Publications by authors named "Catherine Lubetzki"

110 Publications

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

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

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

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

Facing the urgency of therapies for progressive MS - a Progressive MS Alliance proposal.

Nat Rev Neurol 2021 Jan 22. Epub 2021 Jan 22.

Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Faculty of Medicine and Psychology, Sapienza University, Rome, Italy.

Therapies for infiltrative inflammation in multiple sclerosis (MS) have advanced greatly, but neurodegeneration and compartmentalized inflammation remain virtually untargeted as in other diseases of the nervous system. Consequently, many therapies are available for the relapsing-remitting form of MS, but the progressive forms remain essentially untreated. The objective of the International Progressive MS Alliance is to expedite the development of effective therapies for progressive MS through new initiatives that foster innovative thinking and concrete advancements. Based on these principles, the Alliance is developing a new funding programme that will focus on experimental medicine trials. Here, we discuss the reasons behind the focus on experimental medicine trials, the strengths and weaknesses of these approaches and of the programme, and why we hope to advance therapies while improving the understanding of progression in MS. We are soliciting public and academic feedback, which will help shape the programme and future strategies of the Alliance.
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http://dx.doi.org/10.1038/s41582-020-00446-9DOI Listing
January 2021

Multiple sclerosis in 2020: un bon cru.

Lancet Neurol 2021 01;20(1):12-13

Assistance Publique des Hôpitaux de Paris, Sorbonne University, Paris Brain Institute, Groupe Hospitalier Pitié-Salpêtrière, Paris 75013, France. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(20)30441-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837095PMC
January 2021

Bruton's Tyrosine Kinase Inhibition Promotes Myelin Repair.

Brain Plast 2020 Oct 1;5(2):123-133. Epub 2020 Oct 1.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière, GH Pitié-Salpêtrière, F-75013 Paris, France.

Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor . However, the role of BTK in the CNS is unknown.

Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in and experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated transgenic tadpoles.

Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination.

Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair.
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http://dx.doi.org/10.3233/BPL-200100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685672PMC
October 2020

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

J Neurol 2020 Sep 12. Epub 2020 Sep 12.

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

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

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

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

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

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

Remyelination in multiple sclerosis: from basic science to clinical translation.

Lancet Neurol 2020 08;19(8):678-688

Sorbonne University, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau (ICM), Groupe Hospitalier APHP-Sorbonne University, Paris, France; Neurology Department Saint-Antoine, Groupe Hospitalier APHP-Sorbonne University, Paris, France.

The treatment of multiple sclerosis has been transformed by the successful development of immunotherapies that efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, the prevention of disability progression, which is due to axonal and neuronal damage and loss, has yet to be achieved and is therapeutically challenging, particularly during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon. Animal studies have provided targets for interventions to improve brain and spinal cord remyelination, paving the way for the translation of this research to humans. From these initial and promising forays, further problems have emerged, including questions on how best to design these clinical trials and appropriately measure the outcomes. Solving these problems will need additional work before efficacious pro-remyelination therapies will be ready for people with multiple sclerosis, but there is a real sense of hope that researchers are getting closer to a successful therapy.
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http://dx.doi.org/10.1016/S1474-4422(20)30140-XDOI Listing
August 2020

Remyelination: a brief history.

Lancet Neurol 2020 08;19(8):649

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http://dx.doi.org/10.1016/S1474-4422(20)30209-XDOI Listing
August 2020

Nodes of Ranvier during development and repair in the CNS.

Nat Rev Neurol 2020 Aug 10;16(8):426-439. Epub 2020 Jul 10.

Sorbonne University, Inserm, CNRS, ICM-Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Saltatory conduction of action potentials along myelinated axons depends on the nodes of Ranvier - small unmyelinated axonal domains where voltage-gated sodium channels are concentrated. Our knowledge of the complex molecular composition of these axonal domains continues to accumulate, although the mechanisms of nodal assembly, which have been elucidated in the PNS, remain only partially understood in the CNS. Besides the key role of the nodes in accelerating conduction, nodal variations are thought to allow the fine tuning of axonal conduction speed to meet information processing needs. In addition, through their multiple glial contacts, nodes seem to be important for neuron-glia interactions. As we highlight in this Review, the disorganization of axonal domains has been implicated in the pathophysiology of various neurological diseases. In multiple sclerosis, for example, nodal and perinodal disruption following demyelination, with subsequent changes in ion channel distribution, leads to altered axonal conduction and integrity. The nodal clusters regenerate concurrently with but also prior to remyelination, allowing the restoration of axonal conduction. In this article, we review current knowledge of the organization and function of nodes of Ranvier in the CNS. We go on to discuss dynamic changes in the nodes during demyelination and remyelination, highlighting the impact of these changes on neuronal physiology in health and disease as well as the associated therapeutic implications.
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http://dx.doi.org/10.1038/s41582-020-0375-xDOI Listing
August 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

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis.

