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Background: Dissecting trends and contributing risk factors for intracranial hemorrhage (ICH) in patients treated for acute pulmonary embolism (PE) may allow for a better patient selection for existing and emerging treatment options., Methods: The German nationwide inpatient sample was screened for patients admitted due to PE 2005-2020. Hospitalizations were stratified for the occurrence of ICH; risk factors for ICH and temporal trends were investigated., Results: Overall, 816,653 hospitalizations due to acute PE in the period 2005-2020 were analyzed in the study. ICH was reported in 2516 (0.3 %) hospitalizations, and time trend analysis revealed a fluctuating but overall, largely unchanged annual incidence. There was an increase of ICH with age. Patients with ICH had a higher comorbidity burden (Charlson-Comorbidity-Index [CCI], 5.0 [4.0-7.0] vs. 4.0 [2.0-5.0]; P < 0.001), and higher CCI was associated with an OR of 1.26 (95%CI 1.24-1.27) for ICH. Further independent risk factors for ICH were age ≥ 70 years (OR 1.23 [1.12-1.34]), severe (versus low-risk) PE (OR 3.09 [2.84-3.35]), surgery (OR 1.59 [1.47-1.72]), acute kidney injury (OR 3.60 [3.09-4.18]), and ischemic stroke (OR 14.64 [12.61-17.00]). The identified risk factors for ICH varied among different reperfusion treatment groups. As expected, ICH had a substantial impact on case-fatality of PE (OR 6.16 [5.64-6.72]; P < 0.001)., Conclusions: Incidence of ICH in patients hospitalized for acute PE in Germany was overall low and depended on the patients' comorbidity burden. Identifying patients at risk for ICH allows tailored patient selection for the different reperfusion treatments and might prevent ICH., Competing Interests: Declaration of competing interest KCC, KM, TU, MJ, LV, ITF, TM, KK report no conflicts of interests. PL has received institutional fees and research grants from Abbott Vascular, Edwards Lifesciences, and ReCor, honoraria from Edwards Lifesciences, Abbott Medical, Innoventric, ReCor and Boehringer Ingelheim and has stock options with Innoventric. SK reports institutional grants and personal lecture/advisory fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; institutional grants from Inari Medical; and personal lecture/advisory fees from MSD and Bristol Myers Squibb/Pfizer. LH received lecture/consultant fees from MSD and Actelion, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1 R345T/WT ). Prg-1 R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders., (© 2024. The Author(s).)

Background: Interferon-beta (IFN-β) still plays a fundamental role in immunomodulation of people with multiple sclerosis (MS) with low disease activity and in clinically isolated syndrome (CIS). In 2014, pegylated (PEG) interferon was licensed by the European Medicines Agency (EMA) for relapsing-remitting MS (RRMS), enabling a lower dosing frequency., Objectives: Our retrospective study compares laboratory findings and adverse events between subcutaneous (sc.) PEG-IFN-β-1a and IFN-β-1a in RRMS and CIS patients., Design: Patients with CIS or RRMS fulfilling the revised McDonald criteria from 2017 visiting the neurology department of the University Medical Center of the Johannes Gutenberg University Mainz from 2010 to 2019 and treated with sc. PEG-IFN-β-1a or sc. IFN-β-1a ( n  = 202) were screened for eligibility. Patients who underwent regular laboratory controls in-house were included in our analysis ( n  = 128)., Methods: We evaluate disease progression through clinical examination, relapse history, and magnetic resonance imaging (MRI) disease activity (gadolinium-enhancing or new T2 lesions). Relevant laboratory findings such as leukopenia (leukocyte count < 3.5/nl) and neutropenia (neutrophil count <43% of lymphocytes or <1500/µl) were assessed. Telephone interviews evaluated the side effects of the respective medication. A subgroup of patients was analyzed regarding neutrophil quantities and qualities., Results: Patients treated with sc. PEG-IFN-β-1a had significantly lower leukocyte counts ( p  = 0.046) and higher incidences of leukopenia ( p  = 0.006) and neutropenia ( p  = 0.03) compared to sc. IFN-β-1a. Clinical and MRI disease activity showed no significant differences, but people treated with sc. PEG-IFN-β-1a reported more common adverse events such as joint/muscle pain, injection-site reaction, and infections. No serious adverse events were reported., Conclusion: Treatment with sc. PEG-IFN-β-1a compared to unpegylated sc. IFN-β resulted in a significantly greater reduction in leukocyte and neutrophil levels with a higher incidence of side effects. We suggest mandatory monitoring of differential blood counts before and during treatment., (© The Author(s), 2024.)

