Publications by authors named "Deiva Kumaran"

55 Publications

French recommendations for the management of Behçet's disease.

Orphanet J Rare Dis 2021 Feb 24;16(Suppl 1):352. Epub 2021 Feb 24.

UPMC Université Paris 06, Inserm UMR S 959, Immunology Immunopathology Immunotherapy (I3), Sorbonne Universités, 75005, Paris, France.

Behçet's disease (BD) is a systemic variable vessel vasculitis that involves the skin, mucosa, joints, eyes, arteries, veins, nervous system and gastrointestinal system, presenting with remissions and exacerbations. It is a multifactorial disease, and several triggering factors including oral cavity infections and viruses may induce inflammatory attacks in genetically susceptible individuals. BD vasculitis involves different vessel types and sizes of the vascular tree with mixed-cellular perivascular infiltrates and is often complicated by recurrent thrombosis, particularly in the venous compartment. Several new therapeutic modalities with different mechanisms of action have been studied in patients with BD. A substantial amount of new data have been published on the management of BD, especially with biologics, over the last years. These important therapeutic advances in BD have led us to propose French recommendations for the management of Behçet's disease [Protocole National de Diagnostic et de Soins de la maladie de Behçet (PNDS)]. These recommendations are divided into two parts: (1) the diagnostic process and initial assessment; (2) the therapeutic management. Thirty key points summarize the essence of the recommendations. We highlighted the main differential diagnosis of BD according to the type of clinical involvement; the role of genetics is also discussed, and we indicate the clinical presentations that must lead to the search for a genetic cause.
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http://dx.doi.org/10.1186/s13023-020-01620-4DOI Listing
February 2021

E.U. paediatric MOG consortium consensus: Part 3 - Biomarkers of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Eur J Paediatr Neurol 2020 Nov 7;29:22-31. Epub 2020 Nov 7.

Assistance Publique-Hôpitaux de Paris, Pediatric Neurology Department, University Hospitals Paris Saclay, Bicêtre Hospital, Le Kremlin Bicêtre, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases, Le Kremlin Bicêtre, France and European Reference Network-RITA, France.

A first episode of acquired demyelinating disorder (ADS) in children is a diagnostic challenge as different diseases can express similar clinical features. Recently, antibodies against myelin oligodendrocyte glycoprotein (MOG) have emerged as a new ADS biomarker, which clearly allow the identification of monophasic and relapsing ADS forms different from MS predominantly in children. Due to the novelty of this antibody there are still challenges and controversies about its pathogenicity and best technique to detect it. In this manuscript we will discuss the recommendations and caveats on MOG antibody assays, role in the pathogenesis, and additionally discuss the usefulness of other potential new biomarkers in MOG-antibody associated disorders (MOGAD).
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http://dx.doi.org/10.1016/j.ejpn.2020.11.001DOI Listing
November 2020

E.U. paediatric MOG consortium consensus: Part 5 - Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Eur J Paediatr Neurol 2020 Nov 4;29:41-53. Epub 2020 Nov 4.

Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.

In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centre-specific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methylprednisolone (IVMP) leads to a favourable outcome in the majority of patients and can be followed by tapering of oral steroids up to a maximum of three months to maintain the benefit of acute treatment by suppressing disease activity. Intravenous immunoglobulins (IVIG) and plasmapheresis constitute second-line therapies in case of insufficient response to IVMP. After a first relapse, maintenance treatment should be started in order to prevent further relapses and the possibility of permanent sequelae. Four first-line therapies consisting of rituximab (RTX), azathioprine, mycophenolate mofetil or monthly IVIG have been identified by the consensus group. In case of further relapses despite maintenance treatment, the consensus group recommends treatment escalation with RTX or IVIG, followed by combining those two, and ultimately adding maintenance oral steroids. Many open questions remain which need to be addressed in further international prospective evaluation of MOGAD treatment. This international collaboration is essential to expand the state of current knowledge.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.005DOI Listing
November 2020

E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Eur J Paediatr Neurol 2020 Nov 4;29:2-13. Epub 2020 Nov 4.

Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.006DOI Listing
November 2020

Acute Disseminated Encephalomyelitis: Current Perspectives.

Children (Basel) 2020 Nov 3;7(11). Epub 2020 Nov 3.

Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated central nervous system (CNS) disorder, characterized by polyfocal symptoms, encephalopathy and typical magnetic resonance imaging (MRI) findings, that especially affects young children. Advances in understanding CNS neuroimmune disorders as well as the association of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) with both monophasic and recurrent forms of ADEM have led to new insights into its definition, management and outcome. In this review, we aim to provide an update based on current epidemiologic, clinical, radiological and immunopathological aspects and clinical outcome of ADEM.
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http://dx.doi.org/10.3390/children7110210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692206PMC
November 2020

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

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

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

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

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

Results: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280).

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

Treatment and outcome of aquaporin-4 antibody-positive NMOSD: A multinational pediatric study.

Neurol Neuroimmunol Neuroinflamm 2020 09 30;7(5). Epub 2020 Jul 30.

From the Department of Neurology (R.B.P., S.L.A.-P., J.A.d.P.) and Department of Radiology (INRAD) (C.d.M.R.), Hospital das Clínicas, Faculty of Medicine, University of São Paulo (HCFMUSP), Brazil; Queen Square MS Centre (Y.H., O.C.), UCL Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Paediatric Neurology (Y.H., C.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Assistance Publue-Hôpitaux de Paris (E.Y., K.D.), University Hospitals Paris South, Bicêtre Hospital, Le Kremlin Bicêtre, France; Neuroimmunology Program (T.A.) and Neurology Service (A.S.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Deu (SJD) Children's Hospital, Universitat de Barcelona, Spain; Department of Neurology (A.B., R.N.), Erasmus University Medical Center, Rotterdam, the Netherlands; Division of Paediatric Neurology (C.L., M.B.), Department of Pediatrics I, Medical University of Innsbruck, Austria; Medical Center of Physical Therapy and Pain Medicine INNOVO (Y.M.), Lviv, Ukraine; Division of Pediatric Neurology (M.B.), Department of Pediatrics and Adolescent Medicine, and Department of Neurology (B.K.), Medical University of Vienna, Austria; Pediatric Neurology (E.W.), Birmingham Women and Children's Hospital, United Kingdom; Department of Neuroscience (L.P.), Pediatric Multiple Sclerosis Center, Bambino Gesù Children Hospital, IRCCS, Rome, Italy; Department of Neurology (M.C.) and Regional Multiple Sclerosis Centre (M.C.), University Hospital San Luigi Gonzaga, Orbassano, Italy; Department of Pediatric Neurology (K.R.), Vestische Kinder und Jugendklinik, Witten/Herdecke University, Datteln, Germany; Children's Neurosciences (M.L.), Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre; Faculty of Life Sciences and Medicine (M.L.), King's College Hospital, London, United Kingdom; Neurology Department (R.M.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (R.M., K.D.), Le Kremlin Bicêtre, France; School of Medicine (D.K.S.), Brain Institute of Rio Grande do Sul (Brains), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil; and Inserm UMR 1184 (K.D.), Immunology of Viral Infections and Autoimmune Diseases, CEA, IDMIT, Le Kremlin Bicêtre, France.

Objective: To describe the clinical phenotypes, treatment response, and outcome of children with antibodies against aquaporin-4 (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD).

Methods: Retrospective, multicenter, and multinational study of patients with AQP4-Ab NMOSD aged <18 years at disease onset from a center in Brazil and 13 European centers. Data on demographics, clinical findings, and laboratory results were analyzed; calculation of annualized relapse rates (ARRs) pre- and on-treatment with disease-modifying therapies (DMTs) and of ORs for predictors of poor outcome was performed.

Results: A total of 67 children were identified. At last follow-up (median 4 years, interquartile range 2-10 years), 37/67(57.8%) were found to have permanent disability. A more severe disease course was seen in the non-White ethnicity with both a shorter time to first relapse ( = 0.049) and a worse Expanded Disability Status Scale score at last follow-up ( = 0.008). The median ARR on treatment was 0.18 on azathioprine (n = 39, range 0-4), 0 on mycophenolate mofetil (n = 18, range 0-3), and 0 on rituximab (n = 29, range 0-2). No patient treated with rituximab as first-line therapy relapsed. Optic neuritis at onset was associated with a poor visual outcome below 20/200 (OR 8.669, 95% CI 1.764-42.616, = 0.008), and a younger age at onset was associated with cognitive impairment (OR 0.786, 95% CI 0.644-0.959, = 0.018).

