Publications by authors named "Sven Schippling"

78 Publications

The APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts, and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: One hundred sixteen authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point-checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans; we suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence class III, GRADE criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, fundoscopic imaging, post-acquisition data selection, post-acquisition analysis, nomenclature and abbreviations, and statistical approach. It will still be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
April 2021

A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis.

Mult Scler 2021 Apr 6:13524585211003020. Epub 2021 Apr 6.

Biogen, Cambridge, MA, USA.

Background: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing-remitting multiple sclerosis (RRMS) patients.

Objective: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients.

Methods: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60.

Results: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable.

Conclusion: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
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http://dx.doi.org/10.1177/13524585211003020DOI Listing
April 2021

Structure-Function Relationship of Retinal Ganglion Cells in Multiple Sclerosis.

Int J Mol Sci 2021 Mar 26;22(7). Epub 2021 Mar 26.

Department of Ophthalmology, University Hospital Magdeburg, 39120 Magdeburg, Germany.

The retinal ganglion cells (RGC) may be considered an easily accessible pathophysiological site of degenerative processes in neurological diseases, such as the RGC damage detectable in multiple sclerosis (MS) patients with (HON) and without a history of optic neuritis (NON). We aimed to assess and interrelate RGC functional and structural damage in different retinal layers and retinal sites. We included 12 NON patients, 11 HON patients and 14 healthy controls for cross-sectional multifocal pattern electroretinography (mfPERG) and optical coherence tomography (OCT) measurements. Amplitude and peak times of the mfPERG were assessed. Macula and disc OCT scans were acquired to determine macular retinal layer and peripapillary retinal nerve fiber layer (pRNFL) thickness. In both HON and NON patients the foveal N2 amplitude of the mfPERG was reduced compared to controls. The parafoveal P1 peak time was significantly reduced in HON only. For OCT, parafoveal (pfGCL) and perifoveal (pGCL) ganglion cell layer thicknesses were decreased in HON vs. controls, while pRNFL in the papillomacular bundle sector (PMB) showed reductions in both NON and HON. As the mfPERG derived N2 originates from RGC axons, these findings suggest foveal axonal dysfunction not only in HON, but also in NON patients.
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http://dx.doi.org/10.3390/ijms22073419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037992PMC
March 2021

Predicting disability worsening in relapsing and progressive multiple sclerosis.

Curr Opin Neurol 2021 Jun;34(3):312-321

Mellen Center for Multiple Sclerosis, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.

Purpose Of Review: Multiple sclerosis (MS) is a clinically heterogeneous disease, which complicates expectant management as well as treatment decisions. This review provides an overview of both well established and emerging predictors of disability worsening, including clinical factors, imaging factors, biomarkers and treatment strategies.

Recent Findings: In addition to well known clinical predictors (age, male sex, clinical presentation, relapse behaviour), smoking, obesity, vascular and psychiatric comorbidities are associated with subsequent disability worsening in persons with MS. A number of imaging features are predictive of disability worsening and are present to varying degrees in relapsing and progressive forms of MS. These include brain volumes, spinal cord atrophy, lesion volumes and optical coherence tomography features. Cerebrospinal and more recently blood biomarkers including neurofilament light show promise as more easily attainable biomarkers of future disability accumulation. Importantly, recent observational studies suggest that initiation of early-intensive therapy, as opposed to escalation based on breakthrough disease, is associated with decreased accumulation of disability overall, although randomized controlled trials investigating this question are underway.

Summary: Understanding risk factors associated with disability progression can help to both counsel patients and enhance the clinician's availability to provide evidence-based treatment recommendations.
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http://dx.doi.org/10.1097/WCO.0000000000000928DOI Listing
June 2021

Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS.

Mult Scler Relat Disord 2021 Feb 10;48:102673. Epub 2020 Dec 10.

Department of Neurology, Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 USA. Electronic address:

Background: Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS).

Methods: In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18‒55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging.

Results: Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031‒0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg‒treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained improvement at month 12. Brain volume loss was similar for those with SDMT improvement versus worsening at month 12.

Conclusions: In these exploratory analyses, ozanimod had modestly beneficial effects on CPS in RMS participants. The effects of ozanimod on SDMT are being further evaluated in an ongoing 3-year clinical trial. SUNBEAM is registered on clinicaltrials.gov (NCT02294058) and the European Clinical Trials Database (EudraCT 2014-002320-27).
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http://dx.doi.org/10.1016/j.msard.2020.102673DOI Listing
February 2021

Age-dependent cut-offs for pathological deep gray matter and thalamic volume loss using Jacobian integration.

Neuroimage Clin 2020 27;28:102478. Epub 2020 Oct 27.

Multimodal Imaging in Neuroimmunological Diseases (MINDS), University of Zurich, Zurich, Switzerland; Center for Neuroscience Zurich (ZNZ), ETH Zurich, Zurich, Switzerland.

