Publications by authors named "Clarisse Carra-Dalliere"

45 Publications

Cerebral Vasoreactivity as an Indirect MRI Marker of White Matter Tracts Alterations in Multiple Sclerosis.

Brain Topogr 2021 Mar 23;34(2):245-255. Epub 2021 Jan 23.

Department of Neuroradiology, University Hospital Center, I2FH, Institut d'Imagerie Fonctionnelle Humaine, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Cedex 5, Montpellier, France.

Patients with multiple sclerosis (MS) show a diffuse cerebral perfusion decrease, presumably related to multiple metabolism and vascular alterations. It is assumed that white matter fiber alterations cause a localized cerebral vasoreactivity (CVR) disruption through astrocytes metabolism alteration, leading to hypoperfusion. We proposed to (1) evaluate the CVR disruptions in MS, (2) in relation to white matter lesions and (3) compare CVR disruptions maps with standard imaging biomarkers. Thirty-five MS patients (10 progressive, 25 relapsing-remitting) and 22 controls underwent MRI with hypercapnic challenge, DTI imaging and neuropsychological assessment. Areas with disrupted CVR were assessed using a general linear model. Resulting maps were associated with clinical scores, compared between groups, and related to DTI metrics and white matter lesions. MS patients showed stronger disrupted CVR within supratentorial white matter, linking the left anterior insula to both the precentral gyrus and the right middle and superior frontal gyrus through the corpus callosum (P < 0.05, FWE corrected). Patient's verbal intellectual quotient was negatively associated with a pathway linking both hippocampi to the ispilateral prefrontal cortex (P < 0.05, FWE corrected). Disrupted CVR maps unrelated to DTI metrics and white matter lesions. We have demonstrated for the first time that white matter alterations can be indirectly identified through surrounding vessel alterations, and are related to clinical signs of MS. This offers a new, likely independent marker to monitor MS and supports a mediator role of the astrocytes in the fibers/vessels relationship.
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http://dx.doi.org/10.1007/s10548-021-00819-3DOI Listing
March 2021

First line treatment failure: Predictive factors in a cohort of 863 Relapsing Remitting MS patients.

Mult Scler Relat Disord 2021 Feb 13;48:102686. Epub 2020 Dec 13.

CRC SEP, Montpellier University Hospital, INSERM, Univ Montpellier, Montpellier. Electronic address:

Background: The advent of new, potent, disease-modifying therapies has dramatically changed the management of multiple sclerosis (MS). Along with these possibilities, it is crucial to better recognize patients who are at risk of first line treatment (FLT) failure and switch to highly effective therapies (HET).

Objectives: To identify baseline prognostic factors associated with FLT failure in relapsing remitting MS (RR-MS) patients.

Methods: We included recently diagnosed RR-MS patients starting an FLT identified from 3 French MS centers databases. Baseline characteristics were included in a multivariable Cox analysis to identify the main factors associated with FLT failure.

Results: Eight hundred sixty-three patients were included. We observed an overall rate of treatment failure of 23.5%. The main baseline characteristics associated with treatment failure were age <26 years at treatment start (HR= 2.1, p<0.001), EDSS ≥2 (HR=2.1, p<0.001) and ≥2relapses in the previous year (HR=1.5, p=0.04). The association with the presence of gadolinium enhancement on MRI was not statistically significant. EDSS progression was only significantly associated with age at treatment start and treatment failure.

Conclusion: Our series demonstrates that some clinical and imaging factors are associated with treatment failure, and should be considered when planning treatment strategy in patients with recently diagnosed RR-MS.
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http://dx.doi.org/10.1016/j.msard.2020.102686DOI Listing
February 2021

Pregnancy in MNGIE: a clinical and metabolic honeymoon.

Ann Clin Transl Neurol 2020 12 7;7(12):2484-2488. Epub 2020 Nov 7.

