Publications by authors named "Klemens Ruprecht"

162 Publications

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

J Neuroinflammation 2021 May 1;18(1):105. Epub 2021 May 1.

Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG) NMOSD.

Methods: sGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG patients over a median observation period of 4.25 years.

Results: In patients with AQP4-IgG NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG, but not MOG-IgG patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = - 1.28, p = 0.01). While in AQP4-IgG, but not MOG-IgG patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = - 1.75, p = 0.06) in patients with AQP4-IgG NMOSD. Patients with AQP4-IgG NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3-105.6], p = 0.03). In contrast, baseline sNfL levels above the 75 age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG NMOSD.

Conclusion: These findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG NMOSD in phases of clinical remission.
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http://dx.doi.org/10.1186/s12974-021-02138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088712PMC
May 2021

Longitudinal analysis of T1w/T2w ratio in patients with multiple sclerosis from first clinical presentation.

Mult Scler 2021 Apr 15:13524585211003479. Epub 2021 Apr 15.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany/ NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany/Einstein Center for Neurosciences, Berlin, Germany/Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS).

Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally.

Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1-60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria.

Results: At baseline, sT1w/T2w ( = 0.152) and cortical thickness ( = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal  = 0.061). The association was modulated by failing NEDA-3 (marginal  = 0.097).

Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.
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http://dx.doi.org/10.1177/13524585211003479DOI Listing
April 2021

Lateral geniculate nucleus volume changes after optic neuritis in neuromyelitis optica: A longitudinal study.

Neuroimage Clin 2021 Mar 4;30:102608. Epub 2021 Mar 4.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, University of California Irvine, CA, USA. Electronic address:

Objectives: Lateral geniculate nucleus (LGN) volume is reduced after optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD). We aimed at a longitudinal assessment of LGN volume in NMOSD.

Methods: Twenty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 47.8 ± 14.6 years (y), female: n = 27, history of ON (NMO-ON): n = 17, median time since ON: 3[1.2-12.1]y) and 18 healthy controls (HC; age: 39.3 ± 15.8y; female: n = 13) were included. Median follow-up was 4.1[1.1-4.7]y for patients and 1.7[0.9-3.2]y for HC. LGN volume was measured using a multi-atlas-based approach of automated segmentation on 3 Tesla magnetic resonance images. Retinal optical coherence tomography and probabilistic tractography of the optic radiations (OR) were also performed.

Results: At baseline, NMO-ON patients had lower LGN volumes (395.4 ± 48.9 mm) than patients without ON (NMO-NON: 450.7 ± 55.6 mm; p = 0.049) and HC (444.5 ± 61.5 mm, p = 0.025). LGN volume was associated with retinal neuroaxonal loss and microstructural OR damage. Longitudinally, there was no change in LGN volumes in the absence of ON, neither in all patients (B = -0.6, SE = 1.4, p = 0.670), nor in NMO-ON (B = -0.8, SE = 1.6, p = 0.617) and NMO-NON (B = 1.7, SE = 3.5, p = 0.650). However, in four patients with new ON during follow-up, LGN volume was reduced at last visit (median time since ON: 2.6 [1.8-3.9]y) compared to the measurement before ON (352 ± 52.7 vs. 371.1 ± 55.9 mm; t = -3.6, p = 0.036).

Conclusion: Although LGN volume is reduced after ON in NMOSD, this volume loss is not progressive over longer follow-up or independent of ON. Thus, our findings -at least in this relatively small cohort- do not support occult neurodegeneration of the afferent visual pathway in NMOSD.
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http://dx.doi.org/10.1016/j.nicl.2021.102608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974320PMC
March 2021

Multiple Sclerosis Is Rare in Epstein-Barr Virus-Seronegative Children with Central Nervous System Inflammatory Demyelination.

Ann Neurol 2021 Mar 11. Epub 2021 Mar 11.

Department of Neurology, University of California, San Francisco, San Francisco, CA.

Although Epstein-Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV-seronegative. When re-evaluating 25 EBV-seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti-myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV-seronegative but only 9 of 164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV-seronegative/MOG antibody-negative patients. In children with an MS-like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG-antibody disease. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26062DOI Listing
March 2021

Foveal changes in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder are independent of optic neuritis and not overtly progressive.