Introduction: Several recent studies indicate that deep gray matter or thalamic volume loss (VL) might be promising surrogate markers of disease activity in multiple sclerosis (MS) patients. To allow applying these markers to individual MS patients in clinical routine, age-dependent cut-offs distinguishing physiological from pathological VL and an estimation of the measurement error, which provides the confidence of the result, are to be defined.

Methods: Longitudinal MRI scans of the following cohorts were analyzed in this study: 189 healthy controls (HC) (mean age 54 years, 22% female), 98 MS patients from Zurich university hospital (mean age 34 years, 62% female), 33 MS patients from Dresden university hospital (mean age 38 years, 60% female), and publicly available reliability data sets consisting of 162 short-term MRI scan-rescan pairs with scan intervals of days or few weeks. Percentage annualized whole brain volume loss (BVL), gray matter (GM) volume loss (GMVL), deep gray matter volume loss (deep GMVL), and thalamic volume loss (ThalaVL) were computed deploying the Jacobian integration (JI) method. BVL was additionally computed using Siena, an established method used in many Phase III drug trials. A linear mixed effect model was used to estimate the measurement error as the standard deviation (SD) of model residuals of all 162 scan-rescan pairs For estimation of age-dependent cut-offs, a quadratic regression function between age and the corresponding annualized VL values of the HC was computed. The 5th percentile was defined as the threshold for pathological VL per year since 95% of HC subjects exhibit a less pronounced VL for a given age. For the MS patients BVL, GMVL, deep GMVL, and ThalaVL were mutually compared and a paired t-test was used to test whether there are systematic differences in VL between these brain regions.

Results: Siena and JI showed a high agreement for BVL measures, with a median absolute difference of 0.1% and a correlation coefficient of r = 0.78. Siena and GMVL showed a similar standard deviation (SD) of the scan-rescan error of 0.28% and 0.29%, respectively. For deep GMVL, ThalaVL the SD of the scan-rescan error was slightly higher (0.43% and 0.5%, respectively). Among the HC the thalamus showed the highest mean VL (-0.16%, -0.39%, and -0.59% at ages 35, 55, and 75, respectively). Corresponding cut-offs for a pathological VL/year were -0.68%, -0.91%, and -1.11%. The MS cohorts did not differ in BVL and GMVL. However, both MS cohorts showed a significantly (p = 0.05) stronger deep GMVL than BVL per year.

Conclusion: It might be methodologically feasible to assess deep GMVL using JI in individual MS patients. However, age and the measurement error need to be taken into account. Furthermore, deep GMVL may be used as a complementary marker to BVL since MS patients exhibit a significantly stronger deep GMVL than BVL.
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http://dx.doi.org/10.1016/j.nicl.2020.102478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645288PMC
October 2020

Fully automated longitudinal segmentation of new or enlarged multiple sclerosis lesions using 3D convolutional neural networks.

Neuroimage Clin 2020 24;28:102445. Epub 2020 Sep 24.

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and Federal Institute of Technology (ETH), Zurich, Switzerland.

The quantification of new or enlarged lesions from follow-up MRI scans is an important surrogate of clinical disease activity in patients with multiple sclerosis (MS). Not only is manual segmentation time consuming, but inter-rater variability is high. Currently, only a few fully automated methods are available. We address this gap in the field by employing a 3D convolutional neural network (CNN) with encoder-decoder architecture for fully automatic longitudinal lesion segmentation. Input data consist of two fluid attenuated inversion recovery (FLAIR) images (baseline and follow-up) per patient. Each image is entered into the encoder and the feature maps are concatenated and then fed into the decoder. The output is a 3D mask indicating new or enlarged lesions (compared to the baseline scan). The proposed method was trained on 1809 single point and 1444 longitudinal patient data sets and then validated on 185 independent longitudinal data sets from two different scanners. From the two validation data sets, manual segmentations were available from three experienced raters, respectively. The performance of the proposed method was compared to the open source Lesion Segmentation Toolbox (LST), which is a current state-of-art longitudinal lesion segmentation method. The mean lesion-wise inter-rater sensitivity was 62%, while the mean inter-rater number of false positive (FP) findings was 0.41 lesions per case. The two validated algorithms showed a mean sensitivity of 60% (CNN), 46% (LST) and a mean FP of 0.48 (CNN), 1.86 (LST) per case. Sensitivity and number of FP were not significantly different (p < 0.05) between the CNN and manual raters. New or enlarged lesions counted by the CNN algorithm appeared to be comparable with manual expert ratings. The proposed algorithm seems to outperform currently available approaches, particularly LST. The high inter-rater variability in case of manual segmentation indicates the complexity of identifying new or enlarged lesions. An automated CNN-based approach can quickly provide an independent and deterministic assessment of new or enlarged lesions from baseline to follow-up scans with acceptable reliability.
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http://dx.doi.org/10.1016/j.nicl.2020.102445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554211PMC
September 2020

Multiple sclerosis lesion activity segmentation with attention-guided two-path CNNs.

