Publications by authors named "Markus Breu"

14 Publications

  • Page 1 of 1

E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Eur J Paediatr Neurol 2020 Nov 4;29:32-40. Epub 2020 Nov 4.

Neuropaediatric Unit, Karolinska University Hospital, Sweden.

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.007DOI 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

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients.

J Neuroinflammation 2020 Sep 3;17(1):262. Epub 2020 Sep 3.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany.

Background: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD).

Objective: To describe systematically the CSF profile in children with MOG-EM.

Material And Methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively.

Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age.

Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.
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http://dx.doi.org/10.1186/s12974-020-01825-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470445PMC
September 2020

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

Epidemiology of Pediatric NMOSD in Germany and Austria.

Front Neurol 2020 15;11:415. Epub 2020 May 15.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany.

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory demyelinating disorders of the central nervous system mainly characterized by recurrent episodes of uni- or bilateral optic neuritis (ON), transverse myelitis (TM) and brainstem syndromes (BS). The majority of adult patients has serum antibodies directed against the water channel protein aquaporin 4 (AQP4-abs). In pediatric patients, AQP4-abs are less, while antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) are more frequently detectable than in adults. Some children with NMOSD have neither AQP4- nor MOG-ab (double-seronegative). Evaluation of epidemiological data regarding incidence and prevalence of pediatric NMOSD in Germany and Austria. We recruited pediatric NMOSD patients between 1 March 2017 and 28 February 2019 with five different tools: (1) ESPED (Surveillance Unit for Rare Pediatric Disorders in Germany), (2) ESNEK (Surveillance for Rare Neurological Disorders during Childhood), (3) pediatric neurology working group within the Austrian Society of Pediatrics and Adolescent Medicine, (4) BIOMARKER Study and (5) NEMOS (Neuromyelitis optica Study Group). We requested data regarding clinical symptoms, antibody status, therapy regimen and response via a standardized questionnaire. During the 2-year recruitment period, 46 (both incidental and prevalent) patients with a suspected diagnosis of NMOSD were brought to our attention. Twenty-two of these patients did not fulfill the inclusion criteria. Of the remaining 24 children, 22 had a median age at onset of 11 (range 3-17) years and 16/22 were female (72.7%) (no data in two patients). Sixteen of 24 patients were AQP4-ab positive (67%), 4/24 MOG-ab positive (16.7%), three children were double-seronegative and in one patient no antibody testing was done. We calculated an incidence rate of 0.022 per 100,000 person-years for Germany, while there was no incidental case in Austria during the recruitment period. The prevalence rate was 0.147 and 0.267 per 100,000 persons in Germany and Austria, respectively. Pediatric NMOSD, with and without associated antibodies, are very rare even considering the different limitations of our study. An unexpected finding was that a considerable proportion of patients was tested neither for AQP4- nor MOG-abs during diagnostic work-up, which should prompt to establish and disseminate appropriate guidelines.
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http://dx.doi.org/10.3389/fneur.2020.00415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326092PMC
May 2020

Antibodies to nodal/paranodal proteins in paediatric immune-mediated neuropathy.

Neurol Neuroimmunol Neuroinflamm 2020 07 2;7(4). Epub 2020 Jun 2.

From the Division of Neuropathology and Neurochemistry (D.D.S., G.R., M.W., I.K., R.H.), Department of Neurology, Medical University of Vienna, Austria; Department of Neurology (D.D.S.), University Hospital St. Poelten, Austria; Department of General Pediatrics, Neonatology and Pediatric Cardiology (M.K.), University Children's Hospital, Heinrich Heine University Duesseldorf, Germany; Department of Neuropediatric Rehabilitation (U.H.), Vamed Clinic Hattingen, Germany; Department of Neuropediatrics (U.S.), Charité University, Berlin, Germany; Paediatric Neurology (O.A.-M.), Great Ormond Street Hospital for Children, London, United Kingdom; Dubowitz Neuromuscular Centre (P.M.), Great Ormond Street Hospital for Children, London, United Kingdom; Nuffield Department of Clinical Neurosciences (S.R.), University of Oxford and Oxford University Hospitals NHS Foundation Trust; Department of Paediatric and Adolescent Medicine (C.S.), St Joseph Hospital, Berlin, Germany; Department of Pediatrics and Adolescent Medicine (M.F., M.B., R.S.), Medical University of Vienna, Austria; Department of Neurology (M.R., J.W.), Medical University of Innsbruck, Austria; Neuromuscular Diseases Unit (C.L., L.Q.), Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Spain; SMZ Süd (G.B.), Kaiser-Franz Josef Hospital with Gottfried von Preyer Children Hospital, Vienna, Austria; Institute of Clinical Chemistry (K.-P.W., R.J., F.L.), University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel, Germany; and Department of Pediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286658PMC
July 2020

Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Radiology (A.W.-P., R.C.), Children's Hospital Datteln, University Witten/Herdecke; Department of Pediatrics (E.-M.W.), Olgahospital, Klinikum Stuttgart, Germany; Division of Pediatric Neurology (M. Baumann, C.L.), Department of Pediatrics I, Medical University of Innsbruck, Austria; Department of Pediatric Neurology (A.B., K.R.), Children's Hospital Datteln, University Witten/Herdecke; Department of Pediatrics (M.H.), Division of Neuropediatrics and Social Pediatrics, Medical University RWTH Aachen, Germany; Charité-Universitätsmedizin Berlin (E.K.), Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Germany; Department of Neuropediatrics (E.K.), Berlin, Germany; Department of Pediatrics and Adolescent Medicine (E.R.-F., M. Breu), Medical University of Vienna; St. Anna Children´s Hospital (E.R.-F.), Vienna, Austria; Klinik für Kinder und Jugendmedizin (Ö.S.), Evangelisches Krankenhaus Hamm, Germany; Department of Neuropediatrics (A.D.M.), Developmental Neurology and Social Pediatrics, Children's Hospital, University of Duisburg-Essen, Germany; Department of Pediatrics (R.P.), Christliches Kinderhospital Osnabrück, Germany; Department of Pediatric Neurology (M.P.), Children's Hospital Auf der Bult, Hannover Germany; Department of Neonatology (C.R.), Pediatric Intensive Care, Sleep Medicine, Children's Hospital Datteln, University Witten/Herdecke, Germany; Institute of Neurology (R.H.), Medical University of Vienna, Austria; Neuroimmunology (F.L.), Institute of Clinical Chemistry and Department of Neurology, Christian-Albrechts-University Kiel and Medical University Hospital Schleswig-Holstein, Germany; and Clinical Department of Neurology (M.R.), Medical University of Innsbruck, Austria.

Objective: To describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs).

Methods: Identification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry.

Results: Ten children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4-16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/μL, range: 21-256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320-1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis.

Discussion: AE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE.
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http://dx.doi.org/10.1212/NXI.0000000000000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217659PMC
July 2020

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Ann Neurol 2020 07 29;88(1):148-159. Epub 2020 May 29.

Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Objective: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients.

Methods: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity.

Results: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome.

Interpretation: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.
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http://dx.doi.org/10.1002/ana.25754DOI Listing
July 2020

In vivo high-resolution diffusion tensor imaging of the developing neonatal rat cortex and its relationship to glial and dendritic maturation.

Brain Struct Funct 2019 Jun 22;224(5):1815-1829. Epub 2019 Apr 22.

Department of Radiology, New York University School of Medicine, 660 First Avenue, Room 207, New York, NY, 10016, USA.

Diffusion tensor imaging (DTI) is increasingly utilized as a sensitive tool for studying brain maturation and injuries during the neonatal period. In this study, we acquired high resolution in vivo DTI data from neonatal rat brains from postnatal day 2 (P2) to P10 and correlated temporal changes in DTI derived markers with microstructural organization of glia, axons, and dendrites during this critical period of brain development. Group average images showed dramatic temporal changes in brain morphology, fractional anisotropy (FA) and mean diffusivity (MD). Most cortical regions showed a monotonous decline in FA and an initial increase in MD from P2 to P8 that declined slightly by P10. Qualitative histology revealed rapid maturation of the glial and dendritic networks in the developing cortex. In the cingulate and motor cortex, the decreases in FA over time significantly correlated with structural anisotropy values computed from histological sections stained with glial and dendritic markers. However, in the sensory and visual cortex, other factors probably contributed to the observed decreases in FA. We did not observe any significant correlations between FA and structural anisotropy computed from the axonal histological marker.
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http://dx.doi.org/10.1007/s00429-019-01878-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565480PMC
June 2019

Two Cases of Pediatric AQP4-Antibody Positive Neuromyelitis Optica Spectrum Disorder Successfully Treated with Tocilizumab.