Eur J Neurol 2021 Feb 6. Epub 2021 Feb 6.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Background And Purpose: Foveal changes were reported in aquaporin-4 antibody (AQP4-Ab) seropositive neuromyelitis optica spectrum disorder (NMOSD) patients; however, it is unclear whether they are independent of optic neuritis (ON), stem from subclinical ON or crossover from ON in fellow eyes. Fovea morphometry and a statistical classification approach were used to investigate if foveal changes in NMOSD are independent of ON and progressive.

Methods: This was a retrospective longitudinal study of 27 AQP4-IgG + NMOSD patients (49 eyes; 15 ON eyes and 34 eyes without a history of ON [NON eyes]), follow-up median (first and third quartile) 2.32 (1.33-3.28), and 38 healthy controls (HCs) (76 eyes), follow-up median (first and third quartile) 1.95 (1.83-2.54). The peripapillary retinal nerve fibre layer thickness and the volume of combined ganglion cell and inner plexiform layer as measures of neuroaxonal damage from ON were determined by optical coherence tomography. Nineteen foveal morphometry parameters were extracted from macular optical coherence tomography volume scans. Data were analysed using orthogonal partial least squares discriminant analysis and linear mixed effects models.

Results: At baseline, foveal shape was significantly altered in ON eyes and NON eyes compared to HCs. Discriminatory analysis showed 81% accuracy distinguishing ON vs. HCs and 68% accuracy in NON vs. HCs. NON eyes were distinguished from HCs by foveal shape parameters indicating widening. Orthogonal partial least squares discriminant analysis discriminated ON vs. NON with 76% accuracy. In a follow-up of 2.4 (20.85) years, no significant time-dependent foveal changes were found.

Conclusion: The parafoveal area is altered in AQP4-Ab seropositive NMOSD patients suggesting independent neuroaxonal damage from subclinical ON. Longer follow-ups are needed to confirm the stability of the parafoveal structure over time.
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http://dx.doi.org/10.1111/ene.14766DOI Listing
February 2021

Pain, depression, and quality of life in adults with MOG-antibody-associated disease.

Eur J Neurol 2021 May 11;28(5):1645-1658. Epub 2021 Feb 11.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background And Purpose: Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD.

Methods: Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items.

Results: Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p < 0.001) than in pain-free patients, being most severely reduced by neuropathic pain (p = 0.016). Pain severity, visual impairment, and gait impairment independently predicted lower physical QoL. Depression was the only factor reducing mental QoL. Twelve patients still suffering from moderate pain (pain severity 4.6 ± 2.3) received pain medication. Only four out of 10 patients with moderate to severe depression took antidepressants.

Conclusions: Being highly prevalent, pain and depression strongly affect QoL and ADL in MOGAD. Both conditions remain insufficiently controlled in real-life clinical practice.
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http://dx.doi.org/10.1111/ene.14729DOI Listing
May 2021

Delayed onset hypophysitis after therapy with daclizumab for multiple sclerosis - A report of two cases.

J Neuroimmunol 2021 Feb 25;351:577469. Epub 2020 Dec 25.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.

Daclizumab (DAC), a humanized monoclonal antibody that binds to the interleukin (IL)-2-receptor alpha chain, was approved in May 2016 for treatment of relapsing-remitting multiple sclerosis (RRMS). Approval was suspended in March 2018 after occurrence of severe liver failure and fatal meningoencephalitis in several patients treated with DAC. We report the clinical, laboratory and neuroimaging findings of 2 patients, who developed hypophysitis about 4 months after cessation of therapy with DAC. This report identifies delayed onset hypophysitis as a previously unrecognized severe side effect of DAC, highlighting the importance of continuous pharmacovigilance and patient monitoring even after cessation of DAC therapy.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577469DOI Listing
February 2021

Ventral posterior nucleus volume is associated with neuropathic pain intensity in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Nov 13;46:102579. Epub 2020 Oct 13.

Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, University of California Irvine, CA, USA.