Comput Med Imaging Graph 2020 09 8;84:101772. Epub 2020 Aug 8.

Hamburg University of Technology, Institute of Medical Technology, Am Schwarzenberg-Campus 3, 21073 Hamburg, Germany. Electronic address:

Multiple sclerosis is an inflammatory autoimmune demyelinating disease that is characterized by lesions in the central nervous system. Typically, magnetic resonance imaging (MRI) is used for tracking disease progression. Automatic image processing methods can be used to segment lesions and derive quantitative lesion parameters. So far, methods have focused on lesion segmentation for individual MRI scans. However, for monitoring disease progression, lesion activity in terms of new and enlarging lesions between two time points is a crucial biomarker. For this problem, several classic methods have been proposed, e.g., using difference volumes. Despite their success for single-volume lesion segmentation, deep learning approaches are still rare for lesion activity segmentation. In this work, convolutional neural networks (CNNs) are studied for lesion activity segmentation from two time points. For this task, CNNs are designed and evaluated that combine the information from two points in different ways. In particular, two-path architectures with attention-guided interactions are proposed that enable effective information exchange between the two time point's processing paths. It is demonstrated that deep learning-based methods outperform classic approaches and it is shown that attention-guided interactions significantly improve performance. Furthermore, the attention modules produce plausible attention maps that have a masking effect that suppresses old, irrelevant lesions. A lesion-wise false positive rate of 26.4% is achieved at a true positive rate of 74.2%, which is not significantly different from the interrater performance.
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http://dx.doi.org/10.1016/j.compmedimag.2020.101772DOI Listing
September 2020

Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study.

CNS Drugs 2020 09;34(9):973-988

MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, USA.

Background: Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.

Objectives: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.

Methods: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.

Results: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.

Conclusions: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS.

Gov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.
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http://dx.doi.org/10.1007/s40263-020-00749-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447657PMC
September 2020

Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT.

Neurology 2020 05 16;94(18):e1950-e1960. Epub 2020 Apr 16.

From the Department of Nutrition (M.C., K.L.M, A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Bergen, Norway; Department of Neurology (E.H.M.-L.), Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Departments of Medicine, Biomedicine and Clinical Research (C.B., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel, Basel, Switzerland; CHU Hôpital Pontchaillou (G.E.), Rennes, France; University of Ottawa and Ottawa Hospital Research Institute (M.S.F.), Ottawa, Canada; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf, Germany; St. Michael's Hospital (X.M.), University of Toronto, Canada and Multiple Sclerosis Center of Catalonia (Cemcat) (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain; Ferkauf Graduate School of Psychology (F.W.F.), Yeshiva University, New York, NY; Department of Neurology (I.K.P.), Medical Faculty, Heinrich-Heine Universität, Düsseldorf and COGITO Center for Applied Neurocognition and Neuropsychological Research (I.K.P.), Düsseldorf, Germany; Technical University of Munich (B.H.), School of Medicine and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Central Texas Neurology Consultants (E.J.F.), Round Rock, TX; Neuroimmunology and Multiple Sclerosis Research (S.S.), Department of Neurology, University Hospital Zurich, University of Zurich and Center for Neuroscience Zurich (S.S.), Federal Institute of Technology (ETH), Zurich, Switzerland; Bayer AG (E.-M.W.), Berlin, Germany; Department of Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA and Channing Division of Network Medicine (A.A.); and Department of Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: To investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS).

Methods: This study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) and completed the 11-year assessment (BENEFIT-11). We measured serum 25-hydroxyvitamin-D (25(OH)D), cotinine (smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) at baseline and at months 6, 12, and 24 and examined whether these biomarkers contributed to predict Paced Auditory Serial Addition Test (PASAT)-3 scores and serum neurofilament light chain (NfL) concentrations at 11 years. Linear and logistic regression models were adjusted for sex, baseline age, treatment allocation, steroid treatment, multifocal symptoms, T2 lesions, and body mass index.

Results: Higher vitamin D predicted better, whereas smoking predicted worse cognitive performance. A 50-nmol/L higher mean 25(OH)D in the first 2 years was related to 65% lower odds of poorer PASAT performance at year 11 (95% confidence intervals [95% CIs]: 0.14-0.89). Standardized PASAT scores were lower in smokers and heavy smokers than nonsmokers ( = 0.026). Baseline anti-EBNA-1 IgG levels did not predict cognitive performance ( = 0.88). Associations with NfL concentrations at year 11 corroborated these findings-a 50-nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL (95% CI: -36% to 0%), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI: 2%-40%). Anti-EBNA-1 antibodies were not associated with NfL.

Conclusions: Lower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS.
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http://dx.doi.org/10.1212/WNL.0000000000009371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274920PMC
May 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

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

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

MS optic neuritis-induced long-term structural changes within the visual pathway.

Neurol Neuroimmunol Neuroinflamm 2020 03 22;7(2). Epub 2020 Jan 22.

