Publications by authors named "Sven G Meuth"

386 Publications

Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition.

Int J Mol Sci 2021 Sep 18;22(18). Epub 2021 Sep 18.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer's or Parkinson's disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer's disease due to the increased synthesis of amyloid β. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.
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http://dx.doi.org/10.3390/ijms221810087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466828PMC
September 2021

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis.

Int J Mol Sci 2021 Sep 14;22(18). Epub 2021 Sep 14.

Department of Neurology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4 T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.
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http://dx.doi.org/10.3390/ijms22189915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465626PMC
September 2021

NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study: Serum NfL predicts relapse-free progression.

EBioMedicine 2021 Sep 24;72:103590. Epub 2021 Sep 24.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilamentandlongtermoutcome inMS (NaloMS) cohort.

Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated.

Findings: During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p<0.017). In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine. In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs. 0.96 (0.75-1.23), p=0.011). This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning.

Interpretation: sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later. While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion.

Funding: This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2021.103590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479646PMC
September 2021

K channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549).

Sci Rep 2021 Sep 15;11(1):18330. Epub 2021 Sep 15.

Institut für Physiologie II, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27b, 48149, Münster, Germany.

Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, K3.1 channels contribute to NSCLC progression so that elevated K3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking K3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of K3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of K3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the K3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the K3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by K3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of K3.1 blockade is further increased by mimicking hypoxia. Our results suggest that K3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.
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http://dx.doi.org/10.1038/s41598-021-97406-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443639PMC
September 2021

Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis.

Brain Commun 2021 23;3(3):fcab198. Epub 2021 Aug 23.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany.

The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory performance and clinical severity. In a large cohort of multiple sclerosis patients ( = 476; 337 females, age 35 ± 10 years, disease duration 16 ± 14 months) and healthy subjects ( = 110, 54 females; age 34 ± 15 years), we utilized MRI at baseline and at 2-year follow-up to quantify regional hippocampal volumetry and reconstruct single-subject hippocampal networks. Through graph analytical tools we assessed the clustered topology of the hippocampal networks. Mixed-effects analyses served to model sex-based differences in hippocampal network and subfield integrity between multiple sclerosis patients and healthy subjects at both time points and longitudinally. Afterwards, hippocampal network and subfield integrity were related to clinical and radiological variables in dependency of sex attribution. We found a more clustered network architecture in both female and male patients compared to their healthy counterparts. At both time points, female patients displayed a more clustered network topology in comparison to male patients. Over time, multiple sclerosis patients developed an even more clustered network architecture, though with a greater magnitude in females. We detected reduced regional volumes in most of the addressed hippocampal subfields in both female and male patients compared to healthy subjects. Compared to male patients, females displayed lower volumes of para- and presubiculum but higher volumes of the molecular layer. Longitudinally, volumetric alterations were more pronounced in female patients, which showed a more extensive regional tissue loss. Despite a comparable cognitive/memory performance between female and male patients over the follow-up period, we identified a strong interrelation between hippocampal network properties and cognitive/memory performance only in female patients. Our findings evidence a more clustered hippocampal network topology in female patients with a more extensive subfield volume loss over time. A stronger relation between cognitive/memory performance and the network topology in female patients suggests greater entrainment of the brain's reserve. These results may serve to adapt sex-targeted neuropsychological interventions.
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http://dx.doi.org/10.1093/braincomms/fcab198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417841PMC
August 2021

Multiple Sclerosis: Switching from Natalizumab to Other High-Efficacy Treatments to Mitigate Progressive Multifocal Leukoencephalopathy Risk.

Neurotherapeutics 2021 Sep 3. Epub 2021 Sep 3.

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

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http://dx.doi.org/10.1007/s13311-021-01102-wDOI Listing
September 2021

Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans.

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Neurology, Focus Program Translational Neuroscience, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement-reconstructed from MRI-is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood-CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.
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http://dx.doi.org/10.1073/pnas.2025000118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433504PMC
September 2021

Paradigm shifts: Early initiation of high-efficacy disease-modifying treatment in multiple sclerosis.

Mult Scler 2021 Sep;27(10):1473-1476

Queen Square MS Centre, UCL Institute of Neurology, London, UK.