Département de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an inherited disease caused by a deficiency in thymidine phosphorylase and characterized by elevated systemic deoxyribonucleotides and gastrointestinal (GI) and neurological manifestations. We report the clinical and biochemical manifestations that were evaluated in a single patient before, during, and after pregnancy, over a period of 7 years. GI symptoms significantly improved, and plasma deoxyribonucleotide concentrations decreased during pregnancy. Within days after delivery, the patient's digestive symptoms recurred, coinciding with a rapid increase in plasma deoxyribonucleotide concentrations. We hypothesize that the clinico-metabolic improvements could be attributed to the enzyme replacement action of the placental thymidine phosphorylase.
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http://dx.doi.org/10.1002/acn3.51202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732247PMC
December 2020

POLR3-related disorder revealed by movement disorders.

Rev Neurol (Paris) 2021 Mar 28;177(3):328-330. Epub 2020 Sep 28.

MS Unit and Reference Center for adult-onset leukoencephalopathies (MT, PP, XA, CCD, PL) and department of Neurology (VG), Montpellier University Hospital, Gui de Chauliac, 34295 Montpellier cedex 5, France. Electronic address:

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http://dx.doi.org/10.1016/j.neurol.2020.06.013DOI Listing
March 2021

Serum GFAP in multiple sclerosis: correlation with disease type and MRI markers of disease severity.

Sci Rep 2020 07 2;10(1):10923. Epub 2020 Jul 2.

Laboratoire de Biochimie-Protéomique Clinique, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, France.

Neurofilament light chain (NfL) has been demonstrated to correlate with multiple sclerosis disease severity as well as treatment response. Nevertheless, additional serum biomarkers are still needed to better differentiate disease activity from disease progression. The aim of our study was to assess serum glial fibrillary acid protein (s-GFAP) and neurofilament light chain (s-NfL) in a cohort of 129 multiple sclerosis (MS) patients. Eighteen primary progressive multiple sclerosis (PPMS) and 111 relapsing remitting MS (RRMS) were included. We showed that these 2 biomarkers were significantly correlated with each other (R = 0.72, p < 0.001). Moreover, both biomarkers were higher in PPMS than in RRMS even if multivariate analysis only confirmed this difference for s-GFAP (130.3 ± 72.8 pg/ml vs 83.4 ± 41.1 pg/ml, p = 0.008). Finally, s-GFAP was correlated with white matter lesion load and inversely correlated with WM and GM volume. Our results seem to confirm the added value of s-GFAP in the context of multiple sclerosis.
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http://dx.doi.org/10.1038/s41598-020-67934-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331703PMC
July 2020

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Brain 2020 07;143(7):2089-2105

NeuroPoly Lab, Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Canada.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.
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http://dx.doi.org/10.1093/brain/awaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364770PMC
July 2020

From Baló's concentric sclerosis to multiple sclerosis: a series of 6 patients.

Mult Scler Relat Disord 2020 Jul 4;42:102078. Epub 2020 May 4.

Clinique de Sclérose en plaques du Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), and department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Introduction: Baló's concentric sclerosis (BCS) is a rare CNS disorder characterized by alternating bands of demyelination on MRI. One of the main issues is its relationship with multiple sclerosis (MS).

Objectives: To describe 6 BCS patients. To review the risk of developing MS in BCS patients.

Methods: We retrospectively recorded clinical and radiological findings of 6 BCS patients and performed a review of the literature.

Results: Six patients (5 women) with a mean age of 25 years old were included. Main symptoms were hemiparesis/hemihypoesthesia. On MRI, two patients had a single BCS lesion and four had additional MS-like lesions. Alternating bands were usually more visible on DWI. A patient had reduced central perfusion and SWI hypointensity suggestive of a central vein. Oligoclonal bands were identified in 5/6 patients. After 7 years of follow-up, all patients achieved MS criteria with mild disability (mean EDSS 1.75; 0-4). Our literature review included 65 BCS patients from 30 studies: although CSF oligoclonal bands and the presence of additional MS lesions were associated with subsequent relapses, this was not significant.

Discussion/conclusion: Our series allows a detailed MRI description in BCS and gives a new insight into BCS evolution and its strong relationship with MS.
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http://dx.doi.org/10.1016/j.msard.2020.102078DOI Listing
July 2020

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

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

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

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

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

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

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

MRI features of demyelinating disease associated with anti-MOG antibodies in adults.

J Neuroradiol 2019 Sep 20;46(5):312-318. Epub 2019 Jun 20.

