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Abstract 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.

Abstract 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. Graphical Abstract

Abstract 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

Abstract Objective Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing. Methods In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030). Results 42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors. Interpretation Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.

Background: For treatment of relapsing-remitting multiple sclerosis (RRMS), a broad range of disease-modifying therapies (DMT) is available. However, few comparative effectiveness studies between different drugs have been performed. Objectives: This study aimed to compare the efficacy and treatment continuation of natalizumab and ocrelizumab in a real-world cohort of patients with relapsing-remitting multiple sclerosis (RRMS) from two German university hospitals. Methods: We performed a retrospective analysis of RRMS patients who initiated treatment with natalizumab or ocrelizumab between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf. Bayesian propensity score matching was conducted to correct for differences in baseline characteristics. Our primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab. Results: We identified 63 patients starting treatment with natalizumab and 76 patients starting with ocrelizumab. Binary logistic regression showed that treatment with natalizumab or a higher number of relapses in the previous year were independently associated with a higher risk for relapses. Patients receiving natalizumab had a higher probability of premature discontinuation of therapy ( p = 0.002). After propensity score matching of the two treatment arms, 55 patients remained per group. NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group ( p = 0.177). Ocrelizumab was superior to natalizumab concerning the occurrence of relapses in log-rank test ( p = 0.019). NfL levels in serum were low under both treatments. Patients who switched from natalizumab to ocrelizumab showed no increased rebound activity. Discussion: This study provides class IV evidence that treatment of RRMS patients with ocrelizumab and natalizumab show comparable effectiveness in combined endpoints, while ocrelizumab might be more effective in preventing the occurrence of relapses.

Background Patients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion. Aim We report humoral responses in a German cohort of MS patients treated with cladribine tablets. Methods This retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4 + T-cells, and CD8 + T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON ® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL. Results In total, 38 patients (73.7% female, aged 23–66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts. Conclusions Treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies.

Background: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student’s t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. Associations of sNfL with clinical and laboratory parameters were assessed by correlation and multiple linear regression analysis. Results: NPSLE patients ( n = 69) had significantly higher sNfL levels than SLE patients without neuropsychiatric disease manifestations ( n = 75; mean difference: 0.13, 95% CI: 0.04–0.22, p = 0.006). With regard to the category of NPSLE manifestation, mean sNfL levels were only increased in NPSLE patients with focal central nervous system (CNS) involvement ( n = 45; mean difference: 0.16, 95% CI: 0.02–0.30, p = 0.019), whereas mean sNfL levels of NPSLE patients with diffuse CNS and peripheral nervous system involvement did not differ from those of SLE patients without neuropsychiatric manifestations. Age and serum creatinine concentrations were identified as relevant contributors to sNfL levels. Conclusion: sNfL is a promising, easily accessible biomarker for neuropsychiatric involvement in SLE patients and might therefore complement the diagnostic workup of SLE patients with suspected involvement of the nervous system.

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.

Background: Serum neurofilament light chain (sNfL) is a promising biomarker to complement the decision-making process in multiple sclerosis (MS) patients. However, although sNfL levels are able to detect disease activity and to predict future disability, the growing evidence has not yet been translated into practicable recommendations for an implementation into clinical routine. Methods: The observation of a patient with extensive inflammatory activity in magnetic resonance imaging (MRI) along with an extremely high sNfL level in the absence of any clinical symptoms prompted us to investigate common characteristics of our MS patients with the highest sNfL levels in a retrospective cohort study. The 97.5th percentile was chosen as a cut-off value because the mean sNfL level of the resulting extreme neurofilament light chain (NfL) cohort corresponded well to the sNfL level of the presented case. Patient characterization included clinical and MRI assessment with a focus on disease activity markers. sNfL levels were determined by single molecule array. Results: The 97.5th percentile of our MS cohort (958 sNfL measurements in 455 patients) corresponded to a threshold value of 46.1 pg/ml. The mean sNfL level of the extreme sNfL cohort ( n = 24) was 95.6 pg/ml (standard deviation 68.4). Interestingly, only 15 patients suffered from a relapse at the time point of sample collection, whereas nine patients showed no signs of clinical disease activity. sNfL levels of patients with and without relapse did not differ [median 81.3 pg/ml (interquartile range [IQR] 48.0–128) versus 80.2 pg/ml (IQR 46.4–97.6), p = 0.815]. The proportion of patients with contrast-enhancing lesions was high and also did not differ between patients with and without relapse (92.9% versus 87.5%, p = 0.538); 78.9% of the patients not receiving a high-efficacious therapy had ongoing disease activity during a 2-year follow-up. Conclusion: Extremely high sNfL levels are indicative of subclinical disease activity and might complement treatment decisions in ambiguous cases.

