Biomarkers to improve functional outcome prediction after ischemic stroke: Results from the SICFAIL, STRAWINSKI, and PREDICT studies.

BACKGROUND AND AIMS: Acute ischemic stroke (AIS) outcome prognostication remains challenging despite available prognostic models. We investigated whether a biomarker panel improves the predictive performance of established prognostic scores. METHODS: We investigated the improvement in discrimination, calibration, and overall performance by adding five biomarkers (procalcitonin, copeptin, cortisol, mid-regional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) to the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and age/NIHSS scores using data from two prospective cohort studies (SICFAIL, PREDICT) and one clinical trial (STRAWINSKI). Poor outcome was defined as mRS > 2 at 12 (SICFAIL, derivation dataset) or 3 months (PREDICT/STRAWINSKI, pooled external validation dataset). RESULTS: Among 412 SICFAIL participants (median age 70 years, quartiles 59-78; 63% male; median NIHSS score 3, quartiles 1-5), 29% had a poor outcome. Area under the curve of the ASTRAL and age/NIHSS were 0.76 (95% CI 0.71-0.81) and 0.77 (95% CI 0.73-0.82), respectively. Copeptin (0.79, 95% CI 0.74-0.84), NT-proBNP (0.80, 95% CI 0.76-0.84), and MR-proANP (0.79, 95% CI 0.75-0.84) significantly improved ASTRAL score's discrimination, calibration, and overall performance. Copeptin improved age/NIHSS model's discrimination, copeptin, MR-proANP, and NT-proBNP improved its calibration and overall performance. In the validation dataset (450 patients, median age 73 years, quartiles 66-81; 54% men; median NIHSS score 8, quartiles 3-14), copeptin was independently associated with various definitions of poor outcome and also mortality. Copeptin did not increase model's discrimination but it did improve calibration and overall model performance. DISCUSSION: Copeptin, NT-proBNP, and MR-proANP improved modest but consistently the predictive performance of established prognostic scores in patients with mild AIS. Copeptin was most consistently associated with poor outcome in patients with moderate to severe AIS, although its added prognostic value was less obvious.

Direct neuronal protection by the protease-activated receptor PAR4 antagonist ML354 after experimental stroke in mice.

BACKGROUND AND PURPOSE: Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms. EXPERIMENTAL APPROACH: Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca2+-imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcomes were assessed. Abundance of target genes, proteins, and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting, and immunofluorescence. KEY RESULTS: Stroke up-regulated PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduced infarct size, apoptotic markers, macrophage accumulation, and interleukin-1ß expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354. CONCLUSIONS AND IMPLICATIONS: Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis, and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action.

Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment.

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity's role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.

Effectiveness and tolerability of eptinezumab in treating patients with migraine resistant to conventional preventive medications and CGRP (receptor) antibodies: a multicentre retrospective real-world analysis from Germany.

BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.

Treatment switches of disease-modifying therapies in people with multiple sclerosis: long-term experience from the German MS Registry.

Background: The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice. Objective: To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT. Methods: Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models. Results: Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014-2017 versus 2018-2021), first DMT class used [mild-to-moderate efficacy (MME) versus high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76-4.61), p < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93-19.94), p < 0.001; reference: 2018-2021], and shorter time on first DMT [OR = 0.22 (0.18-0.27), p < 0.001]. Conclusion: The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.

Impact of Vaccination Status on Outcome of Patients With COVID-19 and Acute Ischemic Stroke Undergoing Mechanical Thrombectomy.

BACKGROUND: Data on impact of COVID-19 vaccination and outcomes of patients with COVID-19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience. METHODS AND RESULTS: This was a retrospective analysis of patients with COVID-19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID-19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients; P=0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group (P=0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome (P=0.957). However, acute COVID-19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007-1.417]; P=0.041). CONCLUSIONS: Our study demonstrated no impact of COVID-19 vaccination on angiographic or clinical outcome of COVID-19-positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID-19 was confirmed.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1-3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1-3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.

Cytokines (IL1ß, IL6, TNFα) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19.