Cell Stem Cell 2020 05;26(5):617-619

Wellcome-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address:

Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.
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http://dx.doi.org/10.1016/j.stem.2020.03.017DOI Listing
May 2020

Highlights from the 2019 European Congress on Treatment and Research in Multiple Sclerosis (ECTRIMS 2019).

Mult Scler 2020 06 4;26(7):859-868. Epub 2020 May 4.

Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain/Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid (UCM) and IdISSC, Madrid, Spain.

The 2019 ECTRIMS Congress, in Stockholm, has had record-breaking figures for both attendance and scientific production. There were 9361 participants from 100 different countries for a total of 1541 abstracts. Upon invitation of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) executive committee, the authors of this meeting report assessed abstracts from all poster and oral presentations for novelty, scientific quality and relevance for basic and clinical multiple sclerosis (MS) research. The objective of this report is to highlight a selection of basic, translational and clinical studies out of the many outstanding projects that were presented. Abstracts and references cited in our report were chosen at the discretion of the authors and all co-authors and the ECTRIMS executive committee agreed on the selection. In the event of discrepancies between the abstract and the uploaded poster or presentation, we aimed to present data derived from the poster or presentation. All abstracts are accessible through the ECTRIMS online library ( https://onlinelibrary.ectrimscongress.eu/ectrims/#!*menu=36*browseby=3*sortby=2*ce_id=160 ) and also published in this journal (Volume 25 Issue 2_suppl, September 2019; https://journals.sagepub.com/toc/msja/25/2_suppl ). A few additional references from the literature were added but were restricted to the ones that authors considered as absolutely required for an optimized understanding of the topics highlighted.
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http://dx.doi.org/10.1177/1352458520918377DOI Listing
June 2020

Myelin Plasticity and Repair: Neuro-Glial Choir Sets the Tuning.

Front Cell Neurosci 2020 28;14:42. Epub 2020 Feb 28.

Institut du Cerveau et de la Moelle épinière, Sorbonne Universités UPMC Université Paris 06, CNRS UMR7225-Inserm U1127, Paris, France.

The plasticity of the central nervous system (CNS) in response to neuronal activity has been suggested as early as 1894 by Cajal (1894). CNS plasticity has first been studied with a focus on neuronal structures. However, in the last decade, myelin plasticity has been unraveled as an adaptive mechanism of importance, in addition to the previously described processes of myelin repair. Indeed, it is now clear that myelin remodeling occurs along with life and adapts to the activity of neuronal networks. Until now, it has been considered as a two-part dialog between the neuron and the oligodendroglial lineage. However, other glial cell types might be at play in myelin plasticity. In the present review, we first summarize the key structural parameters for myelination, we then describe how neuronal activity modulates myelination and finally discuss how other glial cells could participate in myelinic adaptivity.
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http://dx.doi.org/10.3389/fncel.2020.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059744PMC
February 2020

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system.

Glia 2020 Sep 2;68(9):1891-1909. Epub 2020 Mar 2.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle épinière, ICM-GH Pitié-Salpêtrière, Paris, France.

In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We previously described that node-like clusters can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these clusters prior to myelination. We first demonstrated that their components can partially preassemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Na for node-like clustering initiation. We further assessed the fate of these clusters when myelination proceeds. Our results shed light on the intrinsic mechanisms involved in node-like clustering prior to myelination and unravel a potential role of these clusters in node of Ranvier formation and in guiding myelination onset.
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http://dx.doi.org/10.1002/glia.23812DOI Listing
September 2020

Generation of Oligodendrocytes and Oligodendrocyte-Conditioned Medium for Co-Culture Experiments.

J Vis Exp 2020 02 9(156). Epub 2020 Feb 9.

Sorbonne Université, Inserm, CNRS, UMR7225, Institut du Cerveau et de la Moelle épinière, ICM;

In the central nervous system, oligodendrocytes are well-known for their role in axon myelination, that accelerates the propagation of action potentials through saltatory conduction. Moreover, an increasing number of reports suggest that oligodendrocytes interact with neurons beyond myelination, notably through the secretion of soluble factors. Here, we present a detailed protocol allowing purification of oligodendroglial lineage cells from glial cell cultures also containing astrocytes and microglial cells. The method relies on overnight shaking at 37 °C, which allows selective detachment of the overlying oligodendroglial cells and microglial cells, and the elimination of microglia by differential adhesion. We then describe the culture of oligodendrocytes and production of oligodendrocyte-conditioned medium (OCM). We also provide the kinetics of OCM treatment or oligodendrocytes addition to purified hippocampal neurons in co-culture experiments, studying oligodendrocyte-neuron interactions.
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http://dx.doi.org/10.3791/60912DOI Listing
February 2020

Outcomes of ileal conduit urinary diversion in patients with multiple sclerosis.