Neuroradiology department, Pierre-Paul-Riquet/Purpan university hospital, 31300 Toulouse, France. Electronic address:

The spectrum of Myelin Oligodendrocytes Glycoprotein (MOG) antibody disease constitutes a recently described challenging entity, referring to a relatively new spectrum of autoimmune disorders with antibodies against MOG predominantly involving the optic nerve and spinal cord. The purpose of this article is to describe MRI features of MOG-AD involvement in the optic nerves, spinal cord and the brain of adults.
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http://dx.doi.org/10.1016/j.neurad.2019.06.001DOI Listing
September 2019

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

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

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

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

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

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

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

Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions.

J Neurol 2019 Jul 23;266(7):1743-1755. Epub 2019 Apr 23.

Department of Radiology, Strasbourg University Hospital, Strasbourg, France.

Background: 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.

Objectives: Our objectives were to describe radiological and pathological characteristics of patients with acute inflammatory demyelinating lesions.

Methods: 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.

Results: Twenty patients (15 with a single lesion) were included. MRI disclosed a wide range of lesions including infiltrative lesions (40%), ring-like lesion (15%) Baló-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.

Discussion: 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.
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http://dx.doi.org/10.1007/s00415-019-09328-7DOI Listing
July 2019

Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome.

Mult Scler J Exp Transl Clin 2019 Jan-Mar;5(1):2055217319836664. Epub 2019 Mar 20.

Department of Neurology, Keck School of Medicine of University of Southern California, USA.

Background: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination.

Objectives: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome.

Methods: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria.

Results: Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4-88.2%) versus 72.7% (49.8-89.3%); specificity 83.3% (58.6-96.4%) versus 53.9% (37.2-69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1-93.2%) versus 100% (84.6-100%); specificity 72.7% (49.8-89.3%) versus 25.6% (13.0-42.1%).

Conclusions: Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.
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http://dx.doi.org/10.1177/2055217319836664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429663PMC
March 2019

First clinical inflammatory demyelinating events of the central nervous system in a population aged over 70 years: A multicentre study.

Mult Scler Relat Disord 2019 Feb 14;28:309-312. Epub 2018 Dec 14.

Service de Neurologie, CHU de Bordeaux, Place Amélie Raba Léon, F-33076, Bordeaux, France. Electronic address:

Background: Few data are available regarding patients with very late-onset inflammatory demyelinating events. (VLO-IDE).

Objectives: The aim of this study was to describe the clinical, biological, and radiological characteristics and aetiological diagnosis of very late first inflammatory demyelinating events of the central nervous system.

Methods: We conducted a national descriptive retrospective multicentre study on a case series of patients aged >70 years at the time of VLO-IDE. Patients were recruited from a national call on behalf of the 'Société Francophone de la Sclérose en Plaques' (French Multiple Sclerosis Society).

Results: Twenty-five patients were referred (F:M sex ratio 2.1:1). The most frequent clinical impairment was a spinal cord deficit (23/25), usually severe (disability score, median EDSS 4.5 [2-9.5]). Spinal cord lesions were usually extensive, spanning at least three segments (11/25), and large brain lesions were also observed (lesions >20 mm in 6/25). The final aetiological diagnoses comprised multiple sclerosis (9/25), neuromyelitis optica spectrum disorders (7/25), neurosystemic lupus erythematosus (2/25), transverse myelitis without aetiological diagnosis (6/25) and optic neuritis (1/25).

Conclusions: This study highlights a particular phenotype of first clinical inflammatory demyelinating events in predominantly female patients aged >70 years who have severe motor impairment with common longitudinal extensive myelitis and large and common very active radiological inflammatory lesions. Neuromyelitis optica spectrum disorders seem overrepresented.
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http://dx.doi.org/10.1016/j.msard.2018.12.016DOI Listing
February 2019

Multiple sclerosis with atypical MRI presentation: Results of a nationwide multicenter study in 57 consecutive cases.

Mult Scler Relat Disord 2019 Feb 18;28:109-116. Epub 2018 Dec 18.

MS Center and National Reference Center of adult Leukodystrophies, Department of Neurology, Montpellier University Hospital, 34 295 Montpellier Cedex 5, France. Electronic address:

Background: The recent 2017 modification have increased the sensitivity of McDonald criteria for MS. Nevertheless, some MS patients with atypical MRI findings have been identified, leading to prolonged delay to diagnosis and high costs to look for alternative diagnoses.