Background: Post-acute sequelae of COVID-19 (PASC) comprise a broad spectrum of symptoms such as fatigue, general weakness, compromised attention and sleep or anxiety disorders. PASC represents a medical and socio-economic challenge. Objectives: Our study evaluated cytokines (IL-1ß, IL-6 and TNFα) and cortisol levels in a cohort of typical patients with PASC, suffering concentration problems, fatigue and difficulties finding words. Design: This was a prospective cohort study. Four groups were analysed and compared: those who had never contracted SARS-CoV-2 (n = 13), infected but had no PASC (n = 34), infected with former PASC that resolved (n = 40) and patients with ongoing PASC after infection (n = 91). Methods: Cytokine and cortisol serum levels were determined in patients' blood samples. Results: Cytokine levels of IL-1ß, IL-6, TNFα and cortisol levels did not differ between groups analysed. Conclusion: This may indicate a non-organic/psychosomatic genesis of PASC; further studies are needed to elucidate the underlying causes of PACS, and non-organic causes should not be overlooked.

Without clear biological markers for people who will continue to present with post-acute sequelae of COVID-19 (PASC) should we now focus on psychological factors? Many people across the globe are still suffering from post-acute sequelae of COVID-19 (PASC), commonly called post-COVID. Typical symptoms of PASC include severe tiredness (fatigue), concentration deficits (brain fog) or difficulty finding words. We need a better understanding of how these symptoms arise to find ways to help patients. Our team of researchers set out to explore this. We posed the question: could measurements of immune system activity provide an identifier for people who are susceptible to post-COVID? The participants in our study were divided into four groups: 1. A group of 13 people who had never contracted SARS-CoV-2. 2. A group of 34 people who had been infected with SARS-CoV-2 but had no PASC. 3. A group of 40 people who had been infected with SARS-CoV-2 and had already suffered from PASC that had now resolved. 4. A group of 91 people who were no longer sick with COVID-19 but were still suffering from PASC. Serum samples from all participants were taken to measure cytokine and cortisol levels. People with PASC could not be identified by testing their blood samples for cytokines (IL-1ß, IL-6, TNFα) or cortisol. No difference between the four groups was found on any marker. Measuring these cytokines or cortisol is, therefore, unlikely to be useful in predicting which patients will suffer from PASC. Continuation of symptoms long after COVID-19 has passed is distressing for many people worldwide. Psychological factors may play a role and need to be studied further in order to help this patient population.

Iatrogenic Air Embolisms During Endovascular Interventions: Impact of Origin and Number of Air Bubbles on Cerebral Infarctions.

PURPOSE: Cerebral infarctions caused by air embolisms (AE) are a feared risk in endovascular procedures; however, the relevance and pathophysiology of these AEs is still largely unclear. The objective of this study was to investigate the impact of the origin (aorta, carotid artery or right atrium) and number of air bubbles on cerebral infarctions in an experimental in vivo model. METHODS: In 20 rats 1200 or 2000 highly calibrated micro air bubbles (MAB) with a size of 85 µm were injected at the aortic valve (group Ao), into the common carotid artery (group CA) or into the right atrium (group RA) using a microcatheter via a transfemoral access, resembling endovascular interventions in humans. Magnetic resonance imaging (MRI) using a 9.4T system was performed 1 h after MAB injection followed by finalization. RESULTS: The number (5.5 vs. 5.5 median) and embolic patterns of infarctions did not significantly differ between groups Ao and CA. The number of infarctions were significantly higher comparing 2000 and 1200 injected MABs (6 vs. 4.5; p < 0.001). The infarctions were significantly larger for group CA (median infarction volume: 0.41 mm3 vs. 0.19 mm3; p < 0.001). In group RA and in the control group no infarctions were detected. Histopathological analyses showed early signs of ischemic stroke. CONCLUSION: Iatrogenic AEs originating at the ascending aorta cause a similar number and pattern of cerebral infarctions compared to those with origin at the carotid artery. These findings underline the relevance and potential risk of AE occurring during endovascular interventions at the aortic valve and ascending aorta.

Single-cell profiling reveals preferential reduction of memory B cell subsets in cladribine patients that correlates with treatment response.