Conclusions: AQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort. All DMTs were associated with a reduction of ARR. First-line rituximab prevented further clinical relapses. International consensus on treatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide.

Classification Of Evidence: This study provides Class IV evidence that for children with AQP4-Ab NMOSD, all DMTs, particularly first-line rituximab, reduced the ARR and prevented further clinical relapses.
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http://dx.doi.org/10.1212/NXI.0000000000000837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413715PMC
September 2020

Imaging in Pediatric Multiple Sclerosis : An Iconographic Review.

Clin Neuroradiol 2020 Jul 16. Epub 2020 Jul 16.

Pediatric Radiology Department, Hôpitaux Universitaires Paris-Sud, Bicêtre AP-HP, 94270, Le Kremlin-Bicêtre, France.

Pediatric-onset multiple sclerosis (POMS) is defined by a first multiple sclerosis (MS) attack occurring before 18 years old and is diagnosed by demonstration of dissemination in time (DIT) and space (DIS). Although guidelines evolved over the years, they always recognized the importance of magnetic resonance imaging (MRI) for diagnosis. The 2017 McDonald criteria are increasingly used and have been validated in several cohorts. The use of MRI is the most important tool for the early diagnosis, monitoring, and assessment of treatment response of MS and standard protocols include precontrast and postcontrast T1, T2, fluid attenuation inversion recovery (FLAIR) and diffusion sequences. A distinctive MS lesion compromises white matter and it is well-demarcated and confluent, showing demyelination, inflammation, gliosis, and relative axonal preservation. Considering the growing recognition of pediatric MS as a differential diagnosis for children presenting with a clinical central nervous system event, we present a POMS lesions guide (periventricular, juxtacortical, infratentorial, spinal cord, cortical, tumefactive, black hole, contrast-enhanced). Owing to its rareness, POMS is a diagnosis by exclusion and MRI plays a fundamental role in distinguishing POMS from other demyelinating and non-demyelinating conditions. Three main groups of disorders can mimic POMS: inflammatory, metabolic and tumoral; however, imaging patterns earlier described lower the possibilities of alternative diagnoses and strongly suggest POMS when likely.
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http://dx.doi.org/10.1007/s00062-020-00929-8DOI Listing
July 2020

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIG study.

Mult Scler 2020 Jul 7:1352458520936934. Epub 2020 Jul 7.

Division of Paediatric Neurology, Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany.

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment.

Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years.

Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG study ( = 215). Incidence rates (IRs) of infection-related adverse events (AEs)/100 patient-years were analysed by on-study nadir ALC.

Results: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of AEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 10/L: 1.13 and >0.4 × 10/L: 0.91. Three patients had a single episode of ALC <0.2 × 10/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase.

Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.
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http://dx.doi.org/10.1177/1352458520936934DOI Listing
July 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

Risk factors for academic difficulties in children with myelin oligodendrocyte glycoprotein antibody-associated acute demyelinating syndromes.

Dev Med Child Neurol 2020 09 22;62(9):1075-1081. Epub 2020 Jun 22.

National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre, France.

Aim: To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies.

Method: This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured.

Results: Seventy-six children were included in the study with a mean (SD) follow-up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo-13y 11mo; 36 females, 40 males). Thirty-six children relapsed and 20 had academic difficulties at the last follow-up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio [OR] 3.72 [95% confidence interval {CI} 1.19-11.64]; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 [95% CI 5.97-461.4]; p<0.001), and deep grey matter lesions (OR 17.33 [95% CI 3.87-77.72]; p<0.001) were associated with academic difficulties.

Interpretation: MOG antibody-associated ADS have distinct clinical and radiological patterns that are age-dependent. Indirect cognitive evaluation through academic difficulties was prevalent in younger children and is associated with specific clinical and magnetic resonance imaging factors that need to be considered earlier on when assessing this patient population.
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http://dx.doi.org/10.1111/dmcn.14594DOI Listing
September 2020

Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome: An unusual presentation of anti-GFAP astrocytopathy.

Eur J Paediatr Neurol 2020 May 18;26:89-91. Epub 2020 Mar 18.

Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Pediatric Neurology Department, National Referral Center for Rare Inflammatory Brain and Spinal Diseases, France; Université Paris-Sud, UMR 1184-CEA-IDMIT, Center for Immunology of Viral Infections and Autoimmune Diseases, 94275, Le Kremlin Bicêtre, France. Electronic address:

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare recently defined antibody-mediated encephalitis. Meningo-encephalomyelitis presentation is frequent with lymphocytic pleiocytosis in the cerebro-spinal fluid and brain MRI classically demonstrates in 50% of cases, a linear perivascular enhancement extending radially from the ventricles. Here, we describe 2 cases of pediatric autoimmune GFAP astrocytopathy with limbic encephalitis presentation and peculiar MRI characteristics: one with normal MRI and the second suggestive of Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome (MERS). These two cases illustrate that anti-GFAP antibodies should be sought in children presenting limbic encephalitis with a normal and/or MERS suggestive MRI, as treatment strategies may differ.
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http://dx.doi.org/10.1016/j.ejpn.2020.03.002DOI Listing
May 2020

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

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

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

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

Anti-MOG autoantibodies pathogenicity in children and macaques demyelinating diseases.

J Neuroinflammation 2019 Nov 30;16(1):244. Epub 2019 Nov 30.

CEA, Inserm UMR 1184 and Institut de biologie François Jacob, Infectious Diseases Models for Innovative Therapies (IDMIT), Université Paris-Sud, 92265, Fontenay-aux-Roses, France.

Background: Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species.

Methods: The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared.

Results: Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG-. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG- children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration.

Conclusions: Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.
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http://dx.doi.org/10.1186/s12974-019-1637-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884758PMC
November 2019

Long-term outcome of vein of Galen malformation.

Dev Med Child Neurol 2020 06 12;62(6):729-734. Epub 2019 Nov 12.

Neuroradiologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France.

Aim: To describe the long-term outcomes of children by the time they reached school age with vein of Galen aneurysmal malformation (VGAM).

Method: This was a retrospective observational study on a consecutive cohort of patients with VGAM. We included patients with at least one Francophone parent, aged between 6 and 11 years at the time of long-term evaluation. The neurological outcome was assessed with the King's Outcome Scale for Childhood Injury score and eight neurological and behavioural items from the Rivermead Postconcussion Symptoms questionnaire.

Results: All 52 patients (17 females, 32 males [data missing for n=3]) with at least one Francophone parent (5 fetuses and 47 children) were included. At the long-term evaluation time-point, 33 patients were alive and 19 patients had died. Risk of postnatal death was associated with severe neonatal cardiac failure (p=0.007) or isosystemic or suprasystemic pulmonary hypertension (p=0.014). Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome. Moreover, among the good outcome patients, a large proportion had neurodevelopmental alterations.

Interpretation: Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth. Even patients with good outcome often have neuropsychological disorders that may have repercussions on learning and requiring appropriate rehabilitation or medical management.

What This Paper Adds: Long-term outcome appears to be less favourable than described at short- and medium-term follow-up. Even patients with good outcome at these time-points often have minor neuropsychological disorders.
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http://dx.doi.org/10.1111/dmcn.14392DOI Listing
June 2020

Intradermal vaccination prevents anti-MOG autoimmune encephalomyelitis in macaques.

EBioMedicine 2019 Sep 3;47:492-505. Epub 2019 Sep 3.

Laboratoire des Biothérapies, INSERM, UMS27, F-92260 Fontenay-aux-Roses, France; Asfalia Biologics, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitiè-Sâlpétrière, Paris 75013, France. Electronic address:

Background: Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation.

Methods: We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4 lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen).

Findings: rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a DCs or CD163 cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4 T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4CD25FOXP3CD39 regulatory lymphocytes and favoured an upsurge in systemic TGFβ and IL-8 upon rhMOG re-administration in vivo.

Interpretation: We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796575PMC
September 2019

Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIG.

J Neurol Neurosurg Psychiatry 2020 01 29;91(1):58-66. Epub 2019 Aug 29.

Neuroscience Development Unit, Novartis Pharma AG, Basel, Switzerland.

Background: In PARADIG, a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) β-1a.

Objectives: To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression.

Methods: ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc.

Results: In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF β-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%-94.6%. Twice as many IFN β-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively.

Conclusions: Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN β-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years.

Trial Registration Number: NCT01892722.
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http://dx.doi.org/10.1136/jnnp-2019-321124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952840PMC
January 2020

Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases.

Dev Med Child Neurol 2020 02 11;62(2):241-244. Epub 2019 Apr 11.