Background: The COVID-19 pandemic might affect health care resources and alter patient admission to hospital in case of stroke or transient ischemic attack (TIA). We aim to determine whether the COVID-19 pandemic is affecting utilization of recanalization procedures and numbers of patients with stroke and TIA admitted to a primary care stroke center.Methods: In this retrospective observational study, we compared patients admitted from January 2019 until February 2020 with patients admitted during the COVID-19 pandemic (March/April 2020) in Germany. We included patients with stroke (hemorrhagic or ischemic) or TIA as classified by International Statistical Classification of Diseases and Related Health Problems version 10 (ICD-10).Results: The number of patients per month with ischemic stroke or TIA was found to have significantly decreased from January 2019 until February 2020 compared to the COVID-19 pandemic (March/April 2020) (ischemic stroke 69.1 ± 4.5 vs. 55 ± 5.7, p < 0.001, TIA 22.1 ± 4.1 vs. 14.5 ± 6.4, p < 0.034). Contrarily, percentages and numbers of recanalization procedures per month were not influenced by the COVID-19 pandemic (intravenous thrombolysis [iv-tPA] 9.4 ± 3.7 vs. 10.5 ± 0.5, p = 0.697, mechanical thrombectomy [MT] 13.1 ± 3.1 vs. 14.5 ± 3.5, p = 0.580, iv-TPA or MT 19.4 ± 4.1 vs. 19.0 ± 0.0, p = 0.889).Conclusions: During the COVID-19 pandemic, resources of the healthcare system in a primary care university hospital in Germany still allowed for unchanged numbers of recanalization procedures due to ischemic stroke. However, the numbers of patients admitted to the hospital specifically due to ischemic stroke or TIA decreased, suggesting that the awareness for non-disabling stroke symptoms has to be increased.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to CNS inflammation and neurodegeneration. Current anti-inflammatory drugs have only limited efficacy on progressive neurodegenerative processes underlining the need to understand immune-mediated neuronal injury. Cell adhesion molecules play an important role for immune cell migration over the blood-brain barrier whereas their role in mediating potentially harmful contacts between invading immune cells and neurons is incompletely understood. Here, we assess the role of the CNS-specific neuronal adhesion molecule ICAM-5 using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. ICAM-5 knockout mice show a more severe EAE disease course in the chronic phase indicating a neuroprotective function of ICAM-5 in progressive neurodegeneration. In agreement with the predominant CNS-specific function of ICAM-5, lymphocyte function-associated antigen 1 (LFA-1)/ICAM-1 contact between antigen-presenting cells and T helper (Th)17 cells in EAE is not affected by ICAM-5. Strikingly, intrathecal application of the shed soluble form, sICAM-5, ameliorates EAE disease symptoms and thus might serve locally as an endogenous neuronal defense mechanism which is activated upon neuroinflammation in the CNS. In humans, cerebrospinal fluid from patients suffering from progressive forms of MS shows decreased sICAM-5 levels, suggesting a lack of this endogenous protective pathway in these patient groups. Overall, our study points toward a novel role of ICAM-5 in CNS autoinflammation in progressive EAE/MS.