern

Subjects
lymphocytes, [SDV]Life Sciences [q-bio], vitamin D, 610 Medicine & health, immunomodulation, multiple sclerosis, cytokines, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biological Psychiatry
Abstract

Vitamin D deficiency has been associated with the risk of multiple sclerosis, disease activity and progression. Results from in vitro experiments, animal models and analysis of human samples from randomized controlled trials provide comprehensive data illustrating the pleiotropic actions of Vitamin D on the immune system. They globally result in immunomodulation by decreasing differentiation of effector T and B cells while promoting regulatory subsets. Vitamin D also modulates innate immune cells such as macrophages, monocytes and dendritic cells, and acts at the level of the blood–brain barrier reducing immune cell trafficking. Vitamin D exerts additional activity within the central nervous system reducing microglial and astrocytic activation. The immunomodulatory role of Vitamin D detected in animal models of multiple sclerosis has suggested its potential therapeutic use for treating multiple sclerosis. In this review, we focus on recent published data describing the biological effects of Vitamin D in animal models of multiple sclerosis on immune cells, blood–brain barrier function, activation of glial cells and its potential neuroprotective effects. Based on the current knowledge, we also discuss optimization of therapeutic interventions with Vitamin D in patients with multiple sclerosis, as well as new technologies allowing in-depth analysis of immune cell regulations by vitamin D.

Published
2022
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26. Primary acute convexity subarachnoid hemorrhage in older patients: analysis of baseline, clinical and MRI characteristics including quantitative surface study and topographical probabilistic mapping of convexity subarachnoid hemorrhage

Author

Vincenzo Autieri, Nicolas Gaillard, Isabelle Mourand, Sabine Laurent-Chabalier, Thibault Mura, Cassiana Trandafir, Anne Wacongne, Nicolas Menjot de Champfleur, Eric Thouvenot, Fabricio Pereira, and Dimitri Renard

Subjects
Neurology (clinical), General Medicine
Abstract

Primary acute convexity subarachnoid hemorrhage (cSAH) in older patients can be observed in cerebral amyloid angiopathy (CAA) or idiopathic (with cSAH as potential initial manifestation of suspected CAA). We aimed to analyze baseline, clinical and MRI (including quantitative cSAH surface analysis and topographical probabilistic cSAH mapping) characteristics in elderly cSAH patients with CAA.Baseline/clinical/MRI characteristics of 50 consecutive primary acute cSAH patients ≥ 55 years with suspected/possible/probable CAA were retrospectively analyzed.Median age was 74, with 26% of patients showing suspected, 22% possible and 52% probable CAA. Transient focal neurological episode (TFNE) was observed in 78%, with spreading symptoms in 79% (median spreading speed five minutes), a median of two episodes before cSAH diagnosis, and similar symptoms in 91% when multiple TFNE, with a median duration of 15 min. Motor/sensory/speech/visual symptoms were observed in 85%/69%/46%/8%, respectively, and brachiofacial/brachial was the most frequent distribution for sensory-motor symptoms. Positive clinical-radiological correlation was observed in 84%, headache in 22%, and antiepileptics started in 78%. MRI showed chronic intracerebral hemorrhage in 10%, cortical superficial siderosis in 68%, cerebral microbleeds in 48%, median total Fazekas score of 3, lacunes in 6% and DWI lesion (all unique/cortical/ 10 mm) in 6%. cSAH involved a median of 1 sulcus, with central sulcus as most frequently (47.5%) involved followed by precentral sulcus (17%). Median cSAH surface was 2170 mmBaseline, clinical, or MRI features seem not to influence CAA-related cSAH extent.http://www.gov . Unique identifier: NCT04825808.

Published
2022

27. Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis: A Large Multicenter Cohort Study

Author

Michael Levraut, Sabine Laurent-Chabalier, Xavier Ayrignac, Kévin Bigaut, Manon Rival, Sanae Squalli, Hélène Zéphir, Tifanie Alberto, Jean-David Pekar, Jonathan Ciron, Damien Biotti, Bénédicte Puissant-Lubrano, Jean-Philippe Camdessanché, Yannick Tholance, Olivier Casez, Bertrand Toussaint, Jeanne Marion, Thibault Moreau, Daniela Lakomy, Audrey Thomasset, Elisabeth Maillart, Delphine Sterlin, Aude Maurousset, Auriane Rocher, David Axel Laplaud, Edith Bigot-Corbel, Pierre-Olivier Bertho, Jean Pelletier, Joseph Boucraut, Pierre Labauge, Thierry Vincent, Jérôme De Sèze, Isabelle Jahn, Barbara Seitz-Polski, Eric Thouvenot, Christine Lebrun-Frenay, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Unité de Recherche Clinique de la Côte d’Azur (URRIS UR2CA), Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Les Hôpitaux Universitaires de Strasbourg (HUS), Thèses d'exercice et mémoires - UFR de Médecine Montpellier-Nîmes, Université de Montpellier (UM), Laboratoire de Biochimie [CHRU Nîmes], Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pôle Neurosciences [CHU Toulouse], Institut Fédératif de Biologie (IFB), Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire [Grenoble] (CHU), Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service de Biochimie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Team 5 : Neuroinflammation, mechanisms, therapeutic options (NEMO) (U1064 Inserm - CR2TI), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Laboratoire de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Département de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Nord Laennec [CHU Nantes], Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Laboratoire Immunologie [Nice], Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Hôpital de l'Archet-Université Côte d'Azur (UCA), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Société Francophone de la Sclérose En Plaques (SFSEP)., and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
MESH: Humans, MESH: Multiple Sclerosis, Multiple Sclerosis, MESH: Demyelinating Diseases* / diagnosis, [SDV]Life Sciences [q-bio], Oligoclonal Bands, MESH: Immunoglobulin kappa-Chains, MESH: Central Nervous System Diseases, MESH: Oligoclonal Bands, Cohort Studies, Immunoglobulin kappa-Chains, Neurology, Central Nervous System Diseases, MESH: Biomarkers, Humans, Female, Neurology (clinical), MESH: Cohort Studies, MESH: Female, Biomarkers, Demyelinating Diseases
Abstract