Background: Neuropathic pain (NP) is frequent in neuromyelitis optica spectrum disorders (NMOSD). The ventral posterior nucleus (VPN) of the thalamus receives sensory afferences from the spinothalamic tracts and is associated with central pain in other conditions.

Objective: To investigate associations between NP and VPN volume in aquaporin-4-IgG- positive (AQP4-IgG+) NMOSD.

Methods: This cross-sectional study included 32 AQP4-IgG+ NMOSD patients and 37 healthy controls. NP intensity was determined by the PainDetect Questionnaire. Spinal cord lesion number and location as well as VPN volume were assessed by MRI, the latter using a multi-atlas-based automated segmentation.

Results: Twenty-five patients (78%) suffered from NP and seven had no pain. Mean VPN volume did not differ between patients with and without NP (p=0.533) or between patients and controls. However, mean VPN volume correlated with average (rho=-0.486, p=0.019) and worst pain intensity (rho=-0.593, p=0.003). Of note, no other thalamic nuclei volumes correlated with measures of pain intensity. Compared to pain-free patients, patients with NP had more lesions involving the thoracic spinal cord (p=0.007). The relationships between VPN and pain intensity measures remained after adjustment for age, myelitis count, and spinal cord lesion location.

Conclusion: Our data support a model where thoracic spinal cord lesions are associated with the development of NP in AQP4-IgG+ NMOSD and the VPN plays a role in the modulation of NP intensity. VPN volume as assessed in our study may be a clinically meaningful imaging marker of pain severity in AQP4-IgG+ NMOSD.
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http://dx.doi.org/10.1016/j.msard.2020.102579DOI Listing
November 2020

Anti-MOG antibody-associated disorders: differences in clinical profiles and prognosis in Japan and Germany.

J Neurol Neurosurg Psychiatry 2020 Nov 20. Epub 2020 Nov 20.

Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan

Background: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder.

Objective: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients.

Methods: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24).

Results: Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%).

Conclusions: Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.
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http://dx.doi.org/10.1136/jnnp-2020-324422DOI Listing
November 2020

The role of Epstein-Barr virus in the etiology of multiple sclerosis: a current review.

Authors:
Klemens Ruprecht

Expert Rev Clin Immunol 2020 12 17;16(12):1143-1157. Epub 2020 Dec 17.

Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health , Berlin, Germany.

: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. While its exact etiology is unknown, it is generally believed that MS is caused by environmental triggers in genetically predisposed individuals. Strong and consistent evidence suggests a key role of Epstein-Barr virus (EBV), a B lymphotropic human gammaherpesvirus, in the etiology of MS. : This review summarizes recent developments in the field of EBV and MS with a focus on potential mechanisms underlying the role of EBV in MS. PubMed was searched for the terms 'Epstein-Barr virus' and 'multiple sclerosis'. : The current evidence is compatible with the working hypothesis that MS is a rare complication of EBV infection. Under the premise of a causative role of EBV in MS, it needs to be postulated that EBV causes a specific, and likely persistent, change(s) that is necessarily required for the development of MS. However, although progress has been made, the nature of that change and thus the precise mechanism explaining the role of EBV in MS remain elusive. The mechanism of EBV in MS therefore is a pressing question, whose clarification may substantially advance the pathophysiological understanding, rational therapies, and prevention of MS.
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http://dx.doi.org/10.1080/1744666X.2021.1847642DOI Listing
December 2020

Differences in Advanced Magnetic Resonance Imaging in MOG-IgG and AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders: A Comparative Study.

Front Neurol 2020 30;11:499910. Epub 2020 Sep 30.

NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study.
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http://dx.doi.org/10.3389/fneur.2020.499910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554609PMC
September 2020

MOG-expressing teratoma followed by MOG-IgG-positive optic neuritis.

Acta Neuropathol 2021 01 19;141(1):127-131. Epub 2020 Oct 19.

Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.

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http://dx.doi.org/10.1007/s00401-020-02236-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785547PMC
January 2021

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study.