Objective: To describe a series of MS patients with atypical MRI presentation.

Material And Methods: Patients with atypical MS were identified through a nationwide retrospective study. We established a five groups classification: tumefactive demyelinating lesion (TDL)-onset MS, acute disseminated encephalomyelitis (ADEM)-like MS, cavitary MS and leukodystrophy-like MS. All the patients meeting our radiological criteria for atypical MS were included.

Results: A total of 57 patients met the inclusion criteria. 7 cases were classified in the TDL-onset group, 10 in the ADEM-like group, 26 in the cavitary group and 14 in the leukodystrophy-like group. Overall risk of conversion to MS after an isolated TDL was around 30% at five years. Patients in the TDL-onset and ADEM-like groups globally presented an acute onset and a relapsing-remitting evolution. Conversely, patients in the cavitary and leukodystrophy- groups largely evolved with a progressive and severe course.

Conclusion: A significant number of MS patients can have a striking atypical presentation and may be misdiagnosed. This preliminary analysis helps to refine the spectrum of atypical MS patients.
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http://dx.doi.org/10.1016/j.msard.2018.12.022DOI Listing
February 2019

Optic chiasm and oculomotor nerves involvement in active multiple sclerosis.

J Neuroradiol 2020 Feb 10;47(1):62-64. Epub 2018 Nov 10.

Department of neurology, Montpellier university hospital, Gui de Chauliac hospital, 34295 Montpellier cedex 5, France.

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http://dx.doi.org/10.1016/j.neurad.2018.10.007DOI Listing
February 2020

The coexistence of recurrent cerebral tumefactive demyelinating lesions with longitudinally extensive transverse myelitis and demyelinating neuropathy.

Mult Scler Relat Disord 2019 Jan 3;27:223-225. Epub 2018 Nov 3.

Department of Neurology, CHU Montpellier, 80 avenue Augustin Fliche, Montpellier 34000, France.

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. In this article, we report on a CCPD patient with a very unusual pattern of central demyelination, comprising recurrent cerebral tumefactive demyelinating lesions (three times, each one in a new area of the brain) and one episode of longitudinally extensive transverse myelitis. This patient could not be classified as having multiple sclerosis, or neuromyelitis optica spectrum disorder, or any other well-known inflammatory disorder of the central nervous system, associated with demyelinating neuropathy. A diagnosis of idiopathic inflammatory demyelinating disorder (IIDD) was made while waiting for more knowledge concerning the diseases currently characterized as IIDD.
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http://dx.doi.org/10.1016/j.msard.2018.11.002DOI Listing
January 2019

Measurement of magnetization transfer ratio (MTR) from cervical spinal cord: Multicenter reproducibility and variability.

J Magn Reson Imaging 2019 06 22;49(6):1777-1785. Epub 2018 Oct 22.

Univ Rennes, Inria, CNRS, Inserm, IRISA UMR 6074, Visages, U1128, France.

Background: Assessing the multicenter variability of magnetization transfer ratio (MTR) measurements in the spinal cord of healthy controls is the first step toward investigating its clinical use as a biomarker.

Purpose: To analyze the between-session, between-participant, and between-scanner variability of MTR measurements in automatically extracted regions of interest in the cervical cord of healthy controls.

Study Type: Control study.

Population: Forty-four participants, distributed across five MRI scanners (all from the same manufacturer). Ten participants were scanned twice in the same scanner, and 10 others were scanned twice in two different scanners.

Field Strength/sequence: 3D-gradient echo images, centered on C5, without and with magnetization transfer prepulse at 3T.

Assessment: We calculated the mean MTR for different vertebral levels in the whole cord (WC), as well as in the white matter and gray matter, and determined the between-session, between-participant, and between-scanner variabilities.

Statistical Tests: Coefficients of variation and intraclass correlations (ICCs) for the different variabilities and their associated confidence intervals.