Background and ObjectivesKappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS.MethodsWe conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC).ResultsOne thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND (p= 0.123 andp= 0.991 for area under the curve [AUC] comparisons) and performed better than CSF KFLC (p< 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB (p< 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB (p= 0.065). In the multivariate analysis model, female gender (p= 0.003), young age (p= 0.013), and evidence of disease activity (p< 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index.DiscussionKFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS.Classification of EvidenceThis study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders.

Published
2022
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28. 18F-FDOPA-PET in pseudotumoral brain lesions

Author

Laurent Collombier, Dimitri Renard, Eric Thouvenot, Anne Le Floch, Sabine Laurent-Chabalier, Hassan El Fertit, Jean Sebastien Guillamo, and Thibault Mura

Subjects
medicine.diagnostic_test, Receiver operating characteristic, business.industry, Area under the curve, Brain tumor, Magnetic resonance imaging, Grey matter, medicine.disease, Lesion, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Neurology, Positron emission tomography, medicine, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, Nuclear medicine, business, 030217 neurology & neurosurgery, Neuroradiology
Abstract

3,4-Dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) positron emission tomography (PET) is sensitive for identifying primary brain tumors. However, increased FDOPA uptake has been reported in pseudotumoral brain lesions. Our aim was to analyse FDOPA-PET in patients with pseudotumoral brain lesions and to compare them with patients with brain tumors. We retrospectively analysed consecutively recruited patients with suspected primary brain tumor (based on clinical and magnetic resonance imaging findings) referred for FDOPA-PET in our centre between November 2013 and June 2019 (n = 74). FDOPA-PET parameters (maximum and mean lesion standardised uptake values [SUV] and ratios comparing lesion with different background uptake SUV) and thresholds were evaluated to determine which offered optimal discrimination between pseudotumoral and tumoral lesions. Overlapping PET values were observed between pseudotumoral (n = 26) and tumoral (n = 48) lesion, particularly for low-grade tumors. Based on receiver operating characteristic (ROC) analyses, the optimal PET parameters to discriminate pseudotumoral from tumoral lesions were SUVmax lesion/basal ganglia, SUVmax lesion/grey matter, SUVmean lesion/grey matter, and SUVmax lesion/mirror area in contralateral hemisphere (all ratios showing area under the curve [AUC] 0.85, 95% CI). The narrowest 95% sensitivity–95% specificity window was observed for SUVmax lesion/basal ganglia ratio, with ratio values of 0.79 and 1.35 corresponding to 95% sensitivity and 95% specificity, respectively. FDOPA-PET uptake should be interpreted with caution in patients with suspected primary brain tumor, especially in patients showing low or intermediate SUV values and ratios. https://www.clinicaltrials.gov . Unique identifier: NCT04306484

Published
2020
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29. Mechanism of action of s1p receptor modulators in multiple sclerosis: The double requirement

Author

William Camu, Régis Bordet, Eric Thouvenot, David-Axel Laplaud, Jérôme De Seze, Jean-Christophe Ouallet, Département de Pharmacologie Médicale [Lille] (Pôle Recherche), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Nîmes], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Le Bihan, Sylvie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, Institut des Neurosciences de Montpellier (INM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Multiple Sclerosis, Sphingosine-1-phosphate, [SDV]Life Sciences [q-bio], Sphingosine-1-phosphate receptor, Neuroprotection, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neuroinflammation, Sphingosine, Animals, Humans, Medicine, 030212 general & internal medicine, Neurodegeneration, Receptor, Sphingosine-1-Phosphate Receptors, Fingolimod Hydrochloride, business.industry, Multiple sclerosis, Brain, Fingolimod, medicine.disease, [SDV] Life Sciences [q-bio], Neurology, chemistry, Immune System, Neurology (clinical), Lysophospholipids, business, Neuroscience, Immunosuppressive Agents, 030217 neurology & neurosurgery, Signal Transduction, medicine.drug
Abstract

International audience; The ideal treatment for multiple sclerosis (MS) would target both the neuroinflammatory component of the disease (peripheral and central) and its neurodegenerative component, via modulation of a ubiquitous and pleiotropic common target. Sphingosine-1-phosphate (S1P), a product of sphingosine metabolism, regulates many biological functions (including cell proliferation and survival, cell migration, the immune response and cardiovascular function) via five subtypes of receptor. These receptors are expressed in all types of brain cells where they modulate a number of processes involved in neuronal plasticity, including myelination, neurogenesis and neuroprotection. This profile has aroused interest in modulation of S1P function as a therapeutic target in many brain diseases, particularly those in which the immune system plays a role in the development of brain lesions. Fingolimod, a S1P receptor modulator, exerts its beneficial effects in MS through its anti-inflammatory and anti-neurodegenerative effects. This review discusses recent evidence indicating that fingolimod may target both the inflammatory and neurodegenerative components of the disease process in MS.