Neuropediatrics 2019 06 26;50(3):193-196. Epub 2019 Mar 26.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

B cell depletion with the anti-CD20-antibody rituximab is widely considered treatment of choice for long-term immunotherapy in aquaporin-4 (AQP4)-antibody positive neuromyelitis optica spectrum disorder (NMOSD). However, up to 30% of patients suffer from relapses despite complete B cell depletion. In these cases, the IL6 (interleukin-6)-receptor blocking antibody tocilizumab has been suggested as an alternative. We report two female adolescents with AQP4-antibody positive NMOSD who relapsed under rituximab treatment and clinically stabilized after switching to monthly administrations of tocilizumab. Our data suggest that early escalation of therapy with tocilizumab may lead to stabilization of disease activity in pediatric NMOSD patients who relapse under B cell depletion.
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http://dx.doi.org/10.1055/s-0039-1684004DOI Listing
June 2019

ADEM-like presentation, anti-MOG antibodies, and MS pathology: TWO case reports.

Neurol Neuroimmunol Neuroinflamm 2017 May 14;4(3):e335. Epub 2017 Mar 14.

Department of Neurology (P.K., M.P., H.-J.H., M.M.), Institute of Neuropathology (C.M.), University Hospital Magdeburg; German Center for Neurodegenerative Diseases (DZNE) Magdeburg (P.K.), Germany; Institute of Neurology (M.B., G.G.K., R.H.), Department of Pediatric and Adolescent Medicine (M.B.), Department of Neurology (P.R.), Division of Neuroradiology and Musculoskeletal Radiology (C.M.), Department of Biomedical Imaging and Image-guided Therapy, and Department of Neuroimmunology (H.L.), Center for Brain Research, Medical University of Vienna, Austria; Department of Neuropathology (I.M., W.B.), University Medical Center Göttingen; Leibniz Institute for Neurobiology (H.-J.H.), Magdeburg; Department of Neurology (M.M.), MEDIAN NRZ Flechtingen, Germany; Clinical Department of Neurology (M.R.), Innsbruck Medical University, Austria; Neuroimmunology (K.-P.W., F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck; Department of Neurology (K.-P.W.), University Hospital Schleswig-Holstein, Lübeck; and Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350621PMC
May 2017

Diffusion Tensor Imaging Abnormalities in the Cerebral White Matter Correlate with Sex-Dependent Neurobehavioral Deficits in Adult Mice with Neonatal Ischemia.

Dev Neurosci 2016 16;38(2):83-95. Epub 2016 Mar 16.

Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Md., USA.

Background: Neonatal white matter injury (NWMI) is the leading cause of cerebral palsy in prematurely born children. In order to develop a test bed for therapeutics, we recently reported a mouse model of NWMI by using a modified Rice-Vannucci model of neonatal ischemia on postnatal day 5 (P5) in CD-1 mice. We have previously shown that these mice illustrate initial neuroinflammation and oligodendroglial differentiation arrest followed by long-term dysmyelination, periventricular astrogliosis and axonal injury, resembling human NWMI. The objective of this study was to determine the sex-dependent long-term effects of neonatal brain injury on neurobehavioral and advanced in vivo neuroimaging indices in this mouse model, and to correlate these variables with histopathology.

Methods: After right common artery ligation on P5, in vivo T2-weighted imaging and diffusion tensor imaging (DTI) were performed on ligated and control animals at 4 and 8 weeks. Common sets of regions of interest were used to compare fractional anisotropy (FA) values between ischemic and control mice. Behavioral testing (open field, startle response and grip strength) was performed at adult age. Finally, the animals were sacrificed for immunohistochemical (IHC) assessment of major white matter tracts.