Brain Commun 2019 16;1(1):fcz026. Epub 2019 Oct 16.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens ( = -0.85,  = 0.021) and caudate nucleus ( = -0.61,  = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures.
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http://dx.doi.org/10.1093/braincomms/fcz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425339PMC
October 2019

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 Neurology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, 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

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 1: Results from 163 lumbar punctures in 100 adult patients.

J Neuroinflammation 2020 Sep 3;17(1):261. Epub 2020 Sep 3.

Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, 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 MOG-EM.

Material And Methods: Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM 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 163 lumbar punctures in 100 adult 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 almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood-CSF barrier dysfunction was present also during remission in a substantial number of patients.

Conclusion: MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of 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/s12974-020-01824-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470615PMC
September 2020

Cerebrospinal fluid cytology in subacute subarachnoid hemorrhage.

Neurology 2020 10 26;95(15):699-700. Epub 2020 Aug 26.

From the Departments of Neurology (L.M.-J., K.R., C.L.), Neuroradiology (E.D.), and Neuropathology (A.O.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000010713DOI Listing
October 2020

Visual system damage and network maladaptation are associated with cognitive performance in neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2020 Oct 17;45:102406. Epub 2020 Jul 17.

NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine & Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Department of Neurology, University of California, Irvine, CA, USA. Electronic address:

Background Neuromyelitis Optica Spectrum Disorders (NMOSD) is an autoimmune disease leading to disability from optic neuritis, myelitis and more rarely brain stem attacks and encephalitis. Patients with NMOSD also exhibit cognitive deficits, the cause of which remains unclear. Recent evidence highlights sensory-cognitive parallel processing converging on the primary visual cortex. The objective of this study was to investigate the effect of the primary visual network disruption from damage caused by optic neuritis on cognition in NMOSD. Methods Twenty-nine aquaporin-4 antibody seropositive patients with NMOSD and 22 healthy controls (HC) completed the brief repeatable battery of neuropsychological tests (BRB-N) and underwent 3 Tesla MRI. Primary visual network functional connectivity (FC) at resting state was analyzed and correlated with performance on BRB-N. These correlations were compared between the groups. Results Patients performed significantly worse than HC on the BRB-N Index score (t = 2.366, p = 0.02). Among HC, visual network FC decreased significantly as cognitive performance on the BRB-N Index score increased (rho(17)=-0.507, p = 0.02). Among patients, this association was absent (rho(23)=0.197, p = 0.18), and the difference in correlation direction and strength to HC was significant (z=-2.175, p = 0.01). Visual network FC was able to explain 19% of the variance in cognitive performance in HC, but none in patients. Conclusions A physiological association of the primary visual network FC and cognitive performance appears absent in patients with NMOSD, suggesting a partial explanation for cognitive deficits. Our findings extend neuroscientific concepts on sensory-cognitive parallel processing neural networks to a clearly defined pathological state, and may be relevant for other diseases with visual system damage.
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http://dx.doi.org/10.1016/j.msard.2020.102406DOI Listing
October 2020

Pediatric NMOSD: A Review and Position Statement on Approach to Work-Up and Diagnosis.

Front Pediatr 2020 25;8:339. Epub 2020 Jun 25.

Division of Neurology, Department of Pediatrics, SickKids Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) primarily affecting the optic nerves and spinal cord, but also involving other regions of the CNS including the area postrema, periaqueductal gray matter, and hypothalamus. Knowledge related to pediatric manifestations of NMOSD has grown in recent years, particularly in light of newer information regarding the importance of not only antibodies to aquaporin 4 (AQP4-IgG) but also myelin oligodendrocyte glycoprotein (MOG-IgG) in children manifesting clinically with this syndrome. In this review, we describe the current state of the knowledge related to clinical manifestations, diagnosis, and chronic therapies for children with NMOSD, with emphasis on literature that has been published in the last 5 years. Following the review, we propose recommendations for the assessment/follow up clinical care, and treatment of this population.
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http://dx.doi.org/10.3389/fped.2020.00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330096PMC
June 2020

Altered fovea in AQP4-IgG-seropositive neuromyelitis optica spectrum disorders.

Neurol Neuroimmunol Neuroinflamm 2020 09 23;7(5). Epub 2020 Jun 23.