Published
2020
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30. Spinal cord lesion mimicking a dysimmune myelitis revealing CANVAS syndrome

Author

Emilia El Houjeiry, Sarah Coudray, Eric Thouvenot, and Ioana Maria Ion

Subjects
Case Report, Neurology (clinical)
Abstract

CONTEXT: Posterior spinal cord lesions are found in patients with ganglionopathy. These are normally found in later stages of the neuronopathy as a consequence of dorsal root ganglia degeneration. Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) is an emerging neurological disorder. Myelitis lesions have been described in confirmed CANVAS cases. FINDINGS: We describe a case of a 68-year-old woman with slowly progressive ataxia with paresthesia. Laboratory tests were normal. Total spine MRI showed a C4 posterior spinal cord lesion. Lumbar puncture was positive for oligoclonal bands with normal IgG index and protein level. Paraneoplastic antibodies were not detected. Electromyography showed nonlength dependent sensory neuropathy. The patient was treated with intravenous immunoglobulin for suspected dysimmune myelitis. Over 6 years, she progressively developed other neurological manifestations evoking CANVAS. Nerve conduction study showed isolated sensory impairment over the years and peripheral nerve ultrasound revealed abnormally small nerves. Further genetic testing confirmed the diagnosis. CONCLUSION: This is the first case of CANVAS syndrome presenting initially with an isolated spinal cord lesion mimicking dysimmune myelitis. The purpose of this case report is to add to the current literature about this evolving neurological syndrome and to aid clinicians in their diagnostic approach in clinical practice.

Published
2022

31. Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal

Author

Fabien Rollot, Justine Couturier, Romain Casey, Sandrine Wiertlewski, Marc Debouverie, Jean Pelletier, Jérôme De Sèze, Pierre Labauge, Aurélie Ruet, Eric Thouvenot, Jonathan Ciron, Eric Berger, Olivier Gout, Pierre Clavelou, Bruno Stankoff, Olivier Casez, Bertrand Bourre, Hélène Zephir, Thibault Moreau, Christine Lebrun-Frenay, Elisabeth Maillart, Gilles Edan, Jean-Philippe Neau, Alexis Montcuquet, Philippe Cabre, Jean-Philippe Camdessanché, Gilles Defer, Haifa Ben Nasr, Aude Maurousset, Karolina Hankiewicz, Corinne Pottier, Emmanuelle Leray, Sandra Vukusic, David-Axel Laplaud, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Fondation Eugène Devic EDMUS, Centre hospitalier universitaire de Nantes (CHU Nantes), CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance Publique - Hôpitaux de Marseille (APHM), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, CHU Saint-Antoine [AP-HP], Centre Hospitalier Universitaire [Grenoble] (CHU), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de recherche sur le cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Pitié-Salpêtrière [AP-HP], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Rennes], CHU Pontchaillou [Rennes], Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Service de Neurologie [CHU Limoges], Service de neurologie [Fort-de-France, Martinique], CHU de la Martinique [Fort de France], Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Sud Francilien Corbeil-Essonnes, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de neurologie [CH Saint Denis], Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier René Dubos [Pontoise], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), This study was supported by the Association ANTARES and OFSEP, which is supported by a grant provided by the French State and handled by the 'Agence Nationale de la Recherche,' within the framework of the 'Investments for the Future' program, under the reference ANR-10-COHO-002., ANR-10-COHO-0002,OFSEP,Observatoire Français de la Sclérose en Plaques(2010), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Marseille] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)

Subjects
Pharmacology, Flexible model, Fingolimod Hydrochloride, Natalizumab, [SDV]Life Sciences [q-bio], Effectiveness, Fingolimod, Therapeutics, Antigens, CD20, Anti-CD20, Multiple sclerosis, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Humans, Immunologic Factors, Pharmacology (medical), Original Article, Neurology (clinical), Immunosuppressive Agents
Abstract

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing–remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01202-1.

Published
2022
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33. Meningeal vein and subarachnoid FLAIR hyperintensities in polycythaemia vera

Author

Ioana Maria Ion, Eric Thouvenot, Marwane Cheriet, Dimitri Renard, Guerineau, Nathalie C., Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], General Medicine, radiology (diagnostics), neurology (drugs and medicines), [SDV] Life Sciences [q-bio], cancer - see oncology, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Jugular Veins, Polycythemia Vera, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Brachiocephalic Veins, Thrombocythemia, Essential
Abstract

International audience

Published
2022
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34. One-month humoral response following two or three doses of messenger RNA coronavirus disease 2019 vaccines as primary vaccination in specific populations in France: first results from the Agence Nationale Recherche contre le Sida (ANRS)0001S COV-POPART cohort

Author

Paul Loubet, Linda Wittkop, Laetitia Ninove, Mathieu Chalouni, Benoit Barrou, Jean-Yves Blay, Maryvonne Hourmant, Eric Thouvenot, Martine Laville, Bruno Laviolle, Jean-Daniel Lelievre, Jacques Morel, Stéphanie Nguyen Quoc, Jean-Philippe Spano, Benjamin Terrier, Anne Thiebaut, Jean-Francois Viallard, François Vrtovsnik, Sophie Circosta, Laure Esterle, Axel Levier, Philippe Vanhems, Eric Tartour, Beatrice Parfait, Xavier de Lamballerie, and Odile Launay