Pediatric Neurology Department, National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France.

Aim: To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS).

Method: Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation.

Results: Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007).

Interpretation: This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal.

What This Paper Adds: Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning.
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http://dx.doi.org/10.1111/dmcn.14242DOI Listing
February 2020

Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3.

Eur J Paediatr Neurol 2019 May 22;23(3):448-455. Epub 2019 Feb 22.

Department of Pediatrics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address:

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.
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http://dx.doi.org/10.1016/j.ejpn.2019.02.004DOI Listing
May 2019

Cranial nerve involvement in patients with MOG antibody-associated disease.

Neurol Neuroimmunol Neuroinflamm 2019 03 1;6(2):e543. Epub 2019 Feb 1.

Service de neurologie (A.C.-C., S.V., R.M.), sclérose en plaques, pathologies de la myéline et neuroinflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM)- Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, France; Lyon Neuroscience Research Center (A.C.-C., R.M.), U1028 INSERM, UMR5292 CNRS, FLUID Team, Lyon, France; Service de sclérose en plaques (X.A., P.L.), Hôpital Universitaire de Montpellier, France; Service de Neurologie (P.K.), Centre hospitalier de Luxembourg; Inserm (P.H.), U 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud 11, CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Faculté de médecine, Le Kremlin-Bicêtre Cedex, France; Service de Radiologie (F.C.), Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Université Claude Bernard Lyon 1 (F.C., S.V., R.M.), F-69100 Villeurbanne, France; Lyon's Neuroscience Research Center (S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France; Service de neurologie pédiatrique (K.D.), Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle, Le Kremlin-Bicêtre, France; and INSERM US27 MIRCen (C.S.), CEA, Fontenay-aux-Roses, France.

Objective: To describe clinical and radiologic features of cranial nerve (CN) involvement in patients with myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) and to assess the potential underlying mechanism of CN involvement using a nonhuman primate (NHP) model.

Methods: Epidemiologic, clinical, and radiologic features from a national cohort of 273 MOG-IgG-positive patients were retrospectively reviewed for CN involvement between January 2014 and January 2018. MOG-IgG binding was evaluated in CNS, CN, and peripheral nerve tissues from NHP.

Results: We identified 3 MOG-IgG-positive patients with radiologic and/or clinical CN involvement. Two patients displayed either trigeminal or vestibulocochlear nerve lesions at the root level, and the remaining patient had an oculomotor nerve involvement at the root exit and at the cisternal level. Additional CNS involvement was found in all 3 patients. None of the 3 patients' sera recognized MOG expression in CN of NHP.

Conclusion: Craneal nerve involvement can coexist in patients with MOG antibody disease, although the underlying pathophysiology remains elusive.
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http://dx.doi.org/10.1212/NXI.0000000000000543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384017PMC
March 2019

Acute transverse myelitis following an opsoclonus-myoclonus syndrome: An unusual presentation.

Eur J Paediatr Neurol 2018 Sep 8;22(5):878-881. Epub 2018 May 8.

Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Pediatric Neurology Department, National Referral Center for Rare Inflammatory Brain and Spinal Diseases and Université Paris-Sud, UMR 1184-CEA-IDMIT, Center for Immunology of Viral Infections and Autoimmune Diseases, 94275, Le Kremlin Bicêtre, France. Electronic address:

Opso-myoclonus syndrome (OMS) is a very rare and severe condition. Ataxia, opsoclonus, myoclonus and/or behavioral and sleeping disturbances define that autoimmune disorder syndrome which is paraneoplastic or triggered by an infection. Here, we report a 3 year-old immunocompetent boy who developed an atypical OMS which was later complicated by an acute transverse myelitis. Screening for neuroblastoma was negative and extensive infectious screening revealed an active HHV-6 infection confirmed by blood and cerebrospinal fluid PCR. A parainfectious disease was suggested and immunosuppressive treatment was initiated. After 2 years of follow-up, the patient has a left leg paresia needing a splint and is otherwise normal. Transverse myelitis can be associated with parainfectious OMS and earlier immunosuppressive treatment in these cases may be useful especially in young and immunocompetent children.
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http://dx.doi.org/10.1016/j.ejpn.2018.05.002DOI Listing
September 2018

Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

JAMA Neurol 2018 04;75(4):478-487

Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' National Health Service Foundation Trust, King's Health Partners Academic Health Science Centre, London, United Kingdom.