Objectives: To investigate the clinical feasibility and image quality of accelerated brain diffusion-weighted imaging (DWI) with deep learning image reconstruction and super resolution., Methods: 85 consecutive patients with clinically indicated MRI at a 3 T scanner were prospectively included. Conventional diffusion-weighted data (c-DWI) with four averages were obtained. Reconstructions of one and two averages, as well as deep learning diffusion-weighted imaging (DL-DWI), were accomplished. Three experienced readers evaluated the acquired data using a 5-point Likert scale regarding overall image quality, overall contrast, diagnostic confidence, occurrence of artefacts and evaluation of the central region, basal ganglia, brainstem, and cerebellum. To assess interrater agreement, Fleiss' kappa (ϰ) was determined. Signal intensity (SI) levels for basal ganglia and the central region were estimated via automated segmentation, and SI values of detected pathologies were measured., Results: Intracranial pathologies were identified in 35 patients. DL-DWI was significantly superior for all defined parameters, independently from applied averages (p-value <0.001). Optimum image quality was achieved with DL-DWI by utilizing a single average (p-value <0.001), demonstrating very good (80.9%) to excellent image quality (14.5%) in nearly all cases, compared to 12.5% with very good and 0% with excellent image quality for c-MRI (p-value <0.001). Comparable results could be shown for diagnostic confidence. Inter-rater Fleiss' Kappa demonstrated moderate to substantial agreement for virtually all defined parameters, with good accordance, particularly for the assessment of pathologies (p = 0.74). Regarding SI values, no significant difference was found., Conclusion: Ultra-fast diffusion-weighted imaging with super resolution is feasible, resulting in highly accelerated brain imaging while increasing diagnostic image quality., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sebastian Altmann reports writing assistance was provided by Siemens Healthineers AG, Erlangen, Germany. Thomas Benkert reports a relationship with Siemens Healthineers AG, Erlangen, Germany that includes: employment. Thomas Benkert has patent pending to Siemens Healthineers AG. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Invasive dental procedures, such as wisdom teeth removal, have been identified as potential triggers for vascular events due to the entry of oral bacteria into the bloodstream, leading to acute vascular inflammation and endothelial dysfunction. This study presents the case of a 27-year-old healthy male who developed ischemic stroke resulting from bacteremia after undergoing wisdom teeth extraction. Initially, the patient experienced fever and malaise, which were followed by right-sided hemiplegia. Diagnostic imaging, including a CT scan, identified a subacute infarction in the posterior crus of the left internal capsule, and MRI findings indicated inflammatory changes in the masticatory muscles. Further investigations involving biopsies of the masticatory muscles, along with blood and cerebrospinal fluid samples, confirmed bacterial meningitis with associated vasculitis. Notably, oral bacteria linked to periodontitis, including Porphyromonas gingivalis , Fusobacterium nucleatum , Tannerella forsythia , and Parvimonas micra , were found in the biopsies and microbiological analyses. To the best of our knowledge, this is the first reported case showing that bacteremia following dental procedures can lead to such severe neurological outcomes. This case underscores the importance of recognizing bacteremia-induced vasculitis in patients presenting with neurological symptoms post-dental procedures, emphasizing the broader implications of oral infections in such pathologies.

Background: Missing outcome data (MOD) is a common problem in clinical trials and registries, and a potential bias when drawing conclusions from these data. Identifying factors associated with MOD may help to increase follow-up rates and assess the need for imputation strategies. We investigated MOD in a multicenter, prospective registry study of mechanical thrombectomy (MT) in large vessel occlusion ischemic stroke., Methods: 13 082 patients enrolled in the German Stroke Registry-Endovascular Treatment from May 2015 to December 2021 were analyzed with regard to MOD (90 day modified Rankin Scale, mRS). Univariate logistic regression analyses identified factors unbalanced between patients with and without MOD. Subgroup analyses were performed to identify patients for whom increased efforts to perform clinical follow-up after hospital discharge are needed., Results: We identified 19.7% (2580/13 082) of patients with MOD at the 90 day follow-up. MOD was more common with higher pre-stroke disability (mRS 3-5, 32.2% vs mRS 0-2, 13.7%; P<0.001), absence of bridging intravenous thrombolysis, longer time to treatment, and in patients with high post-stroke disability at discharge (mRS 3-5 vs 0-2: OR 1.234 (95% CI 1.107 to 1.375); P<0.001). In contrast, MOD was less common with futile recanalization (thrombolysis in cerebral infarction (TICI) score of 0-2a, 12.4% vs TICI 2b-3, 15.0%; P=0.001). In patients discharged alive with well documented baseline characteristics, shorter hospital stay (OR 0.992 (95% CI 0.985 to 0.998); P=0.010) and discharge to institutional care or hospital (OR 1.754 (95% CI 1.558 to 1.976); P<0.001) were associated with MOD., Conclusion: MOD in routine care MT registry data was not random. Increased efforts to perform clinical follow-up are needed, especially in the case of higher pre-stroke and post-stroke disability and discharge to hospital or institutional care., Trial Registration: NCT03356392., Competing Interests: Competing interests: AO reports speakers bureau from Cerenovus and Canon Medical. KG reports personal fees and/or non-financial support from Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo, and Pfizer. MH reports personal fees from Bristol-Meyers Squibb, outside of the submitted work. TU reports personal fees from Merck Serono and Pfizer, and grants from Else Kröner-Fresenius Stiftung., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale and Objectives: Ruptured intracranial aneurysms (IAs) are the leading cause for atraumatic subarachnoid hemorrhage. In case of aneurysm rupture, patients may face life-threatening complications and require aneurysm occlusion. Detection of the aneurysm in computed