From the Experimental and Clinical Research Center (S.M., F.C.O., J.B.-S., H.G.Z., F.P., A.U.B.), Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; NeuroCure Clinical Research Center (S.M., F.C.O., S.K.Y., E.M.K., J.B.-S., H.G.Z., F.P., A.U.B.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Division of Neuroinflammation and Glial Biology (F.C.O.), University of California, San Francisco; Nocturne GmbH (S.K.Y., E.M.K.), Berlin; Department of Neurology (M.W., M.R., O.A., P.A.), Medical Faculty, Heinrich Heine University, Düsseldorf; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians University, Munich; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; and Department of Neurology (A.U.B.), University of California, Irvine.

Objective: To investigate disease-specific foveal shape changes in patients with neuromyelitis optica spectrum disorders (NMOSDs) using foveal morphometry.

Methods: This cross-sectional study included macular spectral domain optical coherence tomography scans of 52 eyes from 28 patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD, 116 eyes from 60 patients with MS, and 123 eyes from 62 healthy controls (HCs), retrospectively, and an independent confirmatory cohort comprised 33/33 patients with NMOSD/MS. The fovea was characterized using 3D foveal morphometry. We included peripapillary retinal nerve fiber layer (pRNFL) thickness and combined macular ganglion cell and inner plexiform layer (GCIPL) volume to account for optic neuritis (ON)-related neuroaxonal damage.

Results: Group comparison showed significant differences compared with HC in the majority of foveal shape parameters in NMOSD, but not MS. Pit flat disk area, average pit flat disk diameter, inner rim volume, and major slope disk length, as selected parameters, showed differences between NMOSD and MS ( value = 0.017, 0.002, 0.005, and 0.033, respectively). This effect was independent of ON. Area under the curve was between 0.7 and 0.8 (receiver operating characteristic curve) for discriminating between NMOSD and MS. Pit flat disk area and average pit flat disk diameter changes independent of ON were confirmed in an independent cohort.

Conclusions: Foveal morphometry reveals a wider and flatter fovea in NMOSD in comparison to MS and HC. Comparison to MS and accounting for ON suggest this effect to be at least in part independent of ON. This supports a primary retinopathy in AQP4-IgG-seropositive NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413713PMC
September 2020

Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica.

Nat Commun 2020 06 5;11(1):2856. Epub 2020 Jun 5.

Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK, 73104, USA.

Type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and in TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here we report that a cascade involving IFN-I, IL-6 and B cells promotes TH17-mediated neuro-autoimmunity. In NMOSD, elevated IFN-I signatures, IL-6 and IL-17 are associated with severe disability. Furthermore, IL-6 and IL-17 levels are lower in patients on anti-CD20 therapy. In mice, IFN-I elevates IL-6 and exacerbates TH17-EAE. Strikingly, IL-6 blockade attenuates disease only in mice treated with IFN-I. By contrast, B-cell-deficiency attenuates TH17-EAE in the presence or absence of IFN-I treatment. Finally, IFN-I stimulates B cells to produce IL-6 to drive pathogenic TH17 differentiation in vitro. Our data thus provide an explanation for the paradox surrounding IFN-I and TH17 in neuro-autoimmunity, and may have utility in predicting therapeutic response in NMOSD.
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http://dx.doi.org/10.1038/s41467-020-16625-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275086PMC
June 2020

Analysis of soluble interleukin-2 receptor as CSF biomarker for neurosarcoidosis.

Neurol Neuroimmunol Neuroinflamm 2020 07 11;7(4). Epub 2020 May 11.

From the Department of Neurology (C.O., O.W., K.R.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Labor Berlin Charité-Vivantes GmbH (N.U., C.M.); and Institute for Medical Immunology (C.M.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objective: To systematically analyze soluble interleukin-2 receptor (sIL-2R) in CSF as a diagnostic and disease activity biomarker in patients with sarcoidosis involving the CNS (neurosarcoidosis).