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http://dx.doi.org/10.1177/13524585211033190DOI Listing
September 2021

Treatment approaches to patients with multiple sclerosis and coexisting autoimmune disorders.

Ther Adv Neurol Disord 2021 23;14:17562864211035542. Epub 2021 Aug 23.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Rhineland-Palatinate, Mainz 55131, Germany.

The past decades have yielded major therapeutic advances in many autoimmune conditions - such as multiple sclerosis (MS) - and thus ushered in a new era of more targeted and increasingly potent immunotherapies. Yet this growing arsenal of therapeutic immune interventions has also rendered therapy much more challenging for the attending physician, especially when treating patients with more than one autoimmune condition. Importantly, some therapeutic strategies are either approved for several autoimmune disorders or may be repurposed for other conditions, therefore opening new curative possibilities in related fields. In this article, we especially focus on frequent and therapeutically relevant concomitant autoimmune conditions faced by neurologists when treating patients with MS, namely psoriasis, rheumatoid arthritis and inflammatory bowel diseases. We provide an overview of the available disease-modifying therapies, highlight possible contraindications, show pathophysiological overlaps and finally present which therapeutics can be utilized as a combinatory treatment, in order to 'kill two birds with one stone'.
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http://dx.doi.org/10.1177/17562864211035542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388232PMC
August 2021

Innovation in Digital Education: Lessons Learned from the Multiple Sclerosis Management Master's Program.

Brain Sci 2021 Aug 23;11(8). Epub 2021 Aug 23.

Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.

Since 2020, the master's program "Multiple Sclerosis Management" has been running at Dresden International University, offering structured training to become a multiple sclerosis specialist. Due to the COVID-19 pandemic, many planned teaching formats had to be changed to online teaching. The subject of this paper was the investigation of a cloud-based digital hub and student evaluation of the program. Authors analyzed use cases of computer-supported collaborative learning and student evaluation of courses and modules using the Gioia method and descriptive statistics. The use of a cloud-based digital hub as a central data platform proved to be highly successful for learning and teaching, as well as for close interaction between lecturers and students. Students rated the courses very positively in terms of content, knowledge transfer and interaction. The implementation of the master's program was successful despite the challenges of the COVID-19 pandemic. The resulting extensive use of digital tools demonstrates the "new normal" of future learning, with even more emphasis on successful online formats that also increase interaction between lecturers and students in particular. At the same time, there will continue to be tailored face-to-face events to specifically increase learning success.
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http://dx.doi.org/10.3390/brainsci11081110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393651PMC
August 2021

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

Ther Adv Neurol Disord 2021 18;14:17562864211039648. Epub 2021 Aug 18.

Neurologie in Meerbusch, MS-Zentrum, Meerbusch, Germany.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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http://dx.doi.org/10.1177/17562864211039648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377320PMC
August 2021

Amyotrophic lateral sclerosis patients show increased peripheral and intrathecal T-cell activation.

Brain Commun 2021 14;3(3):fcab157. Epub 2021 Jul 14.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster 48149, Germany.

Several studies suggest a role for the peripheral immune system in the pathophysiology of amyotrophic lateral sclerosis. However, comprehensive studies investigating the intrathecal immune system in amyotrophic lateral sclerosis are rare. To elucidate whether compartment-specific inflammation contributes to amyotrophic lateral sclerosis pathophysiology, we here investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis patients and compared them with controls free of neurological disorders (controls) and patients with dementia or primary progressive multiple sclerosis. Routine CSF parameters were examined in 308 patients, including 132 amyotrophic lateral sclerosis patients. In a subgroup of 41 amyotrophic lateral sclerosis patients, extensive flow-cytometric immune cell profiling in peripheral blood and CSF was performed and compared with data from 26 controls, 25 dementia and 21 multiple sclerosis patients. Amyotrophic lateral sclerosis patients presented with significantly altered proportions of monocyte subsets in peripheral blood and increased frequencies of CD4 and CD8 T cells expressing the activation marker HLA-DR in peripheral blood (CD8) and CSF (CD4 and CD8) compared with controls. While dementia and multiple sclerosis patients exhibited a comparable increase in intrathecal CD8 T-cell activation, CD8 T-cell activation in the peripheral blood in amyotrophic lateral sclerosis was higher than in multiple sclerosis patients. Furthermore, intrathecal CD4 T-cell activation in amyotrophic lateral sclerosis surpassed levels in dementia patients. Intrathecal T-cell activation resulted from activation rather than transmigration of activated T cells from the blood. While T-cell activation did not correlate with amyotrophic lateral sclerosis progression, patients with rapid disease progression showed reduced intrathecal levels of immune-regulatory CD56 natural killer cells. The integration of these parameters into a composite score facilitated the differentiation of amyotrophic lateral sclerosis patients from patients of all other cohorts. To conclude, alterations in peripheral monocyte subsets, as well as increased peripheral and intrathecal activation of CD4 and CD8 T cells concomitant with diminished immune regulation by CD56 natural killer cells, suggest an involvement of these immune cells in amyotrophic lateral sclerosis pathophysiology.
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http://dx.doi.org/10.1093/braincomms/fcab157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363480PMC
July 2021