Neurourol Urodyn 2020 02 17;39(2):771-777. Epub 2020 Jan 17.

Department of Urology, Pitié-Salpêtrière Academic Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.

Aim: The objective of this study was to report the long-term outcomes and complications of patients with multiple sclerosis (MS) who underwent noncontinent urinary diversion to treat lower urinary tract symptoms (LUTS).

Material And Methods: A retrospective study included all adult patients with MS who underwent an ileal conduit urinary diversion between 2000 and 2015. Early postoperative complications were reported as well as long-term complications, reoperation rates, and renal function.

Results: Overall, 91 patients were included. The surgery was indicated for refractory urinary incontinence (n = 73), renal failure (n = 8), major perineal skin ulcer due to urinary incontinence (n = 6), and recurrent urinary tract infections (n = 4). The median follow-up was 50 months (range, 3-158 months). A significant reduction (P < .05) of postoperative nonobstructive pyelonephritis rate was observed. There was no significant difference between preoperative and postoperative renal function (P = .32). Early postoperative complications were reported in 24 patients (26%): 4 Clavien I, 6 Clavien II, 9 Clavien III, 4 Clavien IV, and 1 Clavien V. Nine patients required reoperation for these complications (9.9%). Late complications were reported in 28 patients (30.8%): 8 ureteral anastomosis stenosis, 2 stoma stenosis, 2 incisional hernias, 6 kidney or ureteral lithiasis, and 10 pyelonephritis. Among them, 15 patients (16.5%) required reoperation for late complications.

Conclusion: Noncontinent urinary diversion using ileal conduit appears to be an effective end-stage solution in MS patients. The perioperative morbidity rate of 26% and the late complication rate of 31% should be considered to better inform patients before the surgery.
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http://dx.doi.org/10.1002/nau.24279DOI Listing
February 2020

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

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

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

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

Role of a Contactin multi-molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS.

Glia 2019 12 22;67(12):2248-2263. Epub 2019 Jul 22.

Sorbonne Université, Inserm, CNRS, UMR7225, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage-gated sodium channels at nodes of Ranvier. Axo-glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM-induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin-1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin-R). We show that Contactin-1 combined with RPTP/Phosphacan or Tenascin-R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin-1-immunodepleted OCM or OCM from Cntn1-null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin-1. Altogether, our results identify Contactin-1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations.
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http://dx.doi.org/10.1002/glia.23681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851800PMC
December 2019

Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis.

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

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

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

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

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

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

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

Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines.

Brain 2019 07;142(7):1858-1875

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.
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http://dx.doi.org/10.1093/brain/awz144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598631PMC
July 2019

Preparation and Immunostaining of Myelinating Organotypic Cerebellar Slice Cultures.

J Vis Exp 2019 03 20(145). Epub 2019 Mar 20.

Sorbonne Université, Inserm, CNRS, Institut du Cerveau et de la Moelle épinière, ICM-GH Pitié-Salpétrière;

In the nervous system, myelin is a complex membrane structure generated by myelinating glial cells, which ensheathes axons and facilitates fast electrical conduction. Myelin alteration has been shown to occur in various neurological diseases, where it is associated with functional deficits. Here, we provide a detailed description of an ex vivo model consisting of mouse organotypic cerebellar slices, which can be maintained in culture for several weeks and further be labeled to visualize myelin.
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http://dx.doi.org/10.3791/59163DOI Listing
March 2019

Five-year outcome in the copaxone observatory: a nationwide cohort of patients with multiple sclerosis starting treatment with glatiramer acetate in France.

J Neurol 2019 Apr 7;266(4):888-901. Epub 2019 Feb 7.

Teva Santé, La Défense, France.

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing-remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator's normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39-0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9-47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials.
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http://dx.doi.org/10.1007/s00415-019-09211-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420902PMC
April 2019

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

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

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

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

150 years since Charcot's lectures on multiple sclerosis.

Lancet Neurol 2018 Dec 13;17(12):1041. Epub 2018 Nov 13.

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

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http://dx.doi.org/10.1016/S1474-4422(18)30410-1DOI Listing
December 2018

Cerebral folate deficiency in adults: A heterogeneous potentially treatable condition.