Results: DTI revealed significant sex-dependent changes in FA values ipsi- and contralateral to the ligation. Behavioral testing showed decreased reaction to acoustic stimuli in males but not females. Similarly, increased number of rearings and lack of novelty-induced habituation in the open field were encountered only in the male subgroup. Several regional correlations were found between FA values and these behavioral alterations. IHC studies revealed degeneration of mature oligodendrocytes and damage of white matter tracts in ligated animals, as previously reported in this model, and showed regional correlation with in vivo FA values and behavioral alterations.

Conclusions: Our findings suggest structural sex-dependent long-term abnormalities after neonatal ischemia. These changes lead to behavioral deficits resembling common problems of patients with cerebral palsy.
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http://dx.doi.org/10.1159/000442943DOI Listing
December 2017

Childhood onset temporal lobe epilepsy: Beyond hippocampal sclerosis.

Eur J Paediatr Neurol 2016 Mar 31;20(2):228-235. Epub 2015 Dec 31.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria. Electronic address:

Objective: Hippocampal Sclerosis (HS) is widely recognized as a significant underlying cause of drug-resistant temporal lobe epilepsy (TLE) in adults. In contrast, HS is a rare finding in pediatric surgical series, and a higher incidence of HS associated with cortical dysplasia (i.e. FCD type IIIa according to the new ILAE classification) than in adult series has been reported. Data about the electro-clinical characteristics of this subgroup are scarce.

Methods: We studied 15 children and adolescents with drug-resistant TLE and HS who had anterior temporal lobe resection at our center with regard to electroclinical characteristics, MRI features and histopathology. Children in whom histopathology was consistent with Focal Cortical Dysplasia (FCD) type IIIa (n = 7) were compared with those who had HS only (n = 8).

Results: Clinical characteristics associated with this highly selective subset of patients with FCD type IIIa were: the presence of febrile seizures during infancy, a shorter duration of active epilepsy and a lower age at epilepsy surgery. In addition, there were non-significant trends towards more extended abnormalities on both EEG and neuroimaging. We were, however, not able to find group differences with respect to neuropathologic subtyping of the HS.

Conclusion: We present the first detailed description and comprehensive data analysis of children with FCD type IIIa. According to our results, this patient group seems to show a distinct clinical phenotype.
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http://dx.doi.org/10.1016/j.ejpn.2015.12.010DOI Listing
March 2016

Ischemia-induced neuroinflammation is associated with disrupted development of oligodendrocyte progenitors in a model of periventricular leukomalacia.

Dev Neurosci 2013 27;35(2-3):182-96. Epub 2013 Feb 27.

The Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, MD 21205, USA.

Microglial activation in crossing white matter tracts is a hallmark of noncystic periventricular leukomalacia (PVL), the leading pathology underlying cerebral palsy in prematurely born infants. Recent studies indicate that neuroinflammation within an early time window can produce long-lasting defects in oligodendroglial maturation, myelination deficit, as well as disruption of transcription factors important in oligodendroglial maturation. We recently reported an ischemic mouse model of PVL, induced by unilateral neonatal carotid artery ligation, leading to selective long-lasting bilateral myelination deficits, ipsilateral thinning of the corpus callosum, ventriculomegaly, as well as evidence of axonopathy. Here, we report that permanent unilateral carotid ligation on postnatal day 5 in CD-1 mice induces an inflammatory response, as defined by microglial activation and recruitment, as well as significant changes in cytokine expression (increased IL-1β, IL-6, TGF-β1, and TNF-α) following ischemia. Transient reduction in counts of oligodendrocyte progenitor cells (OPCs) at 24 and 48 h after ischemia, a shift in OPC cell size and morphology towards the more immature form, as well as likely migration of OPCs were found. These OPC changes were topographically associated with areas showing microglial activation, and OPC counts negatively correlated with increased microglial staining. The presented data show a striking neuroinflammatory response in an ischemia-induced model of PVL, associated with oligodendroglial injury. Future studies modulating the neuroinflammatory response in this model may contribute to a better understanding of the interaction between microglia and OPCs in PVL and open opportunities for future therapies.
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http://dx.doi.org/10.1159/000346682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764456PMC
March 2014