tomography (CT) imaging is therefore essential for patient outcome. This study provides an evaluation of the diagnostic accuracy of Ultra-High-Resolution Computed Tomography Angiography (UHR-CTA) and Normal-Resolution Computed Tomography Angiography (NR-CTA) concerning IA detection and characterization., Materials and Methods: Consecutive patients with atraumatic subarachnoid hemorrhage who received Digital Subtraction Angiography (DSA) and either UHR-CTA or NR-CTA were retrospectively included. Three readers evaluated CT-Angiography regarding image quality, diagnostic confidence and presence of IAs. Sensitivity and specificity were calculated on patient-level and segment-level with reference standard DSA-imaging. CTA patient radiation exposure (effective dose) was compared., Results: One hundred and eight patients were identified (mean age = 57.8 ± 14.1 years, 65 women). UHR-CTA revealed significantly higher image quality and diagnostic confidence (P < 0.001) for all readers and significantly lower effective dose (P < 0.001). Readers correctly classified ≥55/56 patients on UHR-CTA and ≥44/52 patients on NR-CTA. We noted significantly higher patient-level sensitivity for UHR-CTA compared to NR-CTA for all three readers (reader 1: 41/41 [100%] vs. 28/34 [82%], reader 2: 41/41 [100%] vs. 30/34 [88%], reader 3: 41/41 [100%] vs. 30/34 [88%], P ≤ 0.04). Segment-level analysis also revealed significantly higher sensitivity for UHR-CTA compared to NR-CTA for all three readers (reader 1: 47/49 [96%] vs. 34/45 [76%], reader 2: 47/49 [96%] vs. 37/45 [82%], reader 3: 48/49 [98%] vs. 37/45 [82%], P ≤ 0.04). Specificity was comparable for both techniques., Conclusion: We found Ultra-High-Resolution CT-Angiography to provide higher sensitivity than Normal-Resolution CT-Angiography for the detection of intracranial aneurysms in patients with aneurysmal subarachnoid hemorrhage while improving image quality and reducing patient radiation exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ahmed E. Othman reports a relationship with Canon Medical Systems Corporation Speakers’ Bureau that includes: speaking and lecture fees. Marc A. Brockmann reports a relationship with Canon Medical Systems Corporation Speakers’ Bureau that includes: speaking and lecture fees., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The occurrence of cerebral vasculitis in individuals with neurosarcoidosis (NS) is considered to be rare. Although the number of relevant publications has increased in recent years, evidence is mostly limited to case reports. To obtain a better understanding of this rare and severe manifestation of disease, we carried out a scoping review on cerebral vasculitis in patients diagnosed with NS. The results of the review indicate that the diagnosis of cerebral vasculitis in patients with NS is made especially in patients with systemic sarcoidosis. However, recurrent strokes in patients with NS remains the main indicator of cerebral vasculitis. A tissue biopsy is considered the gold standard to confirm the diagnosis despite occasional false-negative results. Glucocorticoids and steroid-sparing agents are the most successful current treatments. Favorable outcomes were observed with strategies targeting TNFα and B cells. The goal of this review is to summarize the current literature and treatment options for cerebral vasculitis in patients with NS., Competing Interests: Declaration of competing interest YW reports honoraria for educational presentations and consultations from Angelini Pharma, Arvelle Therapeutics, Bayer AG, BIAL, Bioprojet, Eisai, Idorsia Pharmaceuticals, JAZZ Pharmaceuticals, LivaNova, Novartis and UCB Pharma. SG received compensation for professional services from Abbott, Abbvie, Bial, Medtronic, UCB and Zambon; research grants from Abbott, Boston Scientific, MagVenture, German Research Council and German Ministry of Education and Health; received funding from National MS Society and DFG SPP-2177 Radiomics. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. SF received honoraria for educational presentations and consultations from Eisai. TU reports personal fees from Merck Serono and Pfizer, grants from Else Kröner-Fresenius Stiftung and the German Research Council. EH, EE, SF and SB declare nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Immunomodulatory and immunosuppressive therapy is needed in people with a chronic neuroinflammatory disease of the central nervous system such as multiple sclerosis (MS). Therefore, MS requires monitoring for and preventing against infectious diseases like SARS-CoV-2. Vaccination and anti-viral treatments are, in particular, recommended for elderly people and people at risk of a severe course of infection and of MS. Here, we asked whether repetitive infection or vaccination influenced responses upon receiving high efficacy treatments, namely sphingosine-1-phosphate receptor modulator (S1P) or anti-CD20 B cell antibody (anti-CD20) treatments. We performed a prospective real-world study of people with MS (pwMS) under S1P or anti-CD20 with repetitive exposure to the SARS-CoV-2 virus or vaccine. The measurement of anti-SARS-CoV-2 antibody titres was performed by two independent immunoassays after initial immunisation and after booster vaccination or infection. Other laboratory and clinical parameters were included in the analysis of influencing factors. As secondary outcomes, lymphocyte and immunoglobulin levels were observed longitudinally under intravenous and subcutaneous anti-CD20 treatment. In a long-term real-world cohort of 201 pwMS, we found that despite lymphopenia upon S1P drugs, the SARS-CoV-2 immunisation response increased both in selective and non-selective S1P (100% and 88% seroconversion, respectively), whereas those under anti-CD20 therapies merely exhibited a slight long-term increase in antibody titres (52% seroconversion). The latter was independent of immunoglobulin or total lymphocyte levels, which mostly remained stable. If the individual was immunised prior to therapy initiation, their levels of SARS-CoV-2 antibodies remained high under treatment. PwMS under non-selective S1P benefit from repetitive vaccination. The risk of an insufficient vaccination response mirrored by lower SARS-CoV-2 antibodies remains in pwMS receiving anti-CD20 treatment, even after repetitive exposure to the vaccine or virus. Due to the compromised vaccination response in CD20-depleting drugs, prompt antiviral treatment might be necessary.