Subjects
Microbiology (medical), Infectious Diseases, General Medicine
Abstract

We aimed to investigate the 1-month humoral response to two or three doses of a messenger RNA coronavirus disease 2019 (COVID-19) vaccine as a primary vaccination regimen in specific populations compared with that in healthy adults.Agence Nationale Recherche contre le Sida (ANRS)0001S-COV-POPART (NCT04824651) is a French nation-wide, multi-centre, prospective, observational cohort study assessing the immune response to COVID-19 vaccines routinely administered to 11 sub-groups of patients with chronic conditions and two control groups. Patients and controls who received at least two vaccine doses and whose results 1 month after the second dose were available were included. The humoral response was assessed 1 month after the first, second and third doses (if applicable) based on the percentage of responders (positive for anti-Spike severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] IgG antibodies), geometric means of anti-Spike SARS-CoV-2 IgG antibodies (enzyme-linked immunosorbent assay) and proportion of participants with anti-SARS-CoV-2-specific neutralizing antibodies (in vitro neutralization assay for the original SARS-CoV-2 strain). All analyses were centralized.We included 4091 participants in this analysis: 2979 participants from specific sub-populations and 1112 controls. Only 522 (17.5%) participants from the specific populations received three doses as a primary vaccination regimen. Patients living with human immunodeficiency virus, cancer and diabetes had high percentages of responders after two doses, whereas patients with solid organ transplants, allogeneic hematopoietic stem cell transplants and hypogammaglobulinaemia had the lowest percentage of responders (35.9% [95% CI, 29.2-43.0], 57.4% [95% CI, 48.1-66.3] and 77.1% [95% CI, 65.6-86.3], respectively). In those who received the third dose, the percentage of responders reached 54.2% (95% CI, 42.9-65.2) (vs. 32.3% [95% CI, 16.7-51.4] after 2 doses) among those with solid organ transplants and 73.9% (95% CI, 58.9-85.7) (vs. 56.1% [95% CI, 46.2-65.7] after 2 doses) among those with hematopoietic stem cell transplants. Similar results were found with anti-SARS-CoV-2-specific neutralizing antibodies.A lower humoral response to COVID-19 vaccines was observed in the specific populations compared with that in the controls. The third dose of this vaccine in the primary regimen had a positive effect on the percentages of patients who developed anti-Spike IgG antibodies and specific neutralizing antibodies.

Published
2023
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36. Immune Profiling Reveals the T-Cell Effect of Ocrelizumab in Early Relapsing-Remitting Multiple Sclerosis

Author

Alexandra Garcia, Emilie Dugast, Sita Shah, Jérémy Morille, Christine Lebrun-Frenay, Eric Thouvenot, Jérôme De Sèze, Emmanuelle Le Page, Sandra Vukusic, Aude Maurousset, Eric Berger, Olivier Casez, Pierre Labauge, Aurélie Ruet, Catarina Raposo, Fabien Bakdache, Régine Buffels, Fabienne Le Frère, Arnaud Nicot, Sandrine Wiertlewski, Pierre-Antoine Gourraud, Laureline Berthelot, David Laplaud, Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre d’Investigation Clinique de Nantes (CIC Nantes), and Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
MESH: Leukocytes, Mononuclear, MESH: Humans, MESH: Multiple Sclerosis, Relapsing-Remitting, Neurology, MESH: Antibodies, Monoclonal, Humanized, [SDV]Life Sciences [q-bio], MESH: Multiple Sclerosis, Neurology (clinical)
Abstract

Background and ObjectivesOcrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology.MethodsA first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest.ResultsUsing an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4+T cells: one corresponding to naive CD4+T cells was increased, the other clusters corresponded to effector memory (EM) CD4+CCR6−T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8+T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8+CCR5+T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells.DiscussionOur study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5.

Published
2023
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37. Brain hemorrhage on 24h-CT and functional outcome in stroke patients with cerebral amyloid angiopathy features on pre-thrombolysis MRI treated with intravenous thrombolysis: A case series

Author

Adelina, Leonte, Sabine, Laurent-Chabalier, Anne, Wacongne, Teodora, Parvu, Marc, Hackius, Eric, Thouvenot, and Dimitri, Renard

Subjects
Rehabilitation, Surgery, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