Microglia contributes to remyelination in cerebral but not spinal cord ischemia.

Glia 2021 Nov 14;69(11):2739-2751. Epub 2021 Aug 14.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Inflammation after injury of the central nervous system (CNS) is increasingly viewed as a therapeutic target. However, comparative studies in different CNS compartments are sparse. To date only few studies based on immunohistochemical data and all referring to mechanical injury have directly compared inflammation in different CNS compartments. These studies revealed that inflammation is more pronounced in spinal cord than in brain. Therefore, it is unclear whether concepts and treatments established in the cerebral cortex can be transferred to spinal cord lesions and vice versa or whether immunological treatments must be adapted to different CNS compartments. By use of transcriptomic and flow cytometry analysis of equally sized photothrombotically induced lesions in the cerebral cortex and the spinal cord, we could document an overall comparable inflammatory reaction and repair activity in brain and spinal cord between day 1 and day 7 after ischemia. However, remyelination was increased after cerebral versus spinal cord ischemia which is in line with increased remyelination in gray matter in previous analyses and was accompanied by microglia dominated inflammation opposed to monocytes/macrophages dominated inflammation after spinal cord ischemia. Interestingly remyelination could be reduced by microglia and not hematogenous macrophage depletion. Our results show that despite different cellular composition of the postischemic infiltrate the inflammatory response in cerebral cortex and spinal cord are comparable between day 1 and day 7. A striking difference was higher remyelination capacity in the cerebral cortex, which seems to be supported by microglia dominance.
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http://dx.doi.org/10.1002/glia.24068DOI Listing
November 2021

Cerebrospinal fluid flow cytometry distinguishes psychosis spectrum disorders from differential diagnoses.

Mol Psychiatry 2021 Aug 6. Epub 2021 Aug 6.

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

Psychotic disorders are common and disabling mental conditions. The relative importance of immune-related mechanisms in psychotic disorders remains subject of debate. Here, we present a large-scale retrospective study of blood and cerebrospinal fluid (CSF) immune cell profiles of psychosis spectrum patients. We performed basic CSF analysis and multi-dimensional flow cytometry of CSF and blood cells from 59 patients with primary psychotic disorders (F20, F22, F23, and F25) in comparison to inflammatory (49 RRMS and 16 NMDARE patients) and non-inflammatory controls (52 IIH patients). We replicated the known expansion of monocytes in the blood of psychosis spectrum patients, that we identified to preferentially affect classical monocytes. In the CSF, we found a relative shift from lymphocytes to monocytes, increased protein levels, and evidence of blood-brain barrier disruption in psychosis. In fact, these CSF features confidently distinguished autoimmune encephalitis from psychosis despite similar (initial) clinical features. We then constructed machine learning models incorporating blood and CSF parameters and demonstrated their superior ability to differentiate psychosis from non-inflammatory controls compared to individual parameters. Multi-dimensional and multi-compartment immune cell signatures can thus support the diagnosis of psychosis spectrum disorders with the potential to accelerate diagnosis and initiation of therapy.
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http://dx.doi.org/10.1038/s41380-021-01244-5DOI Listing
August 2021

Combined Neurofilament Light and Optical Coherence Tomography Better Predicts Multiple Sclerosis Disease Activity Than Either Measure Alone.

Neurol Neuroimmunol Neuroinflamm 2021 09 4;8(5). Epub 2021 Aug 4.