Objective: To evaluate diagnostic image quality of ultra-high-resolution computed tomography angiography (UHR-CTA) in neurovascular imaging as compared to normal resolution CT-angiography (NR-CTA)., Material and Methods: In this retrospective single-center study brain and neck CT-angiography was performed using an ultra-high-resolution computed tomography scanner (n = 82) or a normal resolution CT scanner (NR-CTA; n = 73). Ultra-high-resolution images were reconstructed with a 1024 × 1024 matrix and a slice thickness of 0.25 mm, whereas NR-CT images were reconstructed with a 512 × 512 matrix and a slice thickness of 0.5 mm. Three blinded neuroradiologists assessed overall image quality, artifacts, image noise, overall contrast and diagnostic confidence using a 4-point Likert scale. Furthermore, the visualization and delineation of supra-aortic arteries with an emphasis on the visualization of small intracerebral vessels was assessed using a cerebral vascular score, also utilizing a 4-point Likert scale. Quantitative analyses included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), noise and the steepness of gray value transition. Radiation exposure was determined by comparison of computed tomography dose index (CTDIvol), dose length product (DLP) and mean effective dose. Interrater agreement was evaluated via determining Fleiss-Kappa., Results: Ultra-high-resolution CT-angiography (UHR-CTA) yielded excellent image quality with superior quantitative (SNR: p < 0.001, CNR: p < 0.001, steepness of gray value transition: p < 0.001) and qualitative results (overall image quality: 4 (Inter quartile range (IQR) = 4-4); p < 0.001, diagnostic confidence: 4 (IQR = 4-4); p < 0.001) compared to NR-CT (overall image quality: 3 (IQR = 3-3), diagnostic confidence: 3 (IQR = 3-4)). Furthermore, UHR-CT enabled significantly superior delineation and visualization of all vascular segments, from proximal extracranial vessels to the smallest peripheral cerebral branches (e.g., , Uhr-Cta Pica: 4 (3-4) vs. NR-CTA PICA: 3 (2-3); UHR-CTA P4: 4 (IQR = 3-4) vs. NR-CTA P4: 2 (IQR = 2-3); UHR-CTA M4: 4 (IQR = 4-4) vs. NR-CTA M4: 3 (IQR = 2-3); UHR-CTA A4: 4 (IQR = 3-4) vs. NR-CTA A4: 2 (IQR = 2-3); all p < 0.001). Noteworthy, a reduced mean effective dose was observed when applying UHR-CT (NR-CTA: 1.8 ± 0.3 mSv; UHR-CTA: 1.5 ± 0.5 mSv; p < 0.001)., Conclusion: Ultra-high-resolution CT-angiography improves image quality in neurovascular imaging allowing the depiction and evaluation of small peripheral cerebral arteries. It may thus improve the detection of pathologies in small cerebrovascular lesions and the resulting diagnosis., (© 2023. The Author(s).)

Background Deep learning (DL)-accelerated MRI can substantially reduce examination times. However, studies prospectively evaluating the diagnostic performance of DL-accelerated MRI reconstructions in acute suspected stroke are lacking. Purpose To investigate the interchangeability of DL-accelerated MRI with conventional MRI in patients with suspected acute ischemic stroke at 1.5 T. Materials and Methods In this prospective study, 211 participants with suspected acute stroke underwent clinically indicated MRI at 1.5 T between June 2022 and March 2023. For each participant, conventional MRI (including T1-weighted, T2-weighted, T2*-weighted, T2 fluid-attenuated inversion-recovery, and diffusion-weighted imaging; 14 minutes 18 seconds) and DL-accelerated MRI (same sequences; 3 minutes 4 seconds) were performed. The primary end point was the interchangeability between conventional and DL-accelerated MRI for acute ischemic infarction detection. Secondary end points were interchangeability regarding the affected vascular territory and clinically relevant secondary findings (eg, microbleeds, neoplasm). Three readers evaluated the overall occurrence of acute ischemic stroke, affected vascular territory, clinically relevant secondary findings, overall image quality, and diagnostic confidence. For acute ischemic lesions, size and signal intensities were assessed. The margin for interchangeability was chosen as 5%. For interrater agreement analysis and interrater reliability analysis, multirater Fleiss κ and the intraclass correlation coefficient, respectively, was determined. Results The study sample consisted of 211 participants (mean age, 65 years ± 16 [SD]); 123 male and 88 female). Acute ischemic stroke was confirmed in 79 participants. Interchangeability was demonstrated for all primary and secondary end points. No individual equivalence indexes (IEIs) exceeded the interchangeability margin of 5% (IEI, -0.002 [90% CI: -0.007, 0.004]). Almost perfect interrater agreement was observed ( P > .91). DL-accelerated MRI provided higher overall image quality ( P < .001) and diagnostic confidence ( P < .001). The signal properties of acute ischemic infarctions were similar in both techniques and demonstrated good to excellent interrater reliability (intraclass correlation coefficient, ≥0.8). Conclusion Despite being four times faster, DL-accelerated brain MRI was interchangeable with conventional MRI for acute ischemic lesion detection. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Haller in this issue.