In stroke patients treated with intravenous thrombolysis (IVT), presence and high number of strictly lobar cerebral microbleeds (compatible with cerebral amyloid angiopathy, CAA) seems to be associated with increased risk of hemorrhagic transformation, symptomatic hemorrhagic transformation, remote hemorrhage, and poor functional outcome. Some of these CAA patients with cerebral microbleeds also have chronic lobar intracerebral hemorrhage. Few data are available on IVT-treated CAA patients showing cortical superficial siderosis. There are no reports studying factors associated with brain hemorrhagic complication or functional outcome in IVT-treated CAA patients. We present a case series study of IVT-treated stroke patients with CAA features on pre-IVT MRI in whom we have evaluated brain hemorrhagic complications on 24 h-CT and functional outcome after IVT.In our stroke center, IVT decision in patients with CAA MRI features is at the physician's discretion. We retrospectively screened our stroke database between January 2015 and July 2022 for pre-IVT imaging of 959 consecutive IVT-treated stroke patients without ongoing anticoagulation therapy for probable CAA MRI features defined by modified Boston criteria. After exclusion of 119 patients with missing MRI (n = 47), MRI showing motion artefacts (n = 49) or with alternative chronic brain hemorrhage cause on MRI (n = 23), 15 IVT-treated patients with probable CAA on pre-IVT MRI were identified. In these 15 patients, clinical, biological and MRI characteristics were compared between patients with vs. without post-IVT hemorrhage and between patients with poor (MRS 3-6) vs. good (MRS 0-2) functional outcome at discharge.Two patients showed brain hemorrhage on 24 h-CT and both died after 40 and 31 days respectively. The remaining patients had no brain hemorrhage and showed very good outcome except one. Atrial fibrillation (p = 0.029) and Fazekas scale (p = 0.029) were associated with brain hemorrhage whereas atrial fibrillation (p = 0.0022), NIHSS (p = 0.027), blood glucose level (p = 0.024), CRP (p = 0.022) and DWI ASPECT (p = 0.016) were associated with poor outcome.Consequences of IVT in CAA patients can be dramatic. Larger studies are needed to compare IVT risks and outcome between CAA and non-CAA patients, also including CAA patients with chronic intracerebral hemorrhage or cortical superficial siderosis. In addition, future studies should try to identify clinical, biological and radiological features at high risk for brain hemorrhage and poor outcome in order to assess the risk-benefit ratio for IVT in CAA.http://www.gov. Unique identifier: NCT05565144.

Published
2023
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39. Stress response in dissociation and conversion disorders: A systematic review

Author

Philippe Courtet, Jorge Lopez-Castroman, Stéphane Mouchabac, Mocrane Abbar, Eric Thouvenot, Emilie Olié, Charlotte Boulet, Ismael Conejero, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Hypothalamo-Hypophyseal System, medicine.drug_class, Cognitive Neuroscience, [SDV]Life Sciences [q-bio], MEDLINE, Pituitary-Adrenal System, Dissociative Disorders, Autonomic Nervous System, Dissociative, Dissociation (psychology), Cortisol, Stress Disorders, Post-Traumatic, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Psychiatric history, medicine, Humans, Dissociative disorders, Conversion disorder, Stress regulation, Autonomous nervous system, business.industry, HPA axis, medicine.disease, 030227 psychiatry, 3. Good health, Dissociative disorder, Autonomic nervous system, Neuropsychology and Physiological Psychology, Systematic review, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Clinical psychology
Abstract

International audience; Dissociative disorders (DD) and conversion disorders (CD) are frequent in general and psychiatric populations. Some evidence suggest that the hypothalamic-pituitary axis (HPA) and autonomic nervous system (ANS) are dysregulated in both disorders. We carried out a systematic review of the literature to summarize the existing knowledge on the stress response, via HPA and/or ANS, in patients with DD, CD, or dissociative symptoms. We systematically searched Medline and Web of Science using the Medical Subject Headings related to stress axis, CD, DD, and dissociative symptoms following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results suggest that in participants without psychiatric history, high cortisol secretion is related to high dissociation scores. Conversely the stress system might be blunted in patients with post-traumatic stress disorder who develop dissociative symptoms. Stress response changes seem to be associated with the emergence and persistence of dissociative and conversion disorders. Hence, monitoring the stress response and examining closely the history of stress exposure in DD and CD should be encouraged in future larger studies.

Published
2021
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43. Neurofilament Light Chain Levels Are Predictive of Clinical Conversion in Radiologically Isolated Syndrome

Author

Manon Rival, Eric Thouvenot, Lucile Du Trieu de Terdonck, Sabine Laurent-Chabalier, Christophe Demattei, Ugur Uygunoglu, Giovanni Castelnovo, Mikael Cohen, Darin T. Okuda, Orhun H. Kantarci, Daniel Pelletier, Christina Azevedo, Philippe Marin, Sylvain Lehmann, Aksel Siva, Thibault Mura, and Christine Lebrun-Frenay

Subjects
Autoimmune Diseases of the Nervous System, Neurology, Oligoclonal Bands, Intermediate Filaments, Humans, Neurology (clinical), Biomarkers, Demyelinating Diseases
Abstract

Background and ObjectivesTo evaluate the predictive value of serum neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with radiologically isolated syndrome (RIS) for evidence of disease activity (EDA) and clinical conversion (CC).MethodssNfL and cNfL were measured at RIS diagnosis by single-molecule array (Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using the Kaplan-Meier analysis and multivariate Cox regression models including age, spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase 3–like protein 1, and CSF white blood cells.ResultsSixty-one patients with RIS were included. At diagnosis, sNfL and cNfL were correlated (Spearman r = 0.78,p< 0.001). During follow-up, 47 patients with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1–86). When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0 pg/mL) levels were predictive of EDA (log rank,p< 0.01 andp= 0.02, respectively). Medium-high cNfL levels were predictive of CC (log rank,p< 0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA, while SC lesions, cNfL, and sNfL were independent factors of CC.DiscussioncNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity better, sNfL is more accessible than cNfL and can be considered when a lumbar puncture is not performed.Classification of EvidenceThis study provides Class II evidence that in people with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are associated with subsequent evidence of disease activity or clinical conversion.