From the Department of Neurology (M.P., M.H., K.L., J.K.), Otto von Guericke University, Magdeburg, Germany; Department of Neurology with Institute of Translational Neurology (M.P., S.G.M.), University Hospital Münster, Germany; Department of Computer Science (K.L.), Otto von Guericke University Magdeburg, Germany; Jung diagnostics GmbH (R.O.), Hamburg, Germany; Department of Ophthalmology (M.W., K.O.A.-N., M.B.H.), Otto von Guericke University, Magdeburg, Germany; Center of Behavioral Brain Sciences (M.B.H.), Magdeburg; Neuroimmunology and Multiple Sclerosis Research (R.O., S.S.), Department of Neurology, University Hospital Zurich, Switzerland; and Center for Neuroscience Zurich (S.S.), Federal Institute of Technology (ETH), Zurich, Switzerland.

Background: The visual pathway is commonly involved in multiple sclerosis (MS), even in its early stages, including clinical episodes of optic neuritis (ON). The long-term structural damage within the visual compartment in patients with ON, however, is yet to be elucidated.

Objective: Our aim was to characterize visual system structure abnormalities using MRI along with optical coherence tomography (OCT) and pattern-reversal visual evoked potentials (VEPs) depending on a single history of ON.

Methods: Twenty-eight patients with clinically definitive MS, either with a history of a single ON (HON) or without such history and normal VEP findings (NON), were included. OCT measures comprised OCT-derived peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell/inner plexiform layer (GCIPL) thickness. Cortical and global gray and white matter, thalamic, and T2 lesion volumes were assessed using structural MRI. Diffusion-weighted MRI-derived measures included fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity within the optic radiation (OR).

Results: Mean (SD) duration after ON was 8.3 (3.7) years. Compared with the NON group, HON patients showed significant RNFL ( = 0.01) and GCIPL thinning ( = 0.002). OR FA ( = 0.014), MD ( = 0.005), RD ( = 0.007), and AD ( = 0.004) were altered compared with NON. Global gray and white as well as other regional gray matter structures did not differ between the 2 groups.

Conclusion: A single history of ON induces long-term structural damage within the retina and OR suggestive of both retrograde and anterograde neuroaxonal degeneration.
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http://dx.doi.org/10.1212/NXI.0000000000000665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057062PMC
March 2020

60/30: 60% of the Morbidity-Associated Multiple Sclerosis Disease Burden Comes From the 30% of Persons With Higher Impairments.

Front Neurol 2020 6;11:156. Epub 2020 Mar 6.

Department of Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Multiple sclerosis (MS) is the most common chronic, non-traumatic, neurologic disease in young adults. While approximate values of the disease burden of MS are known, individual drivers are unknown. To estimate the age-, sex-, and disease severity-specific contributions to the disease burden of MS. We estimated the disease burden of MS using disability-adjusted life years (DALYs) following the Global Burden of Disease study (GBD) methodology. The data sources consisted of the Swiss MS Registry, a recent prevalence estimation, and the Swiss mortality registry. The disease burden of MS in Switzerland in 2016 was 6,938 DALYs (95%-interval: 6,018-7,955), which corresponds to 97 DALYs per 100,000 adult inhabitants. Morbidity contributed 59% of the disease burden. While persons in an asymptomatic (EDSS-proxy 0) and mild (EDSS-proxy >0-3.5) disease stage represent 68.4% of the population, they make up 39.8% of the MS-specific morbidity. The remaining 60.2% of the MS-specific morbidity stems from the 31.6% of persons in a moderate (EDSS-proxy 4-6.5) or severe (EDSS-proxy ≥7) disease stage. Morbidity has a larger influence on the disease burden of MS than mortality and is shared in a ratio of 2:3 between persons in an asymptomatic/mild and moderate/severe disease stage in Switzerland. Interventions to reduce severity worsening in combination with tailored, symptomatic treatments are important future paths to lower the disease burden of MS.
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http://dx.doi.org/10.3389/fneur.2020.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068809PMC
March 2020

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis.

Neurol Neuroimmunol Neuroinflamm 2020 03 22;7(2). Epub 2020 Jan 22.

From the Department of Health Sciences and Technology (C.A.W.), Swiss Federal Institute of Technology; Neuroimmunology and Multiple Sclerosis Research (C.A.W., P.M., T.S., J.V.M.H., S.S.), Department of Neurology, University Hospital Zurich and University of Zurich; Department of Information Technology and Electrical Engineering (P.M.), Swiss Federal Institute of Technology; and Department of Ophthalmology (J.V.M.H.), University Hospital Zurich and University of Zurich.

Objective: This longitudinal study aimed to assess changes in retinal structure and visual function following a first-ever episode of acute optic neuritis (ON).

Methods: Clinical and optical coherence tomography (OCT) data obtained over a period of 12 months were retrospectively analyzed in 41 patients with a first-ever clinical episode of acute ON. OCT scans, high-contrast visual acuity (HCVA), and low-contrast visual acuity (LCVA) were acquired at baseline and at 1, 3, 6, and 12 months thereafter. Macular ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer (pRNFL), and macular inner nuclear layer (INL) thicknesses were assessed by OCT. Linear mixed-effects models were used to analyze OCT variables of ipsilateral ON and contralateral non-ON (NON) eyes over time.

