Publications by authors named "Nathalie Derache"

22 Publications

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[The detection of antithyroid antibodies in cerebrospinal fluid using fluorescent enzyme immuno assay (FEIA) is suitable for biological diagnosis of Hashimoto's encephalopathy].

Ann Biol Clin (Paris) 2021 Apr 5. Epub 2021 Apr 5.

Laboratoire d'immunologie et immunopathologie, Centre Hospitalier Universitaire de Caen, France.

Hashimoto encephalopathy (HE) is a rare condition often underdiagnosed. The clinical picture is heterogeneous with numerous neurological signs and is associated with the presence of high levels of anti-thyroperoxidase (TPO) and / or anti-thyroglobulin (TG) antibodies in the blood and cerebrospinal fluid (CSF). The determination of anti-TPO and anti-TG antibodies in CSF is performed in only few laboratories. The aim of our study was to adapt the EliA fluoroenzymatic immuno assay (FEIA) to the detection of these autoantibodies in the CSF, and to compare the results with our previously published ELISA test (Blanchin S. 2007). For the FEIA technique, the detection threshold, and the quantification threshold have been determined for anti-TPO and anti-TG antibodies. FEIA results were concordant with ELISA at 75% and 100% for anti-TPO and anti-TG antibodies, respectively. Coefficients of variation (CV) of the intra-assay and inter-assay results were calculated as well as the uncertainties of measurement. The anti-TPO and anti-TG antibodies detection in CSF using FEIA technique correlate with the previously published ELISA and show good analytical performances. The availability of Phadia 250 analyzer in a large number of laboratories will allow an easier biological detection. We hope that this test will respond to physician needs and help for HE diagnosis.
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http://dx.doi.org/10.1684/abc.2021.1636DOI Listing
April 2021

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

Eur J Neurol 2021 May 19;28(5):1659-1664. Epub 2021 Feb 19.

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

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

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

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

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

BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS.

Mult Scler 2020 Oct 30:1352458520969145. Epub 2020 Oct 30.

Service de Neurologie, CRCSEP, Unité de Recherche Clinique Cote d'Azur (UR2CA), Centre Hospitalier Universitaire Pasteur 2, Nice, France.

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS).

Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS.

Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity.

Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49,  = 0.029).

Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.
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http://dx.doi.org/10.1177/1352458520969145DOI Listing
October 2020

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

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

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

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

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

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

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

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

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

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

Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort.

Neurotherapeutics 2020 07;17(3):989-993

Department of Neurology, CHU de Caen, F-14000, Caen, France.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Some reports have suggested that HDB treatment may be associated with an increased risk of relapse. We evaluate the relationship between exposure to HDB for treating PMS and the risk of relapse. We screened for PMS patients prospectively registered in a French regional cohort being part of the OFSEP national registry. In a case-crossover design among patients who received HDB, we first compared number of relapses before and after initiation of HDB. Second, time to the first clinical relapse was compared between patients who received HDB (biotin group) and a control group using a Cox survival analysis after a propensity score (PS) matching (1:1) and inverse probability of treatment weighting (IPTW) method. In the 42 PMS patients who received HDB, the number of relapses was statistically and clinically significant higher after biotin initiation than before biotin initiation (incident rate ratio [IRR] 7.4, 95% confidence interval [CI] 3.5-15.9, p < 0.0001). With the PS matching method, the risk of relapse was significantly higher in the biotin group compared to the control group (hazard ratio [HR] 4.3, 95% CI 1.4-13.3, p = 0.01). The IPTW method with 440 control patients revealed consistent results (HR 5.1, 95% CI 2.3-11.3, p < 0.0001). In our non-randomized study, HDB treatment for PMS was associated with an increased risk of relapse. The follow-up of PMS patients initiating HDB should include careful assessment of clinical and radiological activity to monitor the potential pro-inflammatory effect of biotin.
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http://dx.doi.org/10.1007/s13311-020-00880-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641290PMC
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

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

JAMA Neurol 2020 01;77(1):94-102

CHU de Nantes, Service de Neurologie, CIC015 INSERM, Nantes, France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.

Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.

Design, Setting, And Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.

Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main Outcomes And Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).

Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.

Conclusions And Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.2670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724170PMC
January 2020

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

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

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

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

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

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

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

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy.

Neurology 2016 12 4;87(23):2491-2494. Epub 2016 Nov 4.