Rationale and Objectives: To evaluate clinical feasibility and image quality of a comprehensive ultrafast brain MRI protocol with multi-shot echo planar imaging and deep learning-enhanced reconstruction at 1.5T., Materials and Methods: Thirty consecutive patients who underwent clinically indicated MRI at a 1.5 T scanner were prospectively included. A conventional MRI (c-MRI) protocol, including T1-, T2-, T2*-, T2-FLAIR, and diffusion-weighted images (DWI)-weighted sequences were acquired. In addition, ultrafast brain imaging with deep learning-enhanced reconstruction and multi-shot EPI (DLe-MRI) was performed. Subjective image quality was evaluated by three readers using a 4-point Likert scale. To assess interrater agreement, Fleiss' kappa (ϰ) was determined. For objective image analysis, relative signal intensity levels for grey matter, white matter, and cerebrospinal fluid were calculated., Results: Time of acquisition (TA) of c-MRI protocols added up to 13:55 minutes, whereas the TA of DLe-MRI-based protocol added up to 3:04 minutes, resulting in a time reduction of 78%. All DLe-MRI acquisitions yielded diagnostic image quality with good absolute values for subjective image quality. C-MRI demonstrated slight advantages for DWI in overall subjective image quality (c-MRI: 3.93 [+/- 0.25] vs DLe-MRI: 3.87 [+/- 0.37], P = .04) and diagnostic confidence (c-MRI: 3.93 [+/- 0.25] vs DLe-MRI: 3.83 [+/- 3.83], P = .01). For most evaluated quality scores, moderate interobserver agreement was found. Objective image evaluation revealed comparable results for both techniques., Conclusion: DLe-MRI is feasible and allows for highly accelerated comprehensive brain MRI within 3minutes at 1.5 T with good image quality. This technique may potentially strengthen the role of MRI in neurological emergencies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sebastian Altmann reports writing assistance was provided by SIEMENS. Thorsten Feiweier reports a relationship with Siemens Healthineers that includes: employment. Bryan Clifford reports a relationship with Siemens Medical Solutions USA Inc that includes: employment. Thorsten Feiweier & Bryan Clifford has patent pending to US 2022/0343564 A1. Thorsten Feiweier & Bryan Clifford has patent pending to US 2022/0317218 A1. Thorsten Feiweier & Bryan Clifford has patent issued to US 11 215 683 B2., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objective: Mechanical thrombectomy (MT) has become standard treatment in acute ischemic stroke due to large vessel occlusion (LVO). However, optimal blood pressure (BP) management following successful recanalization remains unclear. We aim to investigate the association of strictly achieving BP targets of ≤160/90 mmHg with the extent of neuronal loss and functional outcome., Methods: In patients prospectively enrolled in the Gutenberg-Stroke-Study (May 2018-November 2019), BP was measured half-hourly for 24 h following MT. Based on achieving BP target of ≤160/90 mmHg, patients with successful recanalization of LVO were divided into "low-BP" group (BP ≤ 160/90 mmHg) or "high-BP" group (BP > 160/90 mmHg). Neuronal loss was quantified by serum-based measurement of neurofilament light chain (sNfL) after three days. BP groups and association of BP parameters with sNfL were investigated by correlation analyses and multiple regression modeling., Results: Of 253 enrolled patients (mean age 73.1 ± 12.9 years, 53.4% female), 165 met inclusion criteria. 21.2% (n = 35) strictly achieved "low-BP" target. "low-BP" was associated with unfavorable functional outcome at 90-day follow-up (aOR [95%CI]: 5.88 [1.88-18.32], p = 0.002) and decreased health-related quality of life (mean EQ-5D-index 0.45 ± 0.28 vs 0.63 ± 0.31, p = 0.009). sNfL levels were increased in "low-BP" patients (median [IQR] 239.7 [168.4-303.4] vs 118.8 [52.5-220.5] pg/mL, p = 0.026). Hypotensive episodes were more frequent in the "low-BP" group (48.6% vs 29.2%, p = 0.031). sNfL level could identify patients who had experienced hypotensive episodes with high discriminative ability (AUC [95%CI]: 0.68 [0.56-0.78], p = 0.007)., Interpretation: Strict BP control (≤160/90 mmHg) within 24 h following successful recanalization of LVO by MT is associated with increased neuronal injury, displayed by higher sNfL levels, and poorer functional outcome, potentially indicating hypotension-induced neuronal loss during post-MT phase., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Ongoing neuroaxonal damage is a major contributor to disease progression and long-term disability in multiple sclerosis. However, spatio-temporal distribution and pathophysiological mechanisms of neuroaxonal damage during acute relapses and later chronic disease stages remain poorly understood., Methods: Here, we applied immunohistochemistry, single-molecule array, spatial transcriptomics, and microglia/axon co-cultures to gain insight into spatio-temporal neuroaxonal damage in experimental autoimmune encephalomyelitis (EAE)., Results: Association of spinal cord white matter lesions and blood-based neurofilament light (sNfL) levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: in chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions but showed a widespread distribution in early EAE. Following this pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and microglia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro., Interpretation: Our findings indicate that CNS myeloid cells may play a crucial role in driving neuroaxonal damage in EAE. Moreover, neuroaxonal damage can progress in a stage-dependent centripetal manner, transitioning from normal-appearing white matter to focal white matter lesions. These insights may contribute to a better understanding of neurodegeneration and elevated sNfL levels observed in multiple sclerosis patients at different disease stages., (© 2023. The Author(s).)

Background: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism., Methods: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur., Conclusions: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC)., Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion., Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021., Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation., Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses., Results: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion., Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

Background: Impaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients., Methods: NfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry., Results: CSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = - 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort., Conclusions: The observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis., (© 2023. The Author(s).)