Results: The mean change of GCIP thickness in ON eyes was significant at all follow-up time points, with nearly 75% of the total reduction having occurred by month 1. In ON eyes, thinner GCIP thickness at month 1 correlated with lower LCVA at month 3. Mean pRNFL thickness in ON eyes differed significantly from NON eyes at all postbaseline time points. INL thickness was significantly increased in ON eyes (month 1) but also in contralateral NON eyes (month 12).

Conclusions: Retinal structural damage develops rapidly following acute ON and is associated with subsequent functional visual deficits. Our results also suggest bilateral retinal pathology following unilateral ON, possibly caused by subclinical involvement of the contralateral NON eyes. Moreover, our data may assist in clinical trial planning in studies targeting tissue damage in acute ON.
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http://dx.doi.org/10.1212/NXI.0000000000000671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051214PMC
March 2020

Knowledge Is Power, but Is Ignorance Bliss? Optimising Conversations About Disease Progression in Multiple Sclerosis.

Neurol Ther 2020 Jun 20;9(1):1-10. Epub 2019 Nov 20.

Universitätsspital Zürich and Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich, Zurich, Switzerland.

Communication about multiple sclerosis (MS) disease progression between healthcare professionals (HCPs) and people with MS (PwMS) has historically been considered difficult, and attention to improving it has been neglected. However, a growing number of studies have shown that this is a key area to get right, since negative experiences can affect patient satisfaction, treatment adherence, and clinical outcomes. This article reports on a symposium at the European Charcot Foundation, 2018, led by a panel of leading clinicians and patient experts from MS in the 21st Century, who debated the benefits, drawbacks, and challenges of communicating about disease progression, for both HCPs and PwMS, and potential ways to optimise these discussions. PwMS' preferences and priorities regarding conversations about disease progression vary widely. While the majority want to have these conversations, some will be reluctant and/or emotionally unready. Communication therefore needs to be personalised, and HCPs should always be prepared to have such conversations in an appropriate and sensitive manner. Clinical information can be opaque for PwMS, so HCPs also need to use language that is clear, easily understandable, and patient-friendly. MS in the 21st Century is in the process of developing several resources and programmes to help improve disease progression communication between HCPs and PwMS. FUNDING: Merck KGaA, Darmstadt, Germany. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s40120-019-00170-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229099PMC
June 2020

Correction to: Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

Acta Neuropathol Commun 2019 Oct 18;7(1):157. Epub 2019 Oct 18.

Neuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

In the original publication of this article [1], Fig. 10 contained two panels "C" as panel "F" was accidentally omitted. The incorrect (Fig. 1) and correct (Fig. 2) versions are published in this correction article.
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http://dx.doi.org/10.1186/s40478-019-0825-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798424PMC
October 2019

Joint Healthcare Professional and Patient Development of Communication Tools to Improve the Standard of MS Care.

Adv Ther 2019 11 5;36(11):3238-3252. Epub 2019 Sep 5.

Member of the MS in the 21st Century Steering Group, Southampton, UK.

Introduction: Effective communication between patients and healthcare professionals (HCPs) is important to enhance outcomes in multiple sclerosis (MS). However, in practice, patients often report a disconnect in communication. Communication tools to aid patient-HCP communication have a long history of use in many chronic conditions. For example, symptom diaries have been shown to enhance outcomes in cancer, headache and sleep disorder management. MS in the 21st Century, a Steering Group of HCP specialists and patients with MS (PwMS), has created two communication tools designed for use by both patients and their HCPs.

Methods: The Steering Group first identified prominent issues in patient-HCP communication through group discussions and survey data. Following this, a series of workshops led to the development of two communication tools as potential solutions to these identified issues in communication.

Results: The two most prominent issues identified were HCP time constraints during appointments and the misalignment of patient and HCP priorities-the communication tools developed through the workshops were created to address these. The "myMS priorities" tool [see supplementary materials] is designed to maximize the use of consultation time while the "myMS commitments" tool [see supplementary materials] aims to improve patient-HCP shared decision-making.

Conclusions: The MS in the 21st Century Steering Group adopted a broad, iterative and collaborative approach in the development of these tools to help ensure they would be as useful as possible to both HCPs and PwMS. These tools have been developed through shared patient-HCP expertise and are based on existing tools in other therapy areas as well as a review of the existing literature and data from MS in the 21st Century Steering Group surveys. The next steps will focus on the validation of these tools through testing them in real-world environments and clinical trials.

Funding: Merck KGaA, Darmstadt, Germany.
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http://dx.doi.org/10.1007/s12325-019-01071-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822792PMC
November 2019

How do patients enter the healthcare system after the first onset of multiple sclerosis symptoms? The influence of setting and physician specialty on speed of diagnosis.