Published
2022
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44. Reversible corticosubcortical FLAIR hypointensity in transient focal neurological episode

Author

Emilia El Houjeiry, Eric Thouvenot, Dimitri Renard, Morgane Petot, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Retiveau, Nolwenn

Subjects
medicine.medical_specialty, Subarachnoid hemorrhage, Neuroimaging, Fluid-attenuated inversion recovery, MESH: Stroke, MESH: Magnetic Resonance Imaging, Medicine, Humans, Transient (computer programming), Sensory symptoms, MESH: Neuroimaging, Stroke, MESH: Humans, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, General Medicine, Left upper limb, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, body regions, Radiology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; A 69-year-old woman presented with transient spreading sensory symptoms in the left upper limb compatible with a transient focal neurological episode (TFNE). MRI performed 3.5 hours later revealed an acute focal right rolandic convexity subarachnoid hemorrhage (cSAH), seen as hyperintensity on fluid-attenuated inversion recovery (FLAIR; figure 1A–C, arrows) and as hypointensity on T2*-weighted imaging (figure 1D, arrow). Associated FLAIR hypointensities were observed in the corticosubcortical brain areas adjacent to the cSAH (figure 1A–C, arrowheads), with a mean signal intensity of 139 in the visually involved right perirolandic corticosubcortical area compared with a mean signal intensity of 174 in the contralateral left perirolandic corticosubcortical mirror area. Diffusion-weighted imaging (and apparent diffusion coefficient) were strictly normal. Multifocal cortical superficial siderosis on T2*-weighted imaging (figure 1E,F, arrowheads) evoked underlying cerebral amyloid angiopathy (radiological abnormalities corresponded to possible cerebral amyloid angiopathy according to the modified Boston criteria). Two weeks later, the subarachnoid and adjacent corticosubcortical FLAIR signal changes normalised (figure 1G–I), with a mean signal intensity of the corresponding earlier involved perirolandic corticosubcortical area of 172 on the right and 173 on the left side.

Published
2021
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46. Increased Prevalence of Neurocognitive Impairment in Aging People Living With Human Immunodeficiency Virus: The ANRS EP58 HAND 55–70 Study

Author

Pascale Leclercq, Christian Geny, Jonathan Dubois, Mélanie Simony, Claudine Barbuat, Sabrina Eymard-Duvernay, Alain Makinson, Louis Bernard, Matteo Vassallo, Anna Ozguler, Jacques Reynes, Marie Zins, Dominique Costagliola, Claudine Berr, Eric Thouvenot, Olivia Zaegel-Faucher, Berr, Claudine, Infrastructures - La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance - - CONSTANCES2011 - ANR-11-INBS-0002 - INBS - VALID, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité des Maladies Infectieuses [CHU Grenoble-Alpes], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Fédération d’Infectiologie Multidisciplinaire de l’Arc Alpin [CHU Grenoble-Alpes], Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service de Médecine Interne et Maladies Infectieuses [Tours], Service de Médecine Interne [CH Cannes], Centre Hospitalier de Cannes (CH Cannes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), ANRS France Recherche Nord & sud Sida-hiv hépatites, This study was supported by France Recherche Nord & Sud Sida-VIH Hépatites (ANRS). A donation was also given by Merck & Co. The CONSTANCES Cohort Study is an Infrastructure nationale en Biologie et Santé and benefits from a grant from ANR (ANR-11-INBS-0002). This study was sponsored by Inserm-ANRS (Institut national de la santé et de la recherché médicale - France Recherche Nord & Sud Sida-VIH Hépatites)., ANR-11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique, Université Grenoble Alpes (UGA), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), UMS011 Cohortes épidémiologiques en population (CONSTANCES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), ANR-11-INBS-0002/11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, Microbiology (medical), medicine.medical_specialty, Lymphocyte, HIV Infections, HAND, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Prevalence, neurocognitive impairment, medicine, Humans, 030212 general & internal medicine, Aged, business.industry, aging, Confounding, HIV, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Odds ratio, Middle Aged, Confidence interval, 3. Good health, Clinical trial, Cross-Sectional Studies, Infectious Diseases, medicine.anatomical_structure, Cohort, Female, Frascati criteria, business, Neurocognitive, Viral load, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery
Abstract

Background There are limited data on the comparative prevalence of neurocognitive impairment (NCI) in aging people living with human immunodeficiency virus (PLHIV) and people not living with HIV. Methods This was a cross-sectional study of PLHIV randomly matched by age (±4 years), gender, and education with 5 HIV-uninfected individuals from the CONSTANCES cohort. PLHIV were fluent in French and sequentially included during routine outpatient visits if aged 55–70 years, with HIV viral load Results Two hundred PLHIV were matched with 1000 controls. Median age was 62 years, and 85% were men. In PLHIV, the median T-CD4 lymphocyte level was 650 cells/µL, and median nadir T-CD4 lymphocyte level was 176 cells/µL. NCI was found in 71 (35.5%) PLHIV and in 242 (24.2%) controls (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.25, 2.41). After adjusting for confounders, HIV remained significantly associated with NCI (OR, 1.50; 95% CI, 1.04, 2.16). Adjusted results were similar with NCI defined by MNC (ORMNC, 2.95; 95% CI, 1.13, 3.50) or −1.5 SD (OR−1.5, 2.24; 95% CI, 1.39, 3.62). Conclusions In this matched study of aging individuals, HIV was significantly associated with an increased risk of NCI after adjusting for major confounders. Results were confirmed with more stringent NCI classifications. Clinical Trials Registration NCT02592174.