From the CHU Toulouse Purpan (B.P., F.B., D.B., D.A.-P., D.B.), Pôle Neurosciences; INSERM U1043-CNRS UMR 5282 (B.P., F.B., D.B.), Université Toulouse III, Centre de Physiopathologie Toulouse Purpan, France; University of Münster (N.S., T.S.-H., H.W.), Germany; University of Lille (O.O., H.Z., P.V.); Hôpital Civil (J.-C. Ongagna, J.d.S.), Strasbourg; CHU Pellegrin (B.B., J.-C. Ouallet), Bordeaux; CHU Nancy (M.D., S.P.); CHU Caen (G.D., N.D.); CH St Vincent (P.H.), GHICL, Lille; CHU Reims (A.T.); CHU Montpellier (P.L.); CHU Nîmes (G.C., W.C., O.C.); CHRU Clermont Ferrand (P.C.); CHU Besançon (E.B.); Aix Marseille University (J.P., A.R.), APHM, CHU Timone, Marseille; CHU Nantes (D.L., S.W.); CHU Grenoble (E.T.); CHU Dijon (T.M., A.F.); CHU Lyon (S.V.), Bron; Hôpital de la Salpêtrière (C.P.), Paris, France; Centre d'Esclerosi Múltiple de Catalunya (CEMCAT) (M.C.), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; and CHU Nice (C.L.-F.), France.

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http://dx.doi.org/10.1212/WNL.0000000000003401DOI Listing
December 2016

Is it worth to report the presence of a single and additional band in the cerebrospinal fluid detected by isoelectrofocusing?

Ann Biol Clin (Paris) 2016 Aug;74(4):442-8

Service de biochimie, Centre Hospitalier et Universitaire de Caen, Caen, France.

Despite the revisions of the Mac Donald criteria of multiple sclerosis (MS) in 2010, the cerebrospinal fluid (CSF) analysis by isoelectrofocusing (IEF) remains useful for atypical presentations of MS. The IEF is considered as positive when at least two or more additional bands are detected in the CSF by comparison with the patient's serum but sometimes, the IEF interpretation is more difficult. The goal of our study was to determine the significance when a single band in the CSF is detected by IEF. We conducted a retrospective study on 990 patients who underwent a lumbar puncture followed by a CSF analysis by IEF. Only 2% display such IEF profile (i.e. single and additional band in the CSF). A diagnosis of clinically isolated syndrome or MS was evidenced in 4 among those 21 patients. In conclusion, our data suggest that even if the presence of a single and additional band in the CSF is a rare situation, it should be mentioned to clinicians to not exclude the hypothesis of an inflammatory demyelinating disease of the central nervous system.
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http://dx.doi.org/10.1684/abc.2016.1170DOI Listing
August 2016

Cutaneous and Mixed Nerve Silent Period Recordings in Symptomatic Paroxysmal Kinesigenic Dyskinesia.

Open Neurol J 2016 26;10:9-14. Epub 2016 May 26.

CHU de Caen, Service de Neurologie, CHU de Caen, Caen, F-14000, France.

Objective: The underlying neurophysiologic mechanism responsible for secondary paroxysmal kinesigenic dyskinesia (PKD) is still unclear. Here, we study the pathogenesis of PKD in two patients with a demyelinating lesion in the spinal cord.

Methods: Electromyogram recordings from affected arms of two patients with spinal cord lesions presenting PKD were compared with our laboratory standards. The cutaneous silent period (CuSP), mixed nerve silent period (MnSP) and coincidence period (CiP), defined as the common period between the CuSP and MnSP, were recorded.

Results: A large decrease in the MnSP and disappearance of the CiP were observed in our patients, which was secondary to simultaneous extinction of the third portion of the MnSP, while the CuSP was normal. The MnSP and CiP were normal after recovery.

Conclusions: Our results demonstrate that the third portion of the MnSP and the CuSP do not correspond to the same physiologic process. These findings suggest that PKD patients have abnormal spinal interneuron integration.
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http://dx.doi.org/10.2174/1874205X01610010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891988PMC
June 2016

Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

Brain 2015 Feb 19;138(Pt 2):284-92. Epub 2014 Dec 19.

1 Département de Neurologie, CHU de Montpellier, 34295 Montpellier, France

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.
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http://dx.doi.org/10.1093/brain/awu353DOI Listing
February 2015

No evidence for genetic association between glutamate transporter EAAT2 and Devic's neuromyelitis optica in caucasians and afro-caribbeans.

Mult Scler Relat Disord 2014 Jan 18;3(1):89-93. Epub 2013 Jul 18.