Introduction: Hospitals around the world introduced considerable visitation restrictions to reduce risk of infection during epidemic spread of SARS-CoV2. Understanding of negative impacts of visitation restrictions on subgroups of patients may help to balance and adjust policies accordingly or introduce further measures to mitigate their impact. We aimed to investigate the association of visitation restrictions with delirium incidence in stroke-unit patients., Methods: In a non-randomized observational design, data from 5,779 stroke-unit cases with transient ischemic attack or stroke (ischemic/hemorrhagic) admitted between January 2017 and November 2021 were compared between three groups depending on visitation policy implemented at time of admission: pandemic-associated absolute visitation restriction (n = 1,087), limited visitation policy (n = 862), and pre-pandemic visitation policy (n = 3,830). Univariate comparison and multiple logistic regression analyses were conducted to evaluate the association of delirium with visitation restrictions., Results: We observed delirium incidences of 6.3% during pandemic-associated absolute visitation restriction, 5.8% with limited visitation policy, and 5.1% with pre-pandemic visitation policy (p = 0.239). In multiple logistic regression analyses adjusting for clinically relevant variables, we found the presence of any pandemic-associated visitation restriction (odds ratio [OR] 1.363, 95% confidence interval [CI]: 1.066-1.744, p = 0.014) and specifically absolute visitation restriction (OR 1.368, 95% CI: 1.016-1.843, p = 0.039) independently associated with delirium in patients with acute cerebrovascular disease. Other factors independently associated with delirium were older age, male sex, stroke versus transient ischemic attack, acute infection, history of dementia, and longer duration of hospital stay., Conclusion: Pandemic-associated visitation restrictions and specifically absolute visitation restrictions are associated with a higher incidence of delirium among stroke-unit patients with acute cerebrovascular disease. Benefit and harm of visitation restrictions should be carefully weighed and adjustments considered for patients otherwise at increased risk for delirium., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Disease-modifying therapies (DMT) for multiple sclerosis (MS) influence SARS-CoV-2 vaccination response, which might have implications for vaccination regimens in individual patients. Expanding the knowledge of predictors for an insufficient vaccination response as a surrogate for protection against severe disease courses of infection in people with MS (pwMS) under DMT is of great importance in identifying high-risk populations., Methods: Cross-sectional analysis of vaccination titre and its modifiers, in a prospective real-world cohort of 386 individuals (285 pwMS and 101 healthy controls) by two independent immunoassays between October 2021 and June 2022., Findings: In our cohort, no difference in vaccination antibody level was evident between healthy controls (HC) and untreated pwMS. In pwMS lymphocyte levels, times vaccinated and DMT influence SARS-CoV-2 titre following vaccination. Those treated with selective sphingosine-1-phosphate receptor modulators (S1P) showed comparable vaccination titres to untreated; higher CD8 T cell levels prior to vaccination in B cell-depleted patients resulted in increased anti-spike SARS-CoV2 antibody levels., Interpretation: PwMS under DMT with anti-CD20 treatment, in particular those with decreased CD8 levels before vaccination, as well as non-selective S1P but not selective S1P are at increased risk for insufficient SARS-CoV-2 vaccination response. This argues for a close monitoring of anti-spike antibodies in order to customize individual vaccination regimens within these patients., Funding: This work was supported by the German Research Foundation (DFG, CRC-TR-128 to TU, SB, and FZ)., Competing Interests: Declaration of interests The authors declare no relevant conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Immunomodulatory therapies reduce the relapse rate but only marginally control disability progression in patients with MS. Although serum neurofilament light chain (sNfL) levels correlate best with acute signs of inflammation (e.g., relapses and gadolinium-enhancing [Gd+] lesions), their role in predicting progressive biology and irreversible axonal damage is less clear. We aimed to determine the ability of sNfL to dissect distinct measures of disease severity and predict future (no) evidence of disease activity (EDA/no evidence of disease activity [NEDA])., Methods: One hundred fifty-three of 221 patients with relapsing-remitting MS initially enrolled in the Neurofilament and longterm outcome in MS cohort at the MS outpatient clinic of the University Medical Center Mainz (Germany) met the inclusion criteria for this prospective observational cohort study with a median follow-up of 6 years (interquartile range 4-7 years). Progressive disease forms were excluded. Inclusion criteria consisted of Expanded Disability Status Scale (EDSS) assessment within 3 months and MRI within 12 months around blood sampling at baseline (y0) and follow-up (y6). EDSS progression at y6 had to be confirmed 12 weeks later. sNfL was measured by single-molecule array, and the following additional variables were recorded: therapy, medical history, and detailed MRI parameters (T2 hyperintense lesions, Gd+ lesions, and new persistent T1 hypointense lesions)., Results: Patients experiencing EDSS progression or new persistent T1 lesions at y6 showed increased sNfL levels at y0 compared with stable patients or patients with inflammatory activity only. As a potential readily accessible marker of neurodegeneration, we incorporated the absence of persistent T1 lesions to the NEDA-3 concept (NEDA-3 T1 : n = 54, 35.3%; EDA T1 : n = 99, 64.7%) and then evaluated a risk score with factors that distinguish patients with and without NEDA-3 T1 status. Adding sNfL to this risk score significantly improved NEDA-3 T1 prediction (0.697 95% CI 0.616-0.770 vs 0.819 95% CI 0.747-0.878, p < 0.001). Patients with sNfL values ≤8.6 pg/mL showed a 76% risk reduction for EDA T1 at y6 (hazard ratio 0.244, 95% CI 0.142-0.419, p < 0.001)., Discussion: sNfL levels associate with severe focal axonal damage as reflected by development of persistent T1 lesions. Baseline sNfL values predicted NEDA-3 T1 status at 6-year follow-up., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis., Methods: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up., Results: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88-1.53)/1.05 (95% CI, 0.78-1.42; P =0.629)/0.63 (95% CI, 0.43-0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21-0.99]; P =0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37-1.42]; P =0.343)., Conclusions: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis., Registration: URL: https://www., Clinicaltrials: gov; Unique Identifier: NCT01645306.

Background: Strokes in the working-age population represent a relevant share of ischemic strokes and re-employment is a major factor for well-being in these patients. Income differences by sex have been suspected a barrier for women in returning to paid work following ischemic stroke. We aim to identify predictors of (not) returning to paid work in patients with large vessel occlusion treated with mechanical thrombectomy (MT) to identify potential areas of targeted vocational rehabilitation., Methods: From 6635 patients enrolled in the German Stroke Registry Endovascular Treatment between 2015 and 2019, data of 606 patients of the working population who survived large vessel occlusion at least 90 days past MT were compared based on employment status at day 90 follow-up. Univariate analysis, multiple logistic regression and analyses of area under the curve were performed to identify predictors of re-employment., Results: We report 35.6% of patients being re-employed 3 months following MT (median age 54.0 years; 36.1% of men, 34.5% of women [ P =0.722]). We identified independent negative predictors against re-employment being female sex (odds ratio [OR], 0.427 [95% CI, 0.229-0.794]; P =0.007), higher National Institutes of Health Stroke Scale (NIHSS) score 24 hours after MT (OR, 0.775 [95% CI, 0.705-0.852]; P <0.001), large vessel occlusion due to large-artery atherosclerosis (OR, 0.558 [95% CI, 0.312-0.997]; P =0.049) and longer hospital stay (OR, 0.930 [95% CI, 0.868-0.998]; P =0.043). Positive predictors favoring re-employment were excellent functional outcome (modified Rankin Scale score of 0-1) at 90 day follow-up (OR, 11.335 [95% CI, 4.864-26.415]; P <0.001) and combined treatment with intravenous thrombolysis (OR, 1.904 [95% CI, 1.046-3.466]; P =0.035). Multiple regression modeling increased predictive power of re-employment status significantly over prediction by best single functional outcome parameter (National Institutes of Health Stroke Scale 24 hours after MT ≤5; R 2 : 0.582 versus 0.432; area under the receiver operating characteristic curve: 0.887 versus 0.835, P <0.001)., Conclusions: There is more to re-employment after MT than functional outcome alone. In particular, attention should be paid to possible systemic barriers deterring women from resuming paid work., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03356392.