Published
2019
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47. Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study

Author

Carole Henry, Sandra Vukusic, Alexis Montcuquet, Clarisse Gagou-Scherer, Mikael Cohen, Bruno Brochet, Nathalie Derache, Alvaro Cobo-Calvo, David Brassat, Caroline Papeix, Philippe Kerschen, Françoise Durand-Dubief, Jonathan Ciron, Nicolas Collongues, Hélène Zéphir, Nicolas Maubeuge, Thibault Moreau, Romain Deschamps, Aude Maurousset, Romain Marignier, Matthieu Bereau, Fabien Rollot, Eric Thouvenot, Clarisse Carra-Dalliere, Christophe Prat, David Laplaud, Frederic Taithe, Ayman Tourbah, Elisabeth Maillart, Bertrand Bourre, Guillaume Mathey, Bertrand Audoin, Département de Neurologie [Toulouse], Institut des Neurosciences [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de neurologie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Neurologie [CHU Limoges], CHU Limoges, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier d'Angoulême (CH Angoulême), CHU Clermont-Ferrand, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de neurologie [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Psychopathologie et Neuropsychologie (LPN), Université Paris 8 Vincennes-Saint-Denis (UP8), Université de Lyon, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Myelitis, MESH: Myelitis / physiopathology, Prognosis, Registries, Retrospective Studies, Severity of Illness Index, Young Adult, Transverse myelitis, Myelin oligodendrocyte glycoprotein, 03 medical and health sciences, Myelin, 0302 clinical medicine, MESH: Adult, Aged, Autoantibodies, Disease Progression, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Medicine, 10. No inequality, 030304 developmental biology, 0303 health sciences, biology, business.industry, Multiple sclerosis, Middle Aged, medicine.disease, 3. Good health, medicine.anatomical_structure, Neurology, Cohort, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Myelin-Oligodendrocyte Glycoprotein, Neurology (clinical), MESH: Male, Myelin-Oligodendrocyte Glycoprotein / immunology, Myelitis / diagnosis, Myelitis / immunology, Myelitis / pathology, Antibody, business, 030217 neurology & neurosurgery
Abstract

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), p = 0.007 and p = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p 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.

Published
2019
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48. Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions

Author

Thierry Vincent, A.-M. Guennoc, Pierre Labauge, Anne Kerbrat, François Cotton, Stéphane Kremer, Béatrice Carsin-Nicol, Mahmoud Charif, Sandra Vukusic, Thibaut Allou, Jérôme De Seze, Aurélie Ruet, Laurent Magy, Nicolas Menjot de Champfleur, Clarisse Carra-Dalliere, Guido Ahle, Eric Thouvenot, Françoise Durand-Dubief, Hélène Oesterle, Valérie Rigau, Denis Sablot, Romain Marignier, Nicolas Collongues, Gilles Edan, Mikael Cohen, Sonia Hebbadj, Benoit Lhermitte, Frederic Taithe, M. P. Boncoeur-Martel, Xavier Ayrignac, Grelier, Elisabeth, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Département d’Immunologie, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service de radiologie [Strasbourg], Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Hôpitaux Civils de Colmar, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), RMN et optique : De la mesure au biomarqueur, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pierre Wertheimer, Département de Neurologie, Service de Neurologie [Lyon], CHU Lyon, Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Pasteur [Nice] (CHU), Service de Neurologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Service de neurologie [Rennes], Université de Rennes (UR), Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Neuroinflammation: imagerie et thérapie de la sclérose en plaques, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Radiologie et Imagerie Médicale [CHU Limoges], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Atypical inflammatory demyelinating syndrome, medicine.medical_specialty, Pathology, Multiple Sclerosis, Histopathology, Context (language use), Immunopathology, Cohort Studies, Lesion, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Pathological, Aged, Retrospective Studies, Neuroradiology, Aquaporin 4, medicine.diagnostic_test, business.industry, Multiple sclerosis, Brain biopsy, Neuromyelitis Optica, food and beverages, Magnetic resonance imaging, Middle Aged, medicine.disease, Atypical demyelinating lesions, Magnetic Resonance Imaging, 3. Good health, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Acute Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Neurology (clinical), medicine.symptom, business, Aquaporin-4, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract

The diagnosis of atypical inflammatory demyelinating lesions can be difficult. Brain biopsy is often required to exclude neoplasms. Moreover, the relationship between these lesions and multiple sclerosis and NMOSD is not clear. Our objectives were to describe radiological and pathological characteristics of patients with acute inflammatory demyelinating lesions. We retrospectively identified patients with brain biopsy performed for diagnostic uncertainty revealing a demyelinating lesion. A complete clinical, biological, radiological and pathological analysis was performed. Twenty patients (15 with a single lesion) were included. MRI disclosed a wide range of lesions including infiltrative lesions (40%), ring-like lesion (15%) Balo-like lesion (15%) and acute haemorrhagic leukoencephalitis (20%). In spite of a marked heterogeneity, some findings were common: a peripheral B1000 hyperintense rim (70%), a slight oedema with mild mass effect (75%) and an open-rim peripheral enhancement (75%). Histopathology revealed that all cases featured macrophages distributed throughout, extensive demyelination, axonal preservation and absence of haemorrhagic changes. In the majority of cases, macrophages were the predominant inflammatory infiltrate and astrocytes were reactive and dystrophic. Aquaporin-4 staining was systematically preserved. After a mean follow-up of 5 years (1–12), 16/20 patients had a diagnosis of monophasic acute atypical inflammatory demyelinating lesion. One patient was diagnosed with MS and 3 with AQP4 negative NMOSD. Although imaging findings in patients with atypical inflammatory demyelinating lesions are heterogeneous, some common features such as peripheral DWI hyperintense rim with open-rim enhancement and absence of oedema argue in favour of a demyelinating lesion and should preclude a brain biopsy. In this context, AQP4 staining is systematically preserved and argues against an AQP4-positive NMOSD. Moreover, long-term follow-up is characterized by low recurrence rate.