Methods: sIL-2R was determined by chemiluminescent immunoassays in CSF/serum samples from patients with neurosarcoidosis (n = 23), MS (n = 19), neurotuberculosis (n = 8), viral (n = 18) and bacterial (n = 9) meningitis, cerebral lymphoma (n = 15), Guillain-Barré syndrome (n = 8), and 115 patients with noninflammatory neurologic diseases (NINDs) as controls. The sIL-2R index was calculated by dividing the CSF/serum sIL-2R quotient (Q) through the CSF/serum albumin quotient (Q). sIL-2R quotient diagrams were established by plotting Q against Q. sIL-2R levels were correlated with clinical, MRI, and CSF disease activity markers of neurosarcoidosis.

Results: Patients with neurosarcoidosis had higher CSF sIL-2R, Q, and sIL-2R index values than patients with NINDs ( < 0.0001 for all pairwise group comparisons). sIL-2R quotient diagrams demonstrated an intrathecal sIL-2R synthesis in >50% of neurosarcoidosis samples. Similar findings were observed in viral/bacterial meningitis, CNS lymphoma, and, most pronounced, in neurotuberculosis, but not in patients with MS. CSF sIL-2R parameters were associated with clinical disease activity, leptomeningeal gadolinium enhancement, and the CSF white cell count in patients with neurosarcoidosis.

Conclusions: CSF sIL-2R parameters are elevated in patients with neurosarcoidosis, but this finding is not specific for neurosarcoidosis. Nevertheless, CSF sIL-2R parameters may help distinguishing neurosarcoidosis from MS and are associated with clinical, radiologic, and CSF disease activity markers of neurosarcoidosis.

Classification Of Evidence: This study provides Class II evidence that CSF sIL-2R parameters distinguish neurosarcoidosis from NINDs and MS.
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http://dx.doi.org/10.1212/NXI.0000000000000725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238895PMC
July 2020

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

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

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Optic chiasm measurements may be useful markers of anterior optic pathway degeneration in neuromyelitis optica spectrum disorders.

Eur Radiol 2020 Sep 26;30(9):5048-5058. Epub 2020 Apr 26.

NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Objectives: We aimed to evaluate optic chiasm (OC) measures as potential imaging marker for anterior optic pathway damage assessment in the context of neuromyelitis optica spectrum disorders (NMOSD).

Materials And Method: This cross-sectional study included 39 patients exclusively with aquaporin 4-IgG seropositive NMOSD of which 25 patients had a history of optic neuritis (NMOSD-ON) and 37 age- and sex-matched healthy controls (HC). OC heights, width, and area were measured using standard 3D T1-weighted MRI. Sensitivity of these measures to detect neurodegeneration in the anterior optic pathway was assessed in receiver operating characteristics analyses. Correlation coefficients were used to assess associations with structural measures of the anterior optic pathway (optic nerve dimensions, retinal ganglion cell loss) and clinical measures (visual function and disease duration).

Results: OC heights and area were significantly smaller in NMOSD-ON compared to HC (NMOSD-ON vs. HC p < 0.0001). An OC area smaller than 22.5 mm yielded a sensitivity of 0.92 and a specificity of 0.92 in separating chiasms of NMOSD-ON from HC. OC area correlated well with structural and clinical measures in NMOSD-ON: optic nerve diameter (r = 0.4, p = 0.047), peripapillary retinal nerve fiber layer thickness (r = 0.59, p = 0.003), global visual acuity (r = - 0.57, p = 0.013), and diseases duration (r = - 0.5, p = 0.012).

Conclusion: Our results suggest that OC measures are promising and easily accessible imaging markers for the assessment of anterior optic pathway damage.

Key Points: • Optic chiasm dimensions were smaller in neuromyelitis optica spectrum disorder patients compared to healthy controls. • Optic chiasm dimensions are associated with retinal measures and visual dysfunction. • The optic chiasm might be used as an easily accessible imaging marker of neurodegeneration in the anterior optic pathway with potential functional relevance.
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http://dx.doi.org/10.1007/s00330-020-06859-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431438PMC
September 2020

Evaluation of the 'ring sign' and the 'core sign' as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis.

Mult Scler J Exp Transl Clin 2020 Jan-Mar;6(1):2055217320915480. Epub 2020 Mar 30.

qbig, Department of Biomedical Engineering, University of Basel, Switzerland.