From the Department of Neurology with Institute of Translational Neurology (J.K., H.W.), University Hospital Münster, Germany; and Department of Neurology (S.G.M., P.A.), University Hospital Düsseldorf, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000001054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362346PMC
September 2021

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)].

Nervenarzt 2021 Aug 23;92(8):773-801. Epub 2021 Jul 23.

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG), Münster, Deutschland.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).
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http://dx.doi.org/10.1007/s00115-021-01157-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300076PMC
August 2021

Determinants of cognition in autoimmune limbic encephalitis-A retrospective cohort study.

Hippocampus 2021 Oct 16;31(10):1092-1103. Epub 2021 Jul 16.

Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-University of Münster, Münster, Germany.

Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood-cerebrospinal fluid (CSF)-barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer- and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2-/fluid attenuated inversion recovery (FLAIR)-signal-weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.
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http://dx.doi.org/10.1002/hipo.23375DOI Listing
October 2021

Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.

Neurol Neuroimmunol Neuroinflamm 2021 09 14;8(5). Epub 2021 Jul 14.

From the Department of Neurology with Institute of Translational Neurology (L.R., M.P., S.P., C.N., L.K., H.W.), University Hospital Muenster, Germany; Institute for Biometrics and Bioinformatic (A.L.), Otto-von-Guericke University, Magdeburg, Germany; Department for Neurology (R.P., C.K., K.K., R.R.), University Hospital Essen, Germany; Focus Program Translational Neurosciences (FTN) and Immunology (FZI) (K.P., S.B., F.Z.), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (C.W., Y.G., M.S.), University Hospital Cologne, Germany; and Department of Neurology (J.I., O.A., T.R., S.G.M.), Heinrich-Heine University, Duesseldorf, Germany.

Objective: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).

Results: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free ( 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up ( = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; 0.441). Clinical stability was accompanied by persistent peripheral CD19 B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, 0.463). Disease activity in our cohort was not associated with CD19 B-cell repopulation.

Conclusion: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic.

Classification Of Evidence: This study provides Class IV evidence that for patients with RRMS, an EID of at least 4 weeks does not diminish effectiveness of ocrelizumab.
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http://dx.doi.org/10.1212/NXI.0000000000001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362352PMC
September 2021

Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges.

Nat Neurosci 2021 09 12;24(9):1225-1234. Epub 2021 Jul 12.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Medical Faculty, Münster, Germany.

The CNS is ensheathed by the meninges and cerebrospinal fluid, and recent findings suggest that these CNS-associated border tissues have complex immunological functions. Unlike myeloid lineage cells, lymphocytes in border compartments have yet to be thoroughly characterized. Based on single-cell transcriptomics, we here identified a highly location-specific composition and expression profile of tissue-resident leukocytes in CNS parenchyma, pia-enriched subdural meninges, dura mater, choroid plexus and cerebrospinal fluid. The dura layer of the meninges contained a large population of B cells under homeostatic conditions in mice and rats. Murine dura B cells exhibited slow turnover and long-term tissue residency, and they matured in experimental neuroinflammation. The dura also contained B lineage progenitors at the pro-B cell stage typically not found outside of bone marrow, without direct influx from the periphery or the skull bone marrow. This identified the dura as an unexpected site of B cell residence and potentially of development in both homeostasis and neuroinflammation.
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http://dx.doi.org/10.1038/s41593-021-00880-yDOI Listing
September 2021

Case Report: Successful Stabilization of Marburg Variant Multiple Sclerosis With Ocrelizumab Following High-Dose Cyclophosphamide Rescue.

Front Neurol 2021 23;12:696807. Epub 2021 Jun 23.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

The Marburg variant of multiple sclerosis (Marburg MS) is the most aggressive form of MS, often leading to death soon after onset. Here we describe the case of a 26-year-old Marburg MS patient presenting with severe neurological deficits requiring intensive care. In spite of more than 100 gadolinium-enhancing MRI lesions, the patient recovered almost completely upon high-dose cyclophosphamide (HiCy) rescue treatment (four consecutive days with 50 mg/kg/day, cumulative absolute dose of 14 g). Following the acute treatment, her disease was stabilized by B cell depletion using ocrelizumab. Clinical amelioration was reflected by a decrease of MRI activity and a marked decline of serum neurofilament light chain levels. HiCy rescue treatment followed by ocrelizumab as a maintenance therapy prevented permanent disability and achieved an almost complete clinical and drastic radiological improvement in this Marburg MS patient.
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http://dx.doi.org/10.3389/fneur.2021.696807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260950PMC
June 2021

Autoimmune glomerulonephritis in a multiple sclerosis patient after cladribine treatment.