Background: Specific antiseizure medications (ASM) would improve the outcome in post-stroke epilepsy (PSE). The aim of this multicenter observational study was to compare different antiseizure monotherapies in PSE., Methods: We collected the data from 207 patients with PSE who did not change their initial antiseizure monotherapy during the period of 12 months. Efficacy was assessed by a standardized three month seizure frequency and seizure freedom. Safety was estimated by the reported side effects., Results: The mean three month seizure frequency was 1.9 ± 3.1 on eslicarbazepine, 2.1 ± 3.2 on lacosamide, 3.4 ± 4.4 on levetiracetam, 4.3 ± 6.8 on lamotrigine, and 5.1 ± 7.3 on valproate (p < 0.05 for eslicarbazepine or lacosamide in comparison with levetiracetam, lamotrigine and valproate, respectively). The lowest seizure frequency and the highest seizure freedom was observed on ASMs acting via the slow inactivation of sodium channels in comparison to other mechanisms of action (0.7 ± 0.9 vs 2.2 ± 2.4, p < 0.01). Among side effects, the most frequently reported were vertigo (25%) and tiredness (15.9%). They were similar in all investigated groups of ASM. The independent factors increasing seizure frequency that were identified in multiple regression analyses were increased size of infarction, cortical involvement, hemorrhagic transformation, neurological deficits at admission and functional impairment. Administration of ASM with the mechanism of action via the slow inactivation of sodium channels was an independent factor decreasing the seizure frequency., Conclusion: Our data show that antiseizure medications acting via the slow inactivation of sodium channels, such as lacosamide and eslicarbazepine, are well tolerated and might be associated with better seizure control in PSE., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Disability in multiple sclerosis is generally classified by sensory and motor symptoms, yet cognitive impairment has been identified as a frequent manifestation already in the early disease stages. Imaging- and more recently blood-based biomarkers have become increasingly important for understanding cognitive decline associated with multiple sclerosis. Thus, we sought to determine the prognostic utility of serum neurofilament light chain levels alone and in combination with MRI markers by examining their ability to predict cognitive impairment in early multiple sclerosis. A comprehensive and detailed assessment of 152 early multiple sclerosis patients (Expanded Disability Status Scale: 1.3 ± 1.2, mean age: 33.0 ± 10.0 years) was performed, which included serum neurofilament light chain measurement, MRI markers (i.e. T 2 -hyperintense lesion volume and grey matter volume) acquisition and completion of a set of cognitive tests (Symbol Digits Modalities Test, Paced Auditory Serial Addition Test, Verbal Learning and Memory Test) and mood questionnaires (Hospital Anxiety and Depression scale, Fatigue Scale for Motor and Cognitive Functions). Support vector regression, a branch of unsupervised machine learning, was applied to test serum neurofilament light chain and combination models of biomarkers for the prediction of neuropsychological test performance. The support vector regression results were validated in a replication cohort of 101 early multiple sclerosis patients (Expanded Disability Status Scale: 1.1 ± 1.2, mean age: 34.4 ± 10.6 years). Higher serum neurofilament light chain levels were associated with worse Symbol Digits Modalities Test scores after adjusting for age, sex Expanded Disability Status Scale, disease duration and disease-modifying therapy (B = -0.561; SE = 0.192; P  = 0.004; 95% CI = -0.940 to -0.182). Besides this association, serum neurofilament light chain levels were not linked to any other cognitive or mood measures (all P -values > 0.05). The tripartite combination of serum neurofilament light chain levels, lesion volume and grey matter volume showed a cross-validated accuracy of 88.7% (90.8% in the replication cohort) in predicting Symbol Digits Modalities Test performance in the support vector regression approach, and outperformed each single biomarker (accuracy range: 68.6-75.6% and 68.9-77.8% in the replication cohort), as well as the dual biomarker combinations (accuracy range: 71.8-82.3% and 72.6-85.6% in the replication cohort). Taken together, early neuro-axonal loss reflects worse information processing speed, the key deficit underlying cognitive dysfunction in multiple sclerosis. Our findings demonstrate that combining blood and imaging measures improves the accuracy of predicting cognitive impairment, highlighting the clinical utility of cross-modal biomarkers in multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.