Background: Brain lesions with a hypointense ring or core were described in multiple sclerosis on susceptibility weighted imaging.

Objective: The purpose of this study was to study the evolution and prognostic relevance of susceptibility weighted imaging hypointense lesions in clinically isolated syndrome and early multiple sclerosis.

Methods: Sixty-six early multiple sclerosis and clinically isolated syndrome patients were followed over a median period of 2.9 years (range 1.6-4.6 years) and underwent 3T magnetic resonance imaging including 3D susceptibility weighted imaging and T2-weighted fluid-attenuated inversion recovery. We assessed the presence of susceptibility weighted imaging hypointense core or ring lesions, and Expanded Disability Status Scale at baseline and follow-up.

Results: Of 611 lesions at baseline, 64 (10.5%) had a susceptibility weighted imaging hypointense core, and 28 (4.6%) had a susceptibility weighted imaging hypointense ring. Hypointense ring lesions were larger ( < 0.001) and more T1w hypointense ( = 0.002) than others. During follow-up, hypointense core lesions became susceptibility weighted imaging isointense (52 lesions, 81%); few developed into hypointense ring lesions (two lesions, 3%). Hypointense ring lesions did not shrink on T2-weighted fluid-attenuated inversion recovery images ( = 0.077, trend towards more enlargement compared to others), while hypointense core lesions more often shrunk in comparison to lesions without a hypointense core ( = 0.002). The number of susceptibility weighted imaging hypointense ring lesions at baseline correlated with Expanded Disability Status Scale progression at follow-up ( = 0.021, R = 0.289).

Conclusion: In our cohort of patients with clinically isolated syndrome or early multiple sclerosis, susceptibility weighted imaging hypointense ring lesions were only rarely detectable, but did not shrink and were associated with future disability progression.
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http://dx.doi.org/10.1177/2055217320915480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132556PMC
March 2020

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs, such as HERV-K(HML-2), are reported to be involved in neurological disorders, little is known about their biological function. We report that RNA from an HERV-K(HML-2) envelope gene region binds to and activates human Toll-like receptor (TLR) 8, as well as murine Tlr7, expressed in neurons and microglia, thereby causing neurodegeneration. HERV-K(HML-2) RNA introduced into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer's disease (AD), resulted in neurodegeneration and microglia accumulation. Tlr7-deficient mice were protected against neurodegenerative effects but were resensitized toward HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Transcriptome data sets of human AD brain samples revealed a distinct correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from individuals with AD compared with controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for species-specific TLRs 7/8 and imply a functional contribution of human endogenous retroviral transcripts to neurodegenerative processes, such as AD.
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http://dx.doi.org/10.1172/jci.insight.131093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205273PMC
April 2020

Binding patterns and functional properties of human antibodies to AQP4 and MOG on murine optic nerve and retina.

J Neuroimmunol 2020 Feb 20;342:577194. Epub 2020 Feb 20.

Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791 Bochum, Germany. Electronic address:

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-inflammatory CNS disease affecting spinal cord and optic nerves, mediated by autoantibodies against aquaporin-4 (AQP4) and myelin-oligodendrocyte-glycoprotein (MOG). Effects of those immunoglobulins (Ig) on retina and optic nerve are incompletely understood. We investigated AQP4-IgG and MOG-IgG sera on retina and optic nerve ex vivo and in 2D2 mice, which harbor a transgenic MOG-specific T-cell receptor. Some sera reacted with murine retina and optic nerve showing distinct binding patterns, suggesting different epitopes being targeted in both subgroups. Transfer of total IgG from a MOG-IgG positive patient to 2D2 mice did neither enhance disability nor induce functional or histological alterations in the retina.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577194DOI Listing
February 2020

Cortical topological network changes following optic neuritis.

Neurol Neuroimmunol Neuroinflamm 2020 05 2;7(3). Epub 2020 Mar 2.