Mult Scler 2020 04 18;26(4):489-500. Epub 2019 Jan 18.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: Diagnosing multiple sclerosis (MS) early is crucial to avoid future disability. However, potentially preventable delays in the diagnostic cascade from contact with a physician to definite diagnosis still occur and their causes are still unclear.

Objective: To identify the possible causes of delays in the diagnostic process.

Methods: We analyzed the data of the Swiss MS Registry. With logistic regression, we modeled the time from the first contact to the first consultation (contact-to-evaluation time, ⩽1 month/>1 month) and the evaluation-to-diagnosis time (⩽6 months/>6 months). Potential factors were health system characteristics, sociodemographic variables, first symptoms, and MS type.

Results: We included 522 participants. Mostly, general practitioners (67%) were contacted first, without delaying the diagnosis. In contrast, first symptoms and MS type were the major contributors to delays: gait problems were associated with longer contact-to-evaluation times, depression as a concomitant symptom with longer evaluation-to-diagnosis times, and having primary progressive MS prolonged both phases. In addition, living in mountainous areas was associated with longer contact-to-evaluation times, whereas diagnosis after 2000 was associated with faster diagnoses.

Conclusion: For a quicker diagnosis, awareness of MS as a differential diagnosis of gait disorders and the co-occurrence of depression at onset should be raised, and these symptoms should be attentively followed.
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http://dx.doi.org/10.1177/1352458518823955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140343PMC
April 2020

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

Acta Neuropathol Commun 2019 07 17;7(1):116. Epub 2019 Jul 17.

Neuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.
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http://dx.doi.org/10.1186/s40478-019-0768-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637505PMC
July 2019

Tocilizumab treatment in severe recurrent anti-MOG-associated optic neuritis.

Neurology 2019 04 20;92(16):765-767. Epub 2019 Mar 20.

From Neuroimmunology and MS Research, Neurology Clinic (H.H.-K., R.M., S.S.), University Zurich, Switzerland; and Clinical Department of Neurology (M.R.), Medical University of Innsbruck, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000007312DOI Listing
April 2019

[Neurosarcoidosis remains a diagnostic chameleon : First manifestation of neurosarcoidosis as longitudinal transverse myelitis].

Nervenarzt 2019 Apr;90(4):412-414

Klinik für Innere Medizin, Spital Linth, Gasterstraße 25, 8730, Uznach, Schweiz.

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http://dx.doi.org/10.1007/s00115-018-0652-8DOI Listing
April 2019

Optical coherence tomography as a means to characterize visual pathway involvement in multiple sclerosis.

Curr Opin Neurol 2018 10;31(5):662-668

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology.

Purpose Of Review: Optical coherence tomography (OCT) is a noninvasive in-vivo imaging tool that enables the quantification of the various retinal layer thicknesses. Given the frequent involvement of the visual pathway in multiple sclerosis, OCT has become an important tool in clinical practice, research and clinical trials. In this review, the role of OCT as a means to investigate visual pathway damage in multiple sclerosis is discussed.

Recent Findings: Evidence from recent OCT studies suggests that the peripapillary retinal nerve fibre layer (pRNFL) appears to be an ideal marker of axonal integrity, whereas the macular ganglion cell and inner plexiform layer (GCIP) thickness enables early detection of neuronal degeneration in multiple sclerosis. The thickness of the macular inner nuclear layer (INL) has been suggested as a biomarker for inflammatory disease activity and treatment response in multiple sclerosis. OCT parameters may also be used as an outcome measure in clinical trials evaluating the neuroprotective or regenerative potential of new treatments.

Summary: OCT provides insights into multiple sclerosis beyond the visual pathway. It is capable of quantifying the major pathological hallmarks of the disease, specifically inflammation and neuroaxonal degeneration. OCT, therefore, has the potential to become another mainstay in the monitoring of multiple sclerosis patients.
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http://dx.doi.org/10.1097/WCO.0000000000000604DOI Listing
October 2018

Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.

J Neuroophthalmol 2019 Mar;39(1):3-7

Neuroimmunology and Multiple Sclerosis Research (IJ, JVMH, SL, RM, AL, and SS), Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Ophthalmology (JVMH, KPW, and KL), University Hospital Zurich, Zurich, Switzerland; Department of Ophthalmology (MP), Luzerner Kantonsspital, Lucerne, Switzerland; Clinical Department of Neurology (MR), Medical University of Innsbruck, Innsbruck, Austria; and Neurology Clinic (MW, KPW), University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON.

Methods: Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies.

Results: All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG-seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast-enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy.

Conclusions: MOG-seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD.
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http://dx.doi.org/10.1097/WNO.0000000000000669DOI Listing
March 2019

Exploring experimental autoimmune optic neuritis using multimodal imaging.

Neuroimage 2018 07 6;175:327-339. Epub 2018 Apr 6.