Mult Scler 2021 Oct 24;27(12):1960-1964. Epub 2021 Jun 24.

Department of Neurology, University Medicine Essen, Essen, Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany.

Background: Oral cladribine is an approved disease-modifying drug for the treatment of relapsing multiple sclerosis. In controlled clinical trials as well as in post marketing safety assessments, autoimmune conditions have not yet been reported as a specific side effect of cladribine.

Objective And Results: Here, we report a case of anti-glomerular basement membrane antibody-mediated glomerulonephritis that occurred shortly after the fourth cladribine treatment cycle.

Conclusion: Neurologists should be attentive to the development of secondary autoimmunity in cladribine-treated patients.
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http://dx.doi.org/10.1177/13524585211022719DOI Listing
October 2021

Natural Killer Cells Are Present in Rag1 Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke.

Transl Stroke Res 2021 Jun 8. Epub 2021 Jun 8.

Department of Neurology With Institute of Translational Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany.

Rag1 mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1 mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1IL2rg (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1 and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1 NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1 were comparable in number and function to those in WT mice. Rag1 mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1 controls. Our results indicate that NK cells from Rag1 mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.
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http://dx.doi.org/10.1007/s12975-021-00923-3DOI Listing
June 2021

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis.

Ther Adv Neurol Disord 2021 25;14:17562864211003478. Epub 2021 May 25.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany.

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers.

Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients ( = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes.

Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients ( = -0.016, SE = 0.006,  = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( = -6.734, SE = 2.514,  = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( = 5.974, SE = 2.420,  = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning.

Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.
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http://dx.doi.org/10.1177/17562864211003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155762PMC
May 2021

Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015-2020.

Drugs 2021 Jun 4;81(9):1031-1063. Epub 2021 Jun 4.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.

In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.
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http://dx.doi.org/10.1007/s40265-021-01526-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217012PMC
June 2021

Impact of Diverse Ion Channels on Regulatory T Cell Functions.

Cell Physiol Biochem 2021 May;55(S3):145-156

Department of Neurology, University Hospital Duesseldorf, Duesseldorf, Germany,

The population of regulatory T cells (Tregs) is critical for immunological self-tolerance and homeostasis. Proper ion regulation contributes to Treg lineage identity, regulation, and effector function. Identified ion channels include Ca release-activated Ca, transient receptor potential, P2X, volume-regulated anion and K channels Kv1.3 and KCa3.1. Ion channel modulation represents a promising therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This review summarizes studies with gene-targeted mice and pharmacological modulators affecting Treg number and function. Furthermore, participation of ion channels is illustrated and the power of future research possibilities is discussed.
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http://dx.doi.org/10.33594/000000375DOI Listing
May 2021

Occurrence of status epilepticus in persons with epilepsy is determined by sex, epilepsy classification, and etiology: a single center cohort study.

J Neurol 2021 May 21. Epub 2021 May 21.

Department of Neurology with Institute of Translational Neurology, University of Münster, University Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.

Background: Status epilepticus (SE) can occur in persons with or without epilepsy and is associated with high morbidity and mortality.

Methods: This survey aimed to record self-reported frequency of SE in persons with epilepsy, its association with clinical characteristics and patient level of information on SE and rescue medication. 251 persons with epilepsy at a tertiary epilepsy center were included in the study.

Results: 87 (35%) had a history of SE defined as seizure duration of more than 5 min. These patients were less likely to be seizure-free, and had a higher number of present and past anti-seizure medication. Female sex, cognitive disability, younger age at epilepsy onset, defined epilepsy etiology, and focal epilepsy were associated with a history of SE. On Cox regression analysis, female sex, defined etiology and focal classification remained significant. 67% stated that they had information about prolonged seizures, and 75% knew about rescue medication. 85% found it desirable to receive information about SE at the time of initial diagnosis of epilepsy, but only 16% had been offered such information at the time.