J Neurol Sci 2019 01 10;396:112-118. Epub 2018 Nov 10.

AP-HP, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France; AP-HP, Robert Debré University Hospital, Department of Biochemistry, Paris, France; Lip(Sys)(2), Université Paris Sud, Orsay, France; MedDay Pharmaceuticals, 96 Boulevard Haussmann, Paris, France. Electronic address:

Objective: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases.

Methods: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data.

Results: 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement.

Conclusion: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.
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http://dx.doi.org/10.1016/j.jns.2018.11.014DOI Listing
January 2019

Making a 'JUMP' from paediatric to adult healthcare: A transitional program for young adults with chronic neurological disease.

J Neurol Sci 2018 12 26;395:77-83. Epub 2018 Sep 26.

APHP, Hôpital Salpêtrière, Département of Neurologie, Paris, France; Sorbonne Université, Faculté de Médecine, CNRS UMR 7225, UMR S1127 Institut du Cerveau et de la Moelle Épinière, France.

Background: "JUMP" is a multidisciplinary program based at the Pitie-Salpêtrière Hospital Paris that transitions young adults with chronic neurological conditions from paediatric to adult healthcare. Transitional care programs have been shown to improve medical, educational and psychosocial outcomes for adolescent patients.

Methods: Demographic details and health-related variables of all patients referred to the JUMP program were collected. Satisfaction outcome measures were the 18-item On Your Own Feet Transfer Experience Scale (OYOF-TES) and a visual analogue scale, which assessed overall satisfaction with the transfer process. Scales were sent to JUMP patients attending the JUMP day hospital (n = 94) and their parents (n = 94).

Results: Since its inception, 111 patients have been seen in the JUMP program. Nine neurological clinical syndromes and four main underlying etiologies were identified. Approximately half of all questionnaires and scales (86/188) sent to patients and parents were returned. Eighty-nine percent of patients and 91% of parents were very satisfied with their transfer experience. There was a strong, positive correlation between patient and parent satisfaction [r = 0.910; p < 0.0001].

Conclusion: The JUMP program which is rooted in a multidisciplinary and coordinated approach to transitional care encompasses a broad range of neuro-pathologies. Overall, satisfaction levels were high amongst patients within the program, and their parents. The key role played by the coordination nurse specialists throughout the transfer process is a likely key determinant in satisfaction levels.
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http://dx.doi.org/10.1016/j.jns.2018.09.030DOI Listing
December 2018

Efficacy of rituximab in refractory RRMS.

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

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

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

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

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

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

Steps towards Collective Sustainability in Biomedical Research.

Trends Mol Med 2018 05 24;24(5):429-432. Epub 2018 Mar 24.

Department of Research, Italian Multiple Sclerosis Foundation, Genoa, Italy. Electronic address:

The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry.
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http://dx.doi.org/10.1016/j.molmed.2018.03.001DOI Listing
May 2018

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study.

Ann Clin Transl Neurol 2018 03 30;5(3):346-356. Epub 2018 Jan 30.

McGovern Medical School UT Health Houston Texas.

Objective: To investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial ( = 487; clinicaltrials.gov NCT00731692).

Methods: Magnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease-burden covariates.

Results: Baseline normalized brain volume was predictive of disability worsening: Risk of 3-month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64,  = 0.0339; log-rank test:  = 0.0297). Moreover, on-study brain volume loss was significantly associated with disability worsening ( = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume ( < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium-enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both  < 0.0001).

Interpretation: Baseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti-inflammatory treatment.
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http://dx.doi.org/10.1002/acn3.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846448PMC
March 2018

Early relapse after RTX initiation in a patient with NMO/MS overlap syndrome: How long to conclude to a failure treatment?

Mult Scler Relat Disord 2018 Feb 6;20:220-222. Epub 2018 Feb 6.

AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France.

Background: We report a dramatic clinical and radiological worsening within two months after rituximab initiation in a patient with NeuroMyelitis Optica/Multiple Sclerosis (NMO/MS) overlap syndrome.

Methods: Case study.

Results: A 45-year-old Caucasian woman with NMO/MS overlap syndrome experienced a severe myelitis nine weeks after first rituximab infusion, with extensive new gadolinium-enhanced spinal cord lesions.

Conclusion: This case report illustrates the limits of MS and NMO-Spectrum Disorder classification and challenges the criteria of therapeutic failure within the 6 months after rituximab initiation.
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http://dx.doi.org/10.1016/j.msard.2018.02.004DOI Listing
February 2018