Neuroimmunology and Multiple Sclerosis Research, Clinic for Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: Neuro-axonal injury is a key contributor to non-reversible long-term disability in multiple sclerosis (MS). However, the underlying mechanisms are not yet fully understood. Visual impairment is common among MS patients, in which episodes of optic neuritis (ON) are often followed by structural retinal damage and sustained functional impairment. Alterations in the optic nerve and retina have also been described in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Thus, investigating structural anterior visual pathway damage may constitute a unique model for assessing mechanisms and temporal sequence of neurodegeneration in MS. We used a multimodal imaging approach utilizing optical coherence tomography (OCT) and diffusion tensor imaging (DTI) to explore the mechanisms and temporal dynamics of visual pathway damage in the animal model of MS.

Methods: 7 EAE-MOG and 5 healthy female C57BL/6J mice were used in this study. Ganglion cell complex (GCC) thickness was derived from an OCT volume scan centred over the optic nerve head, while the structure of the optic nerve and tracts was assessed from DTI and co-registered T2-weighted sequences performed on a 7T MRI scanner. Data was acquired at baseline, disease onset, peak of disease and recovery. Linear mixed effect models were used to account for intra-subject, inter-eye dependencies, group and time point. Correlation analyses assessed the relationship between GCC thickness and DTI parameters. Immunofluorescence staining of retina and optic nerve sections was used to assess distribution of marker proteins for microglia and neurodegeneration (nerve filaments).

Results: In EAE mice, a significant increase in GCC thickness was observed at disease onset (p < 0.001) followed by a decrease at recovery (p < 0.001) compared to controls. The EAE group had significant GCC thinning at recovery compared to all other time points (p < 0.001 for each). Signal increase on T2-weighted images around the optic nerves indicative of inflammation was seen in most of the EAE mice but in none of the controls. A significant decrease in axial diffusivity (AD) and increase in radial diffusivity (RD) values in EAE optic nerves (AD: p = 0.02, RD: p = 0.01) and tract (AD: p = 0.02, RD: p = 0.006) was observed compared to controls. GCC at recovery was positively correlated with AD (optic nerve: rho = 0.74, p = 0.04, optic tract: rho = 0.74, p = 0.04) and negatively correlated with RD (optic nerve: rho = -0.80, p = 0.02, optic tract: rho = -0.75, p = 0.04). Immunofluorescence analysis indicated the presence of activated microglia in the retina and optic nerves in addition to astrocytosis and axonal degeneration in the optic nerve of EAE mice.

Conclusion: OCT detected GCC changes in EAE may resemble what is observed in MS-related acute ON: an initial phase of swelling (indicative of inflammatory edema) followed by a decrease in thickness over time (representative of neuro-axonal degeneration). In line with OCT findings, DTI of the visual pathway identifies EAE induced pathology (decreased AD, and increased RD). Immunofluorescence analysis provides support for inflammatory pathology and axonal degeneration. OCT together with DTI can detect retinal and optic nerve damage and elucidate to the temporal sequence of neurodegeneration in this rodent model of MS in vivo.
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http://dx.doi.org/10.1016/j.neuroimage.2018.04.004DOI Listing
July 2018

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

Neurol Neuroimmunol Neuroinflamm 2018 May 13;5(3):e449. Epub 2018 Mar 13.

NeuroCure Clinical Research Center (T.O., F.P., A.U.B.), Charité-Universitätsmedizin Berlin, Germany; Department of Ophthalmology (G.L.T.), University Hospital Zurich, University of Zurich; Neuroimmunology and Multiple Sclerosis Research Section (S.L., S.S.), Department of Neurology, University Hospital Zurich, University of Zurich, Switzerland; Center of Neuroimmunology (I.G., P.V.), Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain; Division of Neuroinflammation and Glial Biology (R.N., C.S., A.J.G.), Department of Neurology, University of California San Francisco; Neuro-ophthalmology Division (A.J.G.), Department of Ophthalmology, University of California, San Francisco; Multiple Sclerosis Center (L.B., A.P.), Departments of Neurology and Ophthalmology, Neuro-ophthalmology Expertise Centre, VUmc, Amsterdam and Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery and UCL, United Kingdom; Clinical and Experimental Multiple Sclerosis Research Center (F.P.), Department of Neurology, Charité-Universitätsmedizin Berlin; Experimental and Clinical Research Center (F.P., A.U.B.), Charité-Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine, Germany; Department of Methods and Experimental Psychology (I.G.), Faculty of Psychology and Education, Universidad de Deusto, Bilbao, Spain.

Objective: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans.

Methods: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps.

Results: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers.

Conclusions: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.
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http://dx.doi.org/10.1212/NXI.0000000000000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852947PMC
May 2018

Within-patient fluctuation of brain volume estimates from short-term repeated MRI measurements using SIENA/FSL.

J Neurol 2018 May 16;265(5):1158-1165. Epub 2018 Mar 16.

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: Measurements of brain volume loss (BVL) in individual patients are currently discussed controversially. One concern is the impact of short-term biological noise, like hydration status.