Conclusion: SE is frequent among persons with epilepsy and there remain unmet needs regarding patient education.
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http://dx.doi.org/10.1007/s00415-021-10600-yDOI Listing
May 2021

Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education.

J Exp Med 2021 07 20;218(7). Epub 2021 May 20.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

Beyond hemostasis, platelets actively participate in immune cell recruitment and host defense, yet their potential in the resolution of inflammatory processes remains unknown. Here, we demonstrate that platelets are recruited into the lung together with neutrophils during the onset of inflammation and alongside regulatory T (T reg) cells during the resolution phase. This partnering dichotomy is regulated by differential adhesion molecule expression during resolution. Mechanistically, intravascular platelets form aggregates with T reg cells, a prerequisite for their recruitment into the lung. This interaction relies on platelet activation by sCD40L and platelet P-selectin binding to PSGL-1 on T reg cells. Physical platelet-T reg cell interactions are necessary to modulate the transcriptome and instruct T reg cells to release the anti-inflammatory mediators IL-10 and TGFβ. Notably, the presence of platelet-T reg cell aggregates in the lung was also required for macrophage transcriptional reprogramming, polarization toward an anti-inflammatory phenotype, and effective resolution of pulmonary inflammation. Thus, platelets partner with successive immune cell subsets to orchestrate both the initiation and resolution of inflammation.
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http://dx.doi.org/10.1084/jem.20201353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142284PMC
July 2021

Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis.

Curr Opin Neurol 2021 08;34(4):598-603

Università Vita Salute San Raffaele, Multiple Sclerosis Centre, Hospital of Gallarate, Italy.

Purpose Of Review: To assess the reasons for considering discontinuation of disease-modifying therapies (DMTs)in patients with multiple sclerosis (MS). Relevant aspects of the natural history, pathology, and immunology are analyzed.

Recent Findings: A number of retrospective observational studies in aggregate indicate that stopping DMTs may be attempted in older individuals with stable disease. Prognostic factors have been identified informing about the risk of recurrence of disease activity after DMT discontinuation.

Summary: Several clinical scenarios provide a rationale to stop DMTs in people with MS. Cumulative evidence has been gathered recently allowing us to more precisely weigh the risks against the benefits. This information aids in the decision process.
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http://dx.doi.org/10.1097/WCO.0000000000000960DOI Listing
August 2021

Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.

Mult Scler 2021 May 12:13524585211012227. Epub 2021 May 12.

Department of Neurology and Center for Translational and Behavioral Neurosciences (C-TNBS), University Medicine Essen, Essen, Germany.

Background: Oral cladribine has been approved for the treatment of relapsing multiple sclerosis (MS) yet real-world evidence regarding its effectiveness and safety remains scarce.

Objective: To evaluate efficacy and safety outcomes of MS patients following induction of cladribine.

Methods: We evaluated our prospective cohort of cladribine-treated MS patients from two tertiary centres in Germany. Relapses, disability worsening and occurrence of new or enlarging T2-hyperintense magnetic resonance imaging (MRI) lesions were assessed as well as lymphocyte counts and herpes virus infections.

Results: Among 270 patients treated with cladribine, we observed a profound reduction of both relapses and new or enlarging MRI lesions. Treatment appeared more efficacious, especially in patients without previous therapy or following platform substances. Patients switching from natalizumab were prone to re-emerging disease activity. Among patients following dimethyl fumarate pre-treatment, severe lymphopenia was common and associated with increased rates of herpes virus manifestations.

Conclusion: Overall, we observed an efficacy and safety profile of cladribine consistent with data from the phase 3 clinical trial. However, patients switching from natalizumab experienced suboptimal disease control beyond rebound activity following cessation of natalizumab. Furthermore, dimethyl fumarate pre-treatment was associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections.
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http://dx.doi.org/10.1177/13524585211012227DOI Listing
May 2021

Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis.

Brain 2021 Apr 12. Epub 2021 Apr 12.

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

Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analyzed 546 patients with autoimmune neuro-inflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters altered across all autoimmune neuro-inflammatory CNS-diseases and differentiating them from other neurological conditions and inter-autoimmunity classifiers sub-differentiating variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist classification of neurological patients. Overall, we show that an integrated analysis of blood and CSF parameters improves differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.
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http://dx.doi.org/10.1093/brain/awab147DOI Listing
April 2021
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