From the fMRI Unit (Y.B., I.B.-S., N.L.), Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Experimental and Clinical Research Center (J.K., N.S., A.B., F.P.), Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany; NeuroCure Clinical Research Center (J.K., N.S., M.S., A.B., F.P.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Department of Neurology (J.K., K.R., F.P.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Department of Neuroradiology (M.S.), Charité-Universitätsmedizin Berlin, Germany; and Department of Neurology (A.B.), University of California, Irvine.

Objective: To differentiate between visual cortical network topology changes following optic neuritis (ON) stemming from different inflammatory disease types, we used mathematical graph theory-based tools to analyze functional imaging data.

Methods: Sixty-two patients were recruited into this cross-sectional study, 23 of whom had neuromyelitis optica spectrum disorder (NMOSD) with ON, 18 with clinically isolated syndrome (CIS)-ON, and 21 with other CIS episodes. Twenty-six healthy controls (HCs) were also recruited. All participants underwent resting-state functional MRI. Visual networks were defined using 50 visual regions of interest. Analysis included graph theory metrics, including degree, density, modularity, and local and global efficiency.

Results: Visual network density shows decreased connectivity in all patient groups compared with controls. A higher degree of connections is seen in both ON groups (CIS and NMOSD) compared with the the non-ON group. This pattern is most pronounced in dorsal-lateral regions. Information transfer efficiency and modularity were reduced in both CIS groups, but not in the NMOSD group, compared with the HC group.

Conclusions: Visual network density appears affected by the neurologic deficit sustained (ON), and connectivity changes are more evident in dorsal-lateral regions. Efficiency and modularity appear to be associated with the specific disease type (CIS vs NMOSD). Thus, topological cortical changes in the visual system are associated with the type of neurologic deficit within the limits set on them by the underlying pathophysiology. We suggest that cortical patterns of activity should be considered in the outcome of the patients despite the localized nature of ON.
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http://dx.doi.org/10.1212/NXI.0000000000000687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136064PMC
May 2020

Prodromal headache in MOG-antibody positive optic neuritis.

Mult Scler Relat Disord 2020 May 25;40:101965. Epub 2020 Jan 25.

Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Background: Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease is an inflammatory autoimmune condition of the central nervous system, defined by antibodies (Abs) against MOG. Of the various clinical phenotypes optic neuritis (ON) is the commonest. We have observed that some patients with MOG-Ab ON present with a severe associated headache.

Objective: To highlight the importance of headache in MOG-Ab related optic neuritis.

Methods: Clinical and MRI data from MOG-Ab patients with ON (n = 129) were obtained from observational cohort studies and clinical notes at the NeuroCure Clinical Research Center, Charité Berlin and at the Diagnostic and Advisory Service for Neuromyelitis Optica, John Radcliffe Hospital, Oxford.

Results: Sixty-four of 129 MOG-Ab patients (49.6%) reported ≥1 headache-related ON. Headache usually started a few days prior to visual loss and extended from the ocular region to the periorbital and fronto-temporal area, sometimes mimicking migraine. Of those, thirty-two patients (50%) reported severe headache. Two patients did not have headache. No headache history was recorded for 63 patients. MRIs performed acutely during headache-related MOG-Ab ON (n = 15) showed anterior ON with extensive swelling and edema of the optic nerve/s in all patients, either unilaterally (n = 5) or bilaterally (n = 10). Peri-optic cerebro-spinal fluid (CSF) was undetectable due to the inflammatory extension in 12 out of 15 patients.

Conclusion: Our findings indicate that acute MOG-Ab ON shows florid intra-orbital and peri‑optic inflammation, likely to involve meninges and nociceptive fibers around the optic nerve. This may explain the frequent and often severe headache that precedes the visual deficit, sometimes misdiagnosed as migraine.
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http://dx.doi.org/10.1016/j.msard.2020.101965DOI Listing
May 2020

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns.

Acta Neuropathol 2020 03 16;139(3):547-564. Epub 2020 Jan 16.

Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.

Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I-III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló's concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló's), healthy controls, patients with Sjögren's syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló's, AQP1 reactivity was also significantly higher compared to patients without Baló's (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló's patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló's patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.
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http://dx.doi.org/10.1007/s00401-019-02120-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035238PMC
March 2020