Background: Mechanical thrombectomy (MT) rates for the treatment of acute ischaemic stroke due to large vessel occlusion are steadily increasing, but are delivered in heterogenic settings. We aim to investigate effects of procedural load in centers with established MT-structures by comparing high- vs. low-volume centers with regard to procedural characteristics and functional outcomes., Methods: Data from 5,379 patients enrolled in the German Stroke Registry Endovascular Treatment (GSR-ET) between June 2015 and December 2019 were compared between three groups: high volume: ≥180 MTs/year, 2,342 patients; medium volume: 135-179 MTs/year, 2,202 patients; low volume: <135 MTs/year, 835 patients. Univariate analysis and multiple linear and logistic regression analyses were performed to identify differences between high- and low-volume centers., Results: We identified high- vs. low-volume centers to be an independent predictor of shorter intra-hospital (admission to groin puncture: 60 vs. 82 min, β = -26.458; p < 0.001) and procedural times (groin puncture to flow restoration: 36 vs. 46.5 min; β = -12.452; p < 0.001) after adjusting for clinically relevant factors. Moreover, high-volume centers predicted a shorter duration of hospital stay (8 vs. 9 days; β = -2.901; p < 0.001) and favorable medical facility at discharge [transfer to neurorehabilitation facility/home vs. hospital/nursing home/in-house fatality, odds ratio ( OR ) 1.340, p = 0.002]. Differences for functional outcome at 90-day follow-up were observed only on univariate level in the subgroup of primarily to MT center admitted patients (mRS 0-2 38.5 vs. 32.8%, p = 0.028), but did not persist in multivariate analyses., Conclusion: Differences in efficiency measured by procedural times call for analysis and optimization of in-house procedural workflows at regularly used but comparatively low procedural volume MT centers., Competing Interests: TU reports personal fees from Merck Serono and Pfizer, grants from Else Kröner-Fresenius Stiftung. KG reports personal fees and/or non-financial support from Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo, and Pfizer. MH reports personal fees from Bristol-Meyers Squibb, outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hahn, Gröschel, Tanyildizi, Brockmann, Gröschel, Uphaus and German Stroke Registry-Endovascular Treatment (GSR-ET) Investigators.)

Background and Purpose: Prolonged electrocardiography (ECG)-monitoring in stroke patients improves the detection of paroxysmal atrial fibrillation (pAF). However, most randomized studies only had short follow-up. We aimed to provide 3-year follow-up data for AF detection and stroke recurrence risk., Methods: We randomized 402 patients aged ≥60 years with acute ischemic strokes without AF to either enhanced and prolonged monitoring (EPM; 3×10-day Holter-ECG-monitoring) or standard-of-care (≥24 hours ECG-monitoring). The endpoint of the current analysis was AF within 36 months analyzed by intention to treat. Long-term follow-up was performed for 36 months., Results: Two hundred and seventy-four patients (80%) participated in the extended follow-up (median duration of follow-up was 36 months [interquartile range, 12 to 36]). During the first 6 months, more AF was documented in the EPM arm compared to the control arm (13.5% vs. 5.1%; 95% confidence interval, 2.9% to 14.4%; P=0.004). During months 6 to 36, AF was less detected in the EPM intervention arm than in the control arm (2.0% vs. 7.3%; 95% confidence interval, 0.7% to 9.9%; P=0.028). Overall, the detection rate of AF within 36 months was numerically higher within the EPM group (15.0% vs. 11.1%, P=0.30). Numerically less patients in the EPM arm had recurrent ischemic strokes (5.5% vs. 9.1%, P=0.18), transient ischemic attacks (3.0% vs. 4.5%, P=0.44) or died (4.5% vs. 6.6%, P=0.37)., Conclusions: Enhanced and prolonged ECG monitoring increased AF detection during the first six months, but there was significantly more clinical AF during months 6 to 36 observed in the usual-care arm. This suggests that EPM leads to an earlier detection of clinically relevant AF.

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., Competing Interests: Declaration of Competing Interest Timo Uphaus has received honoraria from Merck Serono. Tobias Ruck has received travel grants and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen, and Teva. Sven G. Meuth has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. Frauke Zipp has recently received research grants and/or consultation funds from DFG, BMBF, PMSA, Genzyme, Janssen, Merck Serono, Roche, Novartis, Celgene, and Sanofi-Aventis. Stefan Bittner has received honoraria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 ( n  = 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 ( B  = -0.016, SE = 0.006, p  = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( B  = -6.734, SE = 2.514, p  = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( B  = 5.974, SE = 2.420, p  = 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., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Background: Stroke can negatively impact the health-related quality of life (HRQoL). Anxiety or depression after stroke have been associated with poorer HRQoL, higher mortality and greater dependence in activities of daily living. We aimed to analyze HRQoL, anxiety and depressive symptoms in patients with and without atrial fibrillation (AF) up to 12 months post-stroke., Methods: Find-AF RANDOMISED was a prospective, randomized multicenter study, which included 398 patients ≥60 years with acute cerebral ischemia. HRQoL data were collected using the 3-level EuroQol-5D (EQ-5D-3L) and Stroke Impact Scale (SIS-16). Anxiety and depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS). The severity of stroke was measured using the modified Rankin Scale (mRS)., Results: In this study (mean age 72.7 ± 7.5 years, 40.2% females), there was a significant improvement in HRQoL using EQ-5D-3L after 3 months (β = 0.37, p < .01), 6 months (β = 0.43, p < .01) and 12 months (β = 0.44, p < .01) post-stroke compared to baseline. HADS anxiety scores after 3 months (β = -0.22, p < .01) and 12 months (β = -0.28, p < .01) were significantly reduced. Older patients reported reduced HRQoL and more depressive symptoms. Females indicated lower HRQoL and more anxiety. mRS score at baseline was an independent predictor for HRQoL. There was a significant but small effect of AF on EQ-5D-3L and on HADS anxiety., Conclusions: Patients showed significant improvement in HRQoL and reduced anxiety after 3 and 12 months after stroke. We could demonstrate that the severity of stroke as well as sex and age impact long-term post-stroke HRQoL., Clinical Trial Registration: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01855035., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE)., Methods: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array., Results: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals., Significance: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE., (© 2020 International League Against Epilepsy.)