Background: Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect. Objectives: Our aim was to provide a more profound understanding of the detailed effects of cladribine, also with regard to the patients' therapy response. Design: We performed an open-labeled, explorative, prospective, single-arm study, in which we examined the detailed lymphocyte subset development of MS patients who received cladribine treatment over 2 years. Methods: We performed in-depth profiling of the effects of cladribine on peripheral blood lymphocytes by flow cytometry, bulk RNA sequencing of sorted CD4+ T cells, CD8+ T cells, and CD19+ B cells as well as single-cell RNA sequencing of peripheral blood mononuclear cells in a total of 23 MS patients before and at different time points up to 24 months after cladribine treatment. Data were correlated with clinical and cranial magnetic resonance imaging (MRI) disease activity. Results: Flow cytometry revealed a predominant and sustained reduction of memory B cells compared to other B cell subsets after cladribine treatment, whereas T cell subsets were slightly reduced in a more uniform pattern. The overall transcriptional profile of total blood B cells exhibited reduced expression of proinflammatory and T cell activating genes, while single-cell transcriptomics revealed that gene expression within each B cell cluster did not change over time. Stable patients displayed stronger reductions of selected memory B cell clusters as compared to patients with clinical or cerebral MRI disease activity. Conclusion: We describe a pronounced and sustained effect of cladribine on the memory B cell compartment, and the resulting change in B cell subset composition causes a significant alteration of B cell transcriptional profiles resulting in reduced proinflammatory and T cell activating capacities. The extent of reduction in selected memory B cell clusters by cladribine may predict treatment response.

Validation of a German-language modified Rankin Scale structured telephone interview at 3 months in a real-life stroke cohort.

BACKGROUND: The modified Rankin scale (mRS) at 3 months is established as the primary outcome measure in clinical stroke trials. Traditionally, the mRS is assessed through an unstructured face-to-face interview. This approach can be labor-intensive and lead to suboptimal inter-rater reliability. Recently, the Covid-19 pandemic made face-to-face contact even more challenging. To address these issues, we developed and validated a structured German-language questionnaire for mRS testing by telephone. METHODS: In this prospective cohort study, we compared the mRS testing results of the standard face-to-face interview with those obtained in a structured interview by telephone using Cohen's Kappa. RESULTS: At our tertiary care stroke center, we included 108 patients who underwent both assessments. In 80.6% of cases (87/108) face-to-face and telephone interview reached identical scores. Linear weighted Kappa was 0.82 (p < 0.001). Unweighted Kappa for dichotomized mRS between fair (0-2) and poor (3-6) functional outcome was κ = 0.97 (p < 0.001). CONCLUSIONS: Our study validates the use of the German-language structured telephone interview as a reliable instrument for the use in clinical trials. We encourage others to utilize the questionnaire. It is available as an Appendix (Additional file 1) to this publication.

Dimethyl Fumarate Attenuates Lymphocyte Infiltration and Reduces Infarct Size in Experimental Stroke.

Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.

Frequency and Characteristics of Non-Neurological and Neurological Stroke Mimics in the Emergency Department.

BACKGROUND: Stroke mimics are common in the emergency department (ED) and early detection is important to initiate appropriate treatment and withhold unnecessary procedures. We aimed to compare the frequency, clinical characteristics and predictors of non-neurological and neurological stroke mimics transferred to our ED for suspected stroke. METHODS: This was a cross-sectional study of consecutive patients with suspected stroke transported to the ED of the University Hospital Essen between January 2017 and December 2021 by the city's Emergency Medical Service. We investigated patient characteristics, preclinical data, symptoms and final diagnoses in patients with non-neurological and neurological stroke mimics. Multinominal logistic regression analysis was performed to assess predictors of both etiologic groups. RESULTS: Of 2167 patients with suspected stroke, 762 (35.2%) were diagnosed with a stroke mimic. Etiology was non-neurological in 369 (48.4%) and neurological in 393 (51.6%) cases. The most common diagnoses were seizures (23.2%) and infections (14.7%). Patients with non-neurological mimics were older (78.0 vs. 72.0 y, p < 0.001) and more likely to have chronic kidney disease (17.3% vs. 9.2%, p < 0.001) or heart failure (12.5% vs. 7.1%, p = 0.014). Prevalence of malignancy (8.7% vs. 13.7%, p = 0.031) and focal symptoms (38.8 vs. 57.3%, p < 0.001) was lower in this group. More than two-fifths required hospitalization (39.3 vs. 47.1%, p = 0.034). Adjusted multinominal logistic regression revealed chronic kidney and liver disease as independent positive predictors of stroke mimics regardless of etiology, while atrial fibrillation and hypertension were negative predictors in both groups. Prehospital vital signs were independently associated with non-neurological stroke mimics only, while age was exclusively associated with neurological mimics. CONCLUSIONS: Up to half of stroke mimics in the neurological ED are of non-neurological origin. Preclinical identification is challenging and a high proportion requires hospitalization. Awareness of underlying etiologies and differences in clinical characteristics is important to provide optimal care.