Caen University Hospital, Department of Neurology, Caen F-14000, France; INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, GIP Cyceron, Université de Caen Basse-Normandie, Caen F-14000, France.. Electronic address:

Devic's neuromyelitis optica (NMO) is a severe inflammatory and autoimmune disease producing demyelinating lesions. Recent data suggest that a complex genetic component could be involved. While impairment of glutamate homeostasis has emerged as a contributing etiological factor in NMO, a genetic alteration of Excitatory Amino Acid Transporter 2 (EAAT2/SLC1A2), the major glutamate transporter in the Central Nervous System (CNS), could contribute to glutamate excitotoxicity and then must be considered. We evaluated whether mutations and/or single nucleotide polymorphisms (SNPs) in EAAT2 gene, are associated with susceptibility to NMO. We studied a cohort of NMO sporadic cases including afro-caribbean patients (n=81; French cohort of Devic's neuromyelitis optica-NOMADMUS cohort) and compared to control subjects (n=56). We sequenced the whole coding region of EAAT2 gene and splicing consensus sequences flanking each exon. The results obtained from all NMO samples did not show any novel mutations and/or SNPs both in the coding region and splicing sites of EAAT2 gene compared to controls subjects. We reported three synonymous SNPs (rs752949, rs1042113 and rs7102949) but only rs7102949 was found in afro-caribbean. Genotype frequencies did not differ between patients and controls for the three SNPs in caucasians and afro-caribbeans (rs752949: p=0.71 and p=0.37, respectively; rs1042113: p=0.73 and p=0.35, respectively; rs7102949: p=0.08 in afro-caribbeans). Our data showed no evidence for a genetic association between EAAT2 gene and Devic's neuromyelitis optica.
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http://dx.doi.org/10.1016/j.msard.2013.06.012DOI Listing
January 2014

Fatigue is associated with metabolic and density alterations of cortical and deep gray matter in Relapsing-Remitting-Multiple Sclerosis patients at the earlier stage of the disease: A PET/MR study.

Mult Scler Relat Disord 2013 Oct 20;2(4):362-9. Epub 2013 Apr 20.

CHU de Caen, Department of Neurology, Caen F-14000, France; Université de Caen Basse-Normandie, Medical school, Caen F-14000, France.

Background: Fatigue is a common but complex symptom of multiple sclerosis. A central origin is now suggested as a key feature of its pathophysiology and gray matter (GM) structure seems to be (particularly) involved in the neurobiological basis of fatigue in multiple sclerosis (MS) patients.

Methods: We investigated, in a cohort of 17 Relapsing-Remitting-MS patients recruited within three years of disease diagnosis, the link between fatigue severity evaluated by the EMIF-SEP (a validated self-report questionnaire in French), and metabolic and density alterations of GM using positron emission tomography (PET) and magnetic resonance (MR) imaging using SPM5 (statistical parametric morphometry) analysis and voxel-based-morphometry.

Results: Compared to patients without fatigue-MS (NF-MS) group, patients with fatigue-MS (F-MS) had significant reduction (with correctedp<0.05) of GM density in clusters located in the bilateral middle, superior and inferior frontal cortex and in left temporal and parietal cortex. In addition, the total score for fatigue was negatively correlated with GM density in the same regional areas for the whole group. Total fatigue score was negatively correlated with GM density in bilateral thalamus (correctedp=0.04) and with rest cerebral metabolic rate of glucose (rCMRglu) in the basal ganglia (correctedp<0.05). Juxtacortical and/or overlapping corticosubcortical lesion volume in frontal and temporal areas were significantly higher in the F-MS group compared to NF-MS patients.

Conclusions: These results add new data suggesting that fatigue is associated with functional and structural changes of cerebral gray matter especially in frontal cortex and basal ganglia.
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http://dx.doi.org/10.1016/j.msard.2013.03.005DOI Listing
October 2013

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification.

Brain 2013 Nov 24;136(Pt 11):3395-407. Epub 2013 Sep 24.

1 Inserm U1079, Rouen, France.

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.
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http://dx.doi.org/10.1093/brain/awt255DOI Listing
November 2013

Inflammatory-like presentation of CADASIL: a diagnostic challenge.

BMC Neurol 2012 Aug 21;12:78. Epub 2012 Aug 21.

Department of Neurology, Strasbourg University Hospital, 1, Avenue Molière, 67000, Strasbourg, France.

Background: CADASIL is an autosomal dominant genetic leukoencephalopathy linked to mutations in the Notch3 gene. In rare cases, widespread brain lesions on T2 MRI mimicking multiple sclerosis are observed. From a national registry of 268 patients with adult-onset leukodystrophy, we identified two patients with an atypical presentation of CADASIL without co-occurrence of another systemic disease.

Case Presentations: Patient 1 experienced progressive gait disability and patient 2 relapsing optic neuritis and sensory-motor deficit in the leg. Both patients responded to corticotherapy and patient 2 was also responsive to glatiramer acetate. No oligoclonal bands were found in the CSF, and MRI showed myelitis and lesions with gadolinium enhancement in brain (patient 1) or incomplete CADASIL phenotype (patient 2).

Conclusions: In rare cases, an inflammatory-like process can occur in CADASIL. In these patients, immunomodulatory treatments, including corticosteroids, could be effective.
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http://dx.doi.org/10.1186/1471-2377-12-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488471PMC
August 2012

Relapsing polychondritis revealed by basal ganglia lesions.