Published
2019
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49. Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults

Author

Nuria Sola-Valls, Sandra Vukusic, Françoise Durand-Dubief, Eric Thouvenot, Damien Biotti, Hélène Zéphir, Sara Llufriu, Caroline Papeix, Elisabeth Maillart, Romain Deschamps, Nicolas Collongues, Albert Saiz, Pierre Labauge, Alexis Montcuquet, Anne Ruiz, Thaís Armangue, Alvaro Cobo-Calvo, Maria S. Sepúlveda, Xavier Ayrignac, Bertrand Audoin, Jérôme De Seze, Hyacintha d'Indy, Yolanda Blanco, Romain Marignier, Jonathan Ciron, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Sant Joan de Déu-Barcelona Children's Hospital's, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Neurologie [Hôpital Roger Salengro], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Neurologie [Toulouse], Institut des Neurosciences [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHU Limoges], CHU Limoges, Fondation Ophtalmologique Adolphe de Rotschild, Clinical and experimental neuroimmunology [IDIBAPS], Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospices Civils de Lyon, Departement de Neurologie (HCL), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, Visual acuity, Optic neuritis, Logistic regression, Gastroenterology, 0302 clinical medicine, Recurrence, immune system diseases, Medicine, 030212 general & internal medicine, 10. No inequality, First episode, hemic and immune systems, Middle Aged, Myelitis, Prognosis, Neuromyelitis optica, 3. Good health, Titer, MESH: Autoantibodies / blood, Demyelinating diseases / immunology, HEK293 Cells, Young Adults, Neurology, Titre, Cohort, Disease Progression, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biological Assay, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, medicine.medical_specialty, Adolescent, MOG antibodies, Young Adult, 03 medical and health sciences, Internal medicine, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Autoantibodies, Retrospective Studies, business.industry, Proportional hazards model, Retrospective cohort study, medicine.disease, nervous system diseases, nervous system, Myelin-Oligodendrocyte Glycoprotein, Neurology (clinical), business, 030217 neurology & neurosurgery, Demyelinating Diseases, Follow-Up Studies
Abstract

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 MFI) by flow cytometry. MOG-ratio MFI was calculated as follows: (MFI tHEK293cells- MFI non-tHEK293cells)/MFI non-tHEK293cells. MOG-ratio MFI 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 MFI. 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 MFI correlated with MOG-Ab titres in the whole cohort (? = 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 MFI is an alternative and straightforward method to determine MOG-Ab levels.

Published
2019
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50. Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder

Author

Sébastien Guillaume, Eric Thouvenot, Thibault Mura, Isabelle Jaussent, S. Squalli, E. Le Bars, Ismael Conejero, Emilie Olié, Philippe Courtet, Aurélie Cazals, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Adult, Oncology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Interleukin-1beta, Prefrontal Cortex, Suicide, Attempted, Gyrus Cinguli, Suicidal Ideation, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Neuroimaging, Functional neuroimaging, Internal medicine, medicine, Humans, Social Behavior, Biological Psychiatry, Anterior cingulate cortex, Cerebral Cortex, Inflammation, Depressive Disorder, Major, Interleukin-6, Tumor Necrosis Factor-alpha, Endocrine and Autonomic Systems, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Magnetic Resonance Imaging, 030227 psychiatry, Suicide, Psychiatry and Mental health, Distress, Mood, medicine.anatomical_structure, Psychological Distance, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cytokines, Interleukin-2, Female, Orbitofrontal cortex, business, Insula, 030217 neurology & neurosurgery
Abstract

Background Neuroimaging studies suggest that social distress and suicidal vulnerability share common cerebral bases. Moreover, increased peripheral inflammatory activity is involved in both social distress and suicidal behavior. Objective To evaluate, in suicidal and non-suicidal individuals, the association between the activation of specific cerebral regions (anterior cingulate, insula and orbitofrontal cortex) during experimental social exclusion and the baseline blood levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) and of the anti-inflammatory cytokine interleukin-2 (IL-2). Methods In total, 101 euthymic women were recruited: 42 suicide attempters (SA), 40 affective controls (AC), and 19 healthy controls (HC). During functional MRI (fMRI), they performed the Cyberball game, a validated social exclusion task. Blood levels of IL-1β, IL-6, TNF-α and IL-2 were measured prior to fMRI. The activation of insula, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) during the explicit social exclusion (ESE) vs social inclusion (INC) conditions of the Cyberball game was analyzed in function of the baseline cytokine levels. Results IL-1β was negatively associated with right OFC activation (p = 0.01) in ESE vs. INC, whereas IL-2 was positively associated with activation of the right ACC (p = 0.02), insula (p = 0.002) and OFC (p = 0.004) in ESE vs. INC. These associations remained significant after controlling for group, indicating that they were independent of the suicidal status. Conclusion Baseline IL-1β and IL-2 blood levels are differentially associated with cerebral activation involved in the perception of social exclusion, independently of suicidal behavior. Our results may help to better understand the role of basal inflammation in social distress and its link with mood disorder pathophysiology.

Published
2019
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