Treatment of acute ischemic stroke in patients with active malignancy: insight from a comprehensive stroke center.

Background: Despite the high incidence of acute ischemic stroke (AIS) in cancer patients, there is still no consensus about the safety of recanalization therapies in this cohort. Objectives: In this observational study, our aim was to investigate the bleeding risk after acute recanalization therapy in AIS patients with active malignancy. Methods and Study Design: We retrospectively analyzed observational data of 1016 AIS patients who received intravenous thrombolysis with rtPA (IVT) and/or endovascular therapy (EVT) between January 2017 and December 2020 with a focus on patients with active malignancy. The primary safety endpoint was the occurrence of stroke treatment-related major bleeding events, that is, symptomatic intracranial hemorrhage (SICH) and/or relevant systemic bleeding. The primary efficacy endpoint was neurological improvement during hospital stay (NI). Results: None of the 79 AIS patients with active malignancy suffered from stroke treatment-related systemic bleeding. The increased rate (7.6% versus 4.7%) of SICH after therapy compared to the control group was explained by confounding factors. A total of nine patients with cerebral tumor manifestation received acute stroke therapy, two of them suffered from stroke treatment-related intracranial hemorrhage remote from the tumor, both asymptomatic. The group of patients with active malignancy and the control group showed comparable rates of NI. Conclusion: Recanalization therapy in AIS patients with active malignancy was not associated with a higher risk for stroke treatment-related systemic or intracranial bleeding. IVT and/or EVT can be regarded as a safe therapy option for AIS patients with active malignancy.

Are we providing best-available care to newly diagnosed glioblastoma patients? Systematic review of phase III trials in newly diagnosed glioblastoma 2005-2022.

Background: Glioblastoma is the most aggressive primary brain cancer with a poor prognosis. Despite numerous studies in the past 17 years, effective treatment options for glioblastoma remain limited. In this study, we aimed to identify and compare phase III clinical trials for glioblastoma in terms of efficacy and baseline characteristics. Methods: A systematic literature search was conducted using PubMed and ClinicalTrials.gov to identify phase III clinical trials for glioblastoma in adult patients. The target population included adult patients aged 18 years and above (younger cohort) and patients ≥60 years of age (elderly cohort). The search results were screened based on predefined inclusion criteria, and the included trials were analyzed for their study design, baseline characteristics, and survival results. Results: Eleven trials met the inclusion criteria in the younger cohort. Of these, three reported a statistically significant improvement in overall survival (OS), including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409), and CeTeG (NCT01149109). Of the 11 trials, eight were open-label randomized trials, including all of the positive ones, while three negative trials employed treatment blinding and a placebo control. The baseline characteristics of the trials [such as extent of resection, age, gender, and O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status] did not significantly differ between positive and negative trials. Isocitrate dehydrogenase (IDH) mutation status was analyzed in only two trials, with a small percentage of IDH-mutated tumors in each. Additionally, three more trials in the elderly cohort showed a statistically significant improvement of OS, the NOA-08 trial, the ISRCTN81470623-trial by Malmström et al. and NCT00482677-trial by Perry et al. Their baseline characteristics and implications are also analyzed. Conclusion: This analysis of phase III clinical trials for glioblastoma conducted since 2005 showed that the majority of trials did not result in a significant improvement in OS. Among the trials included in this analysis, only the EORTC/NCIC, EF-14, and CeTeG studies demonstrated a positive OS outcome in the younger cohort.