Mov Disord 2012 Aug;27(9):1094-6

Department of Neurology, University-Hospital, Caen, France.

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http://dx.doi.org/10.1002/mds.23993DOI Listing
August 2012

CD49d expression as a promising biomarker to monitor natalizumab efficacy.

J Neurol Sci 2012 Mar 1;314(1-2):138-42. Epub 2011 Nov 1.

CHU de Caen, Department of Neurology, Caen, F-14000, France.

Natalizumab (Tysabri™), a monoclonal antibody against the α4-integrin of VLA-4 (CD49d) antigen of leukocytes, is highly effective in multiple sclerosis (MS). The most common reason for treatment failure is the development of neutralizing antibodies (NAbs). According to health authorities Nabs testing is recommended in case of relapse or repeated infusion reactions. However NAbs may develop in clinically asymptomatic patients. In this study we investigated if CD49d expression could serve as a biomarker of natalizumab bioavailability and treatment response. In a cohort of 49 natalizumab treated relapsing-remitting MS, followed over 2 years, CD49d expression was determined on peripheral blood mononuclear cells (PBMCs) before each infusion and compared to NAbs and serum natalizumab levels. In a majority of patients (41/49) the CD49d expression in PBMCs was strongly inhibited (>50%) after the first infusion and maintained at low levels throughout the treatment period. In contrast, in eight patients (16%) there was an early recovery of CD49d expression to pre-treatment levels related to NABs development. While three cases experienced hypersensitivity reactions, three others were identified solely on the basis of an undiminished level of CD49d, with neither infusion reaction nor clinical worsening. These 3 patients had very high levels of NAbs and no detectable serum natalizumab. Two additional patients had early but transient recovery of CD49d expression. These patients had low levels of transient Nabs and returned to significant CD49d inhibition after few natalizumab infusions. We suggest that monitoring of CD49d expression can be used as a surrogate biomarker of natalizumab efficiency. If the CD49d expression is sustained at pre-treatment levels, patients should be tested for persistent NAbs and considered for treatment interruption.
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http://dx.doi.org/10.1016/j.jns.2011.10.005DOI Listing
March 2012

Reduced thalamic and cerebellar rest metabolism in relapsing-remitting multiple sclerosis, a positron emission tomography study: correlations to lesion load.

J Neurol Sci 2006 Jun 27;245(1-2):103-9. Epub 2006 Apr 27.

Service de Neurologie, Centre Hospitalier Universitaire, 14000 Caen, France.

Magnetic resonance imaging (MRI) is the main tool for detecting central nervous system lesions in MS. However, classical anatomical MRI is unable to assess exactly disease related injury in normal-appearing brain tissue and to give information about the functional consequences of the disease, explaining weak correlation frequently observed between lesion load and clinical data. Recently, functional brain imaging techniques have provided new insights concerning pathophysiological processes of the disease. Among them Positron Emission Tomography (PET), a sensitive technique to evaluate functional consequences of tissue injury in other neurological diseases, has rarely been used in MS. Seventeen Relapsing-Remitting (RR-) MS patients with low disability at the early stage of the disease underwent measurements of cerebral metabolic rate of glucose (rCMRglu) in resting state by PET using [(18)F] fluorodeoxyglucose (FDG) and assessment of regional cortical and white matter lesion volume (LV), using an in-house-developed semi-automatic method, was done at the same time on MRI. rCMRglu of MS patients was compared with rCMRglu of 18 normal control subjects using univariate SPM99 analysis through Matlab 5 and correlations between rCMRglu and LV were tested using multivariate linear regression using SPM99. Statistical threshold was set at p<0.05 corrected for multiple comparisons and correlations. Compared to controls, reduced rCMRglu was found in the right thalamus (p<0.001), in bilateral cerebellum (p<0.05 for right and p<0.01 for left) and the posterior part of left inferior parietal cortex (p<0.05). In addition, higher rCMRglu in patients compared to controls was observed in left inferior frontal cortex, left (anterior part) and right inferior parietal cortex (p<0.001). rCMRglu in right thalamus correlates negatively with different LV: total LV, total juxtacortical and/or overlapping cortico-subcortical LV, total and frontal deep white matter LV. rCMRglu of the right superior frontal cortex negatively correlated with total and parieto-occipital deep white matter LV. The results of this study, performed in a group of recent RR-MS patients with low disability, suggest that demyelinating lesions in MS mainly have a remote effect on cortical, basal ganglia and cerebellum metabolism and that regional cortical compensatory mechanisms may be observed concurrently.
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http://dx.doi.org/10.1016/j.jns.2005.09.017DOI Listing
June 2006