Importance: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated.

Objective: To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab-associated disease.

Design, Setting, And Participants: This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols.

Main Outcomes And Measures: Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs).

Results: A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P < .001). Fifty-two children (51.0%) received DMDs: 28 (53.8%) were treated with 1 DMD, 17 (32.7%) with 2, and 7 (13.5%) with 3 or more sequential DMDs. Patients relapsed during all treatments, with a total of 127 relapses on treatment reported. No changes in median ARR and EDSS score were observed between the preinitiation and postinitiation phases of interferon beta and glatiramer acetate treatment (n = 11). The median ARR was reduced from 1.84 to 1.0 with azathioprine (n = 20, P < .001), 1.79 to 0.52 with mycophenolate mofetil (n = 15, P = .003), and 2.12 to 0.67 with rituximab (n = 9, P < .001), although the median EDSS score remained unchanged. An improvement in ARR (from 2.16 to 0.51, P < .001) and EDSS score (from 2.2 to 1.2, P = .01) was observed in the 12 patients treated with regular intravenous immunoglobulins.

Conclusions And Relevance: Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab-associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab-associated disorders is therefore important to optimize immune treatment.
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http://dx.doi.org/10.1001/jamaneurol.2017.4601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885190PMC
April 2018

Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: Clinical and paraclinical characteristics in Algerian patients.

J Neurol Sci 2017 Oct 31;381:240-244. Epub 2017 Aug 31.

Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Germany.

Background: Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder of the central nervous system. NMO and its abortive forms are referred to as NMO spectrum disorders (NMOSD). NMOSD are mostly associated with antibodies to aquaporin-4 (AQP4-IgG). However, recent studies have demonstrated antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in a subset of patients. Data on NMOSD in North Africa are sparse.

Objective: To describe the frequency of MOG-IgG and AQP4-IgG among patients with optic neuritis (ON) and/or myelitis in Algeria as well as the clinical and paraclinical features associated with these antibodies.

Methods: Retrospective testing of 42 patients with optic neuritis and/or myelitis treated at the teaching hospital of TiziOuzou for MOG-IgG and AQP4-IgG, and retrospective evaluation of the patients' medical records.

Results: Six of 42 (14.3%) patients were positive for AQP4-IgG and 3/42 (7.1%) were positive for MOG-IgG. No patient was positive for both AQP4-IgG and MOG-IgG. All antibody-positive patients were women. MOG-IgG was associated with severe episodes of ON in all MOG-IgG-positive patients. Steroid treatment was followed by complete remission in two patients. AQP4-IgG was associated with ON and/or longitudinally extensive transverse myelitis (LETM), often with severe onset. While all six of the AQP4-IgG-positive patients met the 2015 IPND criteria for NMOSD, only one of the three MOG-IgG-positive patients did so. Interestingly, clinically silent extensive spinal cord or brain lesions were present in two of the three MOG-IgG-positive patients, and altered visual evoked potentials without clinical evidence of ON were found in three of the six AQP4-IgG-positive patients.

Conclusion: MOG-IgG and AQP4-IgG are found in a substantial subset of Algerian patients with ON and/or myelitis, are present predominantly in women, and may be associated with differences in clinical presentation and, possibly, outcome. Only a subset of MOG-IgG positive patients meets the current diagnostic criteria for NMOSD.
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http://dx.doi.org/10.1016/j.jns.2017.08.3254DOI Listing
October 2017

Paediatric optic neuritis: factors leading to unfavourable outcome and relapses.

Br J Ophthalmol 2018 06 13;102(6):808-813. Epub 2017 Sep 13.

Department of Pediatric Neurology, Hôpitaldes Enfants, CHU Purpan, Toulouse, France.

Objectives: To identify prognostic factors associated with poor visual recovery and chronic relapsing diseases, for example, multiple sclerosis (MS), in children with optic neuritis (ON) at onset.

Methods: This multicentre retrospective study included 102 children with a first ON episode between 1990 and 2012. The primary criterion was poor visual recovery determined by visual acuity, and the secondary was relapses following ON.