Results: The MTR measurements for Levels C4-C6 (near the slab center) exhibited a mean value in WC of 34.6 pu and a pooled standard deviation of 0.9 pu. The between-session coefficient of variation was estimated as 2.3% (ICC = 0.63), the between-participant coefficient as 1.6% (ICC = 0.32), and the between-scanner coefficient as 0.7% (ICC = 0.05). The resulting aggregate coefficient of variation was 2.9%, which was sufficiently low to detect an MTR reduction of 1 pu between groups of about 45 participants (Type-I error rate: 0.05; Type-II error rate: 0.10).

Data Conclusion: The good between-scanner reproducibility and low overall variability in cervical spinal cord MTR measurements in a control population might pave the way for multicenter analyses in various neurological diseases with moderate cohort sizes.

Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1777-1785.
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http://dx.doi.org/10.1002/jmri.26537DOI Listing
June 2019

Focal and diffuse cervical spinal cord damage in patients with early relapsing-remitting MS: A multicentre magnetisation transfer ratio study.

Mult Scler 2019 07 18;25(8):1113-1123. Epub 2018 Jun 18.

IRISA, UMR CNRS 6074, VisAGeS U1228, INSERM, INRIA, Université Rennes I, Rennes, France.

Background: Studies including patients with well-established multiple sclerosis (MS) have shown a significant and disability-related reduction in the cervical spinal cord (SC) magnetisation transfer ratio (MTR).

Objectives: The objectives are to (1) assess whether MTR reduction is already measurable in the SC of patients with early relapsing-remitting multiple sclerosis (RRMS) and (2) describe its spatial distribution.

Methods: We included 60 patients with RRMS <12  months and 34 age-matched controls at five centres. Axial T2*w, sagittal T2w, sagittal phase-sensitive inversion recovery (PSIR), 3DT1w, and axial magnetisation transfer (MT) images were acquired from C1 to C7. Lesions were manually labelled and mean MTR values computed both for the whole SC and for normal-appearing SC in different regions of interest.

Results: Mean whole SC MTR was significantly lower in patients than controls (33.7 vs 34.9  pu,   =  0.00005), even after excluding lesions (33.9  pu,   =  0.0003). We observed a greater mean reduction in MTR for vertebral levels displaying the highest lesion loads (C2-C4). In the axial plane, we observed a greater mean MTR reduction at the SC periphery and barycentre.

Conclusion: Cervical SC tissue damage measured using MTR is not restricted to macroscopic lesions in patients with early RRMS and is not homogeneously distributed.
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http://dx.doi.org/10.1177/1352458518781999DOI Listing
July 2019

Efficacy of rituximab in refractory RRMS.

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

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

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

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

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

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

Late activity rebound in non-active multiple sclerosis: A rare event.

Mult Scler 2018 10 13;24(12):1649-1650. Epub 2018 Mar 13.

1 Department of Neurology, Montpellier University Hospital, Montpellier, France.

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http://dx.doi.org/10.1177/1352458518765670DOI Listing
October 2018

Psychological processes associated with insomnia in patients with multiple sclerosis.

Sleep 2018 03;41(3)

Epsylon Laboratory Dynamic of Human Abilities and Health Behaviors, University of Montpellier, Montpellier, France.

Study Objectives: Despite the high comorbidity of insomnia disorder (ID) with multiple sclerosis (MS), the relevance of psychological processes involved in the maintenance of insomnia is yet to be established in this neurological disorder. This study aimed to ascertain to what extent the suggested emotional, cognitive, and behavioral processes maintaining insomnia are relevant in people with insomnia and MS.

Methods: A between-subjects design was used to compare 26 patients with insomnia and MS, with 31 patients with MS only, and with 26 matched neurological disease-free individuals with insomnia. All patients participated in a standardized clinical interview and completed a battery of self-reported measures of cognitive and somatic presleep arousal experienced at bedtime, sleep- or insomnia-related unhelpful beliefs, and sleep-related safety behaviors. All patients with MS underwent a neurological examination.

Results: ID comorbid to MS was strongly associated with increased levels of cognitive and somatic arousal, higher endorsement of dysfunctional beliefs about the consequences of insomnia on daytime functioning, and worry about insomnia and more frequent engagement in sleep-related safety behaviors. Patients with MS with ID did not differ from neurological disease-free individuals with insomnia on these measures. No link was found between MS clinical peculiarities and ID diagnosis.