Methods: Three publicly available reliability MRI datasets with scan intervals of days to weeks were used. An additional cohort of 60 early relapsing multiple sclerosis (MS) patients with MRI follow-ups was analyzed to test whether after 1 year pathological BVL is detectable in a relevant fraction of MS patients. BVL was determined using SIENA/FSL. Results deviating from zero in the reliability datasets were considered as within-patient fluctuation (WPF) consisting of the intrinsic measurement error as well as the short-term biological fluctuations of brain volumes. We provide an approach to interpret BVL measurements in individual patients taking the WPF into account.

Results: The estimated standard deviation of BVL measurements from the pooled reliability datasets was 0.28%. For a BVL measurement of x% per year in an individual patient, the true BVL lies with an error probability of 5% in the interval x% ± (1.96 × 0.28)/(scan interval in years)%. To allow a BVL per year of at least 0.4% to be identified after 1 year, the measured BVL needs to exceed 0.94%. The median BVL per year in the MS patient cohort was 0.44%. In 11 out of 60 MS patients (18%) we found a BVL per year equal or greater than 0.94%.

Conclusion: The estimated WPF may be helpful when interpreting BVL results on an individual patient level in diseases such as MS.
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http://dx.doi.org/10.1007/s00415-018-8825-8DOI Listing
May 2018

Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults.

Neurobiol Aging 2018 05 30;65:1-6. Epub 2017 Dec 30.

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.024DOI Listing
May 2018

Outer Retinal Dysfunction in the Absence of Structural Abnormalities in Multiple Sclerosis.

Invest Ophthalmol Vis Sci 2018 01;59(1):549-560

Department of Ophthalmology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Purpose: Recent evidence suggests structural changes distal to the inner retina in multiple sclerosis (MS) patients. The functional correlates of these proposed structural abnormalities remain unclear. We investigated outer retinal function and structure in MS patients, and quantified to what extent outer retinal structure influenced function in these patients.

Methods: Outer retinal function was assessed using the full-field and multifocal electroretinogram (ERG/MF-ERG), whereas retinal structure was assessed using spectral-domain optical coherence tomography (OCT). Results were compared with preexisting normative data. The relationships between electrophysiology parameters and the OCT values corresponding to the proposed cellular origins of the ERG and MF-ERG were analyzed.

Results: Most electrophysiological responses were delayed in MS patients, independently of optic neuritis (ON). Inner retinal thickness and volumes were reduced, and inner nuclear layer volume marginally increased, in eyes with previous ON; all other OCT parameters were normal. OCT results correlated with ERG amplitudes, but not with ERG peak times or any MF-ERG parameters.

Conclusions: We recorded outer retinal dysfunction without detectable abnormalities of the corresponding retinal layers in MS patients, not ascribable to retrograde degeneration following ON. The findings complement a growing body of literature reporting primary retinal abnormalities distal to the ganglion cell-inner plexiform layer complex in MS patients, with our data suggesting that this may be a more widespread phenomenon than previously thought. ERG may be of more utility in detecting retinal dysfunction in MS patients than MF-ERG. Analysis of peak times, rather than response amplitudes, is recommended.
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http://dx.doi.org/10.1167/iovs.17-22821DOI Listing
January 2018

Outer Retinal Dysfunction in the Absence of Structural Abnormalities in Multiple Sclerosis.

Invest Ophthalmol Vis Sci 2018 01;59(1):549-560

Department of Ophthalmology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Purpose: Recent evidence suggests structural changes distal to the inner retina in multiple sclerosis (MS) patients. The functional correlates of these proposed structural abnormalities remain unclear. We investigated outer retinal function and structure in MS patients, and quantified to what extent outer retinal structure influenced function in these patients.

Methods: Outer retinal function was assessed using the full-field and multifocal electroretinogram (ERG/MF-ERG), whereas retinal structure was assessed using spectral-domain optical coherence tomography (OCT). Results were compared with preexisting normative data. The relationships between electrophysiology parameters and the OCT values corresponding to the proposed cellular origins of the ERG and MF-ERG were analyzed.

Results: Most electrophysiological responses were delayed in MS patients, independently of optic neuritis (ON). Inner retinal thickness and volumes were reduced, and inner nuclear layer volume marginally increased, in eyes with previous ON; all other OCT parameters were normal. OCT results correlated with ERG amplitudes, but not with ERG peak times or any MF-ERG parameters.

Conclusions: We recorded outer retinal dysfunction without detectable abnormalities of the corresponding retinal layers in MS patients, not ascribable to retrograde degeneration following ON. The findings complement a growing body of literature reporting primary retinal abnormalities distal to the ganglion cell-inner plexiform layer complex in MS patients, with our data suggesting that this may be a more widespread phenomenon than previously thought. ERG may be of more utility in detecting retinal dysfunction in MS patients than MF-ERG. Analysis of peak times, rather than response amplitudes, is recommended.
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http://dx.doi.org/10.1167/iovs.17-22821DOI Listing
January 2018