Results: Median age was 11 years, 66% were girls and mean follow-up was 24 months. 58% of children were diagnosed with idiopathic isolated ON, 22% had MS, 5% had Devic's neuromyelitis optica and 6% chronic relapsing inflammatory ON. Complete visual acuity recovery rate was 57% (95% CI=[46%-69%]) at 6 months and 71% (95% CI=[60%-81%]) at 1 and 2 years but was lower in MS (p<0.01), with recovery rate of only 27% (95% CI=[12%-54%]) at 1 year. Age ≥10 years, optic disc pallor at funduscopy and MS were the principal factors associated with poor visual recovery. Age ≥10 years, abnormal brain MRI at onset and oligoclonal banding were significantly associated with MS (p<0.01).

Conclusion: Age ≥10, optic disc pallor and MS were associated with poor recovery. Better identification of these patients may help to adapt treatment and lead to a prospective treatment study.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309978DOI Listing
June 2018

MOG antibody-related disorders: common features and uncommon presentations.

J Neurol 2017 Sep 2;264(9):1945-1955. Epub 2017 Aug 2.

Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Bron, France.

Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) have been reported in acute demyelinating encephalomyelitis (ADEM), optic neuritis (ON), and neuromyelitis optica spectrum disorders (NMOSD) in adults and pediatrics. We aimed to delineate the common features of MOG-Ab-related disorders in children and adults, and report uncommon presentations. Twenty-seven consecutive pediatric and adult patients testing positive for MOG-Ab, with a minimum follow-up of 6 months, were included. Comprehensive epidemiological, clinical, radiological, and laboratory data were retrospectively analyzed. Additionally, we compared radiological features between ADEM MOG-Ab-positive patients, and a group of ADEM MOG-Ab-negative ones, recruited during the same period. Among the whole cohort, 13 (48.1%) were pediatric, and 14 (51.9%) were female. MOG-Ab-related disorders comprised eight ADEM, eight ON, five isolated myelitis, four with NMOSD and two patients with multiple sclerosis, at last follow-up. After a median follow-up of 17.8 months, 11 (40.7%) patients presented a relapse. The most frequent clinical phenotype at onset was encephalopathy in pediatrics (53.9%) and myelitis in adults (50%) (p = 0.013). There were no other differences between both groups. When comparing ADEM MOG-Ab positive and negative patients, bilateral thalamic lesions were more often found in the positive group (p = 0.010). Unusual presentations were identified in three patients: patchy spinal cord gadolinium-enhancing lesions, an associated teratoma, and one presented with status epilepticus. MOG-Ab-related disorders shared common clinical and prognostic features, but encompass a spectrum wider than recently reported.
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http://dx.doi.org/10.1007/s00415-017-8583-zDOI Listing
September 2017

Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.

Lancet Neurol 2017 09 14;16(9):712-720. Epub 2017 Jul 14.

Department of Neuroscience, Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, Paris, France.

Background: Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy.

Methods: Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672.

Findings: Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1-12 months and 3-12 months, respectively, but not at 30 months in three of four patients.

Interpretation: Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development.

Funding: Association Française Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.
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http://dx.doi.org/10.1016/S1474-4422(17)30169-2DOI Listing
September 2017

Neurological outcome of patients with cryopyrin-associated periodic syndrome (CAPS).

Orphanet J Rare Dis 2017 02 14;12(1):33. Epub 2017 Feb 14.

Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Pediatric Neurology Department and National Referral Center for Neuroinflammatory Diseases in Children and Inserm UMR 1184, Center for immunology of viral infections and autoimmune diseases, CEA, IDMIT, University Paris Sud, 63, rue Gabriel Péri, 94276, Le Kremlin-Bicêtre Cedex, France.

Background: To assess the neurological involvement and outcome, including school and professional performances, of adults and children with cryopyrin-associated periodic syndrome (CAPS).

Methods: In this observational study, patients with genetically proven CAPS and followed in the national referral centre for autoinflammatory diseases at Bicêtre hospital were assessed. Neurological manifestations, CSF data and MRI results at diagnosis and during follow-up were analyzed.

Results: Twenty-four patients (15 adults and 9 children at diagnosis) with CAPS were included. The median age at disease onset was 0 year (birth) [range 0-14], the median age at diagnosis was 20 years [range 0-53] and the mean duration of follow-up was 10.4 ± 2 years. Neurological involvement at diagnosis, mostly headaches and hearing loss, was noted in 17 patients (71%). Two patients of the same family had abnormal brain MRI. A439V mutation is frequently associated with a non-neurological phenotype while R260W mutation tends to be associated with neurological involvement. Eleven adult patients (61%) and 3 children (50%) underwent school difficulties.