Conclusions: ID comorbid to MS is associated with the classical psychological factors perpetuating ID in neurological disease-free individuals with insomnia. Primary care providers and neurologists should consider target-oriented therapies like cognitive behavioral therapy for chronic insomnia as a treatment approach for ID comorbid to MS.
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http://dx.doi.org/10.1093/sleep/zsy002DOI Listing
March 2018

Radiologically isolated syndrome in children: Clinical and radiologic outcomes.

Neurol Neuroimmunol Neuroinflamm 2017 Nov 25;4(6):e395. Epub 2017 Sep 25.

Author affiliations are provided at the end of the article.

Objective: To describe clinical and radiologic outcomes of children with incidental findings on neuroimaging suggestive of CNS demyelination (termed "radiologically isolated syndrome" or RIS).

Methods: Clinical and radiologic data were obtained from a historical cohort of children with no symptoms of demyelinating disease who had MRI scans that met the 2010 MRI criteria for dissemination in space for MS.

Results: We identified 38 children (27 girls and 11 boys) with RIS now being prospectively followed at 16 sites in 6 countries. The mean follow-up time was 4.8 ± 5.3 years. The most common reason for initial neuroimaging was headache (20/38, 53%). A first clinical event consistent with CNS demyelination occurred in 16/38 children (42%; 95% confidence interval [CI]: 27%-60%) in a median of 2.0 years (interquartile range [IQR] 1.0-4.3 years). Radiologic evolution developed in 23/38 children (61%; 95% CI: 44%-76%) in a median of 1.1 years (IQR 0.5-1.9 years). The presence of ≥2 unique oligoclonal bands in CSF (hazard ratio [HR] 10.9, 95% CI: 1.4-86.2, = 0.02) and spinal cord lesions on MRI (HR 7.8, 95% CI: 1.4-43.6, = 0.02) were associated with an increased risk of a first clinical event after adjustment for age and sex.

Conclusions: We describe the clinical characteristics and outcomes of children with incidental MRI findings highly suggestive of CNS demyelination. Children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. The presence of oligoclonal bands in CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event.
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http://dx.doi.org/10.1212/NXI.0000000000000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614726PMC
November 2017

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients.

PLoS One 2017 15;12(9):e0183844. Epub 2017 Sep 15.

Department of Internal Medicine, Hôpital de la Timone, AP-HM, Aix-Marseille Université, Marseille, France.

Objectives: To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients.

Methods: Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model.

Results: Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients.

Conclusion: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600376PMC
October 2017

Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies: A Review.

JAMA Neurol 2017 08;74(8):1000-1008

Department of Neurology, Montpellier University Hospital, Montpellier, France.

Importance: Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)-based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes.

Observations: This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy.

Conclusions And Relevance: The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses.
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http://dx.doi.org/10.1001/jamaneurol.2017.1062DOI Listing
August 2017

TREX1 Mutation in Leukodystrophy with Calcifications and Persistent Gadolinium-Enhancement.

Eur Neurol 2017 24;77(3-4):113-114. Epub 2016 Dec 24.

Department of Neurology, Montpellier Universitary Hospital, Montpellier, France.

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http://dx.doi.org/10.1159/000455095DOI Listing
December 2016

Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy.

Neurology 2016 11;87(22):e262-e263

From the Department of Neurology (X.A., C.C.-D., P.L.), CHU Montpellier; Department of Biochemistry (K.M, S.L.), CHU Nimes; and Department of Neurology (E.M, E.B), CHU Besançon, France.

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http://dx.doi.org/10.1212/WNL.0000000000003370DOI Listing
November 2016

Paraplegia related to solitary lesion of the cervicomedullary junction.

Acta Neurol Belg 2017 06 18;117(2):545-546. Epub 2016 Oct 18.

Department of Neurology, CHU Montpellier, Hopital Guy de Chauliac, 80 Avenue Augustin Fliche, 34295, Montpellier Cedex 5, France.

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http://dx.doi.org/10.1007/s13760-016-0711-5DOI Listing
June 2017

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Hum Mutat 2016 12 2;37(12):1340-1353. Epub 2016 Sep 2.

EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University Hospital, Montpellier, France.

Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.
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http://dx.doi.org/10.1002/humu.23063DOI Listing
December 2016