Conclusion: Neurological involvement is frequent in patients with CAPS and the majority of patients presented difficulties in school performances with consequences in the professional outcome during adulthood. Further studies in larger cohorts of children with CAPS focusing in intellectual efficiency and school performances are necessary.
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http://dx.doi.org/10.1186/s13023-017-0589-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309976PMC
February 2017

Vessel Wall Contrast Enhancement on Magnetic Resonance Imaging May Be Suggestive for Future Development of Further Arterial Changes.

Can J Neurol Sci 2016 Sep;43(5):728-30

3Le Service de Neurologie Pédiatrique,Hôpital Bicêtre,Le Kremlin-Bicêtre,France.

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http://dx.doi.org/10.1017/cjn.2016.251DOI Listing
September 2016

Pediatric transverse myelitis.

Neurology 2016 Aug;87(9 Suppl 2):S46-52

From Children's Neurosciences (M.A., M.L.), Evelina London Children's Hospital at Guy's & St Thomas' NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK; Department of Neurology and Neurotherapeutics and Department of Pediatrics (B.M.G.), UT Southwestern and Childrens Health, Dallas, TX; Division of Child Neurology (T.L.), Baylor College of Medicine, Houston, TX; Texas Children's Hospital (T.L.), Houston, TX; Neurology Service (T.T.), Department of Paediatrics, KK Women's and Children's Hospital, Singapore; and Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Pediatric Neurology Department, National Referral Center for Neuro-Inflammatory Diseases in Children, and University Paris Sud (K.D.), Le Kremlin-Bicêtre, France.

Pediatric acute transverse myelitis (ATM) is an immune-mediated CNS disorder and contributes to 20% of children experiencing a first acquired demyelinating syndrome (ADS). ATM must be differentiated from other presentations of myelopathy and may be the first presentation of relapsing ADS such as neuromyelitis optica (NMO) or multiple sclerosis (MS). The tenets of the diagnostic criteria for ATM established by the Transverse Myelitis Consortium Working Group can generally be applied in children; however, a clear sensory level may not be evident in some. MRI lesions are often centrally located with high T2 signal intensity involving gray and neighboring white matter. Longitudinally extensive ATM occurs in the majority. Asymptomatic lesions on brain MRI are seen in more than one-third and predict MS or NMO. The role of antibodies such as myelin oligodendrocyte glycoprotein in monophasic and relapsing ATM and their significance in therapeutic approaches remain unclear. ATM is a potentially devastating condition with variable outcome and presents significant cumulative demands on health and social care resources. Children generally have a better outcome than adults, with one-half making a complete recovery by 2 years. There is need for standardization of clinical assessment and investigation protocols to enable international collaborative studies to delineate prognostic factors for disability and relapse. There are no robust controlled trials in children or adults to inform optimal treatment of ATM, with one study currently open to recruitment. This review provides an overview of current knowledge of clinical features, investigative workup, pathogenesis, and management of ATM and suggests future directions.
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http://dx.doi.org/10.1212/WNL.0000000000002820DOI Listing
August 2016

Catatonia and Autoimmune Conditions in Children and Adolescents: Should We Consider a Therapeutic Challenge?

J Child Adolesc Psychopharmacol 2017 03 19;27(2):167-176. Epub 2016 Apr 19.

1 Department of Child and Adolescent Psychiatry, Université Pierre et Marie Curie , Hôpital Pitié-Salpêtrière, AP-HP, Paris, France .

Objective: Catatonia as a result of autoimmune conditions offers new therapeutic opportunities for patients that child and adolescent psychiatrists should consider. However, the diagnosis is sometimes challenging when an autoimmune signature is not identified.

Methods: In this study, we aim to summarize seven cases from a 20-year series of 84 youths with catatonia, including three cases that represented a diagnostic challenge because of the absence of positive autoimmune testing.

Results: Immunosuppressive/modulatory treatment improved catatonic and psychotic features in all cases.

Conclusion: To facilitate treatment decision-making, we propose a causality assessment score and a treatment algorithm, which may help clinicians consider whether an autoimmune condition is associated with catatonia.
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http://dx.doi.org/10.1089/cap.2015.0086DOI Listing
March 2017