Analysis of Free Circulating Messenger Ribonucleic Acids in Serum Samples from Late-Onset Spinal Muscular Atrophy Patients Using nCounter NanoString Technology.

5q-related Spinal muscular atrophy (SMA) is a hereditary multi-systemic disorder leading to progressive muscle atrophy and weakness caused by the degeneration of spinal motor neurons (MNs) in the ventral horn of the spinal cord. Three SMN-enhancing drugs for SMA treatment are available. However, even if these drugs are highly effective when administrated early, several patients do not benefit sufficiently or remain non-responders, e.g., adults suffering from late-onset SMA and starting their therapy at advanced disease stages characterized by long-standing irreversible loss of MNs. Therefore, it is important to identify additional molecular targets to expand therapeutic strategies for SMA treatment and establish prognostic biomarkers related to the treatment response. Using high-throughput nCounter NanoString technology, we analyzed serum samples of late-onset SMA type 2 and type 3 patients before and six months under nusinersen treatment. Four genes (AMIGO1, CA2, CCL5, TLR2) were significantly altered in their transcript counts in the serum of patients, where differential expression patterns were dependent on SMA subtype and treatment response, assessed with outcome scales. No changes in gene expression were observed six months after nusinersen treatment, compared to healthy controls. These alterations in the transcription of four genes in SMA patients qualified those genes as potential SMN-independent therapeutic targets to complement current SMN-enhancing therapies.

Time for a standardized diagnostic response test in patients with chronic inflammatory demyelinating polyradiculoneuropathy?

Standardized pharmacological response tests are important and established diagnostic tools in the field of neurology. However, regarding therapeutic responses to intravenous immunoglobulins (IVIg) in CIDP, neither a definition of therapeutic response has been established, nor a response test has been suggested so far. Here we suggest a practical clinical approach which is supported by current literature in the field. An established standardized IVIg response test could avoid prolonged therapy without benefit for the patient and ensure a timely therapy switch or treatment escalation if required. This approach would also be advantageous due to the global scarcity of plasma derivatives as a human resource and could be the foundation to be adjusted and improved by subsequent studies.

Telemedicine in Neuro-Oncology-An Evaluation of Remote Consultations during the COVID-19 Pandemic.

In order to minimize the risk of infections during the COVID-19 pandemic, remote video consultations (VC) experienced an upswing in most medical fields. However, telemedicine in neuro-oncology comprises unique challenges and opportunities. So far, evidence-based insights to evaluate and potentially customize current concepts are scarce. To fill this gap, we analyzed >3700 neuro-oncological consultations, of which >300 were conducted as VC per patients' preference, in order to detect how both patient collectives distinguished from one another. Additionally, we examined patients' reasons, suitable/less suitable encounters, VC's benefits and disadvantages and future opportunities with an anonymized survey. Patients that participated in VC had a worse clinical condition, higher grade of malignancy, were more often diagnosed with glioblastoma and had a longer travel distance (all p < 0.01). VC were considered a fully adequate alternative to face-to-face consultations for almost all encounters that patients chose to participate in (>70%) except initial consultations. Most participants preferred to alternate between both modalities rather than participate in one alone but preferred VC over telephone consultation. VC made patients feel safer, and participants expressed interest in implementing other telemedicine modalities (e.g., apps) into neuro-oncology. VC are a promising addition to patient care in neuro-oncology. However, patients and encounters should be selected individually.

Feasibility and tolerability of trofosfamide and etoposide in progressive glioblastoma.

Background: Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. Methods: We collected clinicopathological data from adult progressive glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators' discretion balanced for tumor entity and canonical prognostic factors served as control. Results: A total of n = 22 progressive glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 vs 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, P = .0274) and median overall survival (9.0 vs 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, P = .0003) were significantly prolonged compared to the control cohort (n = 17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n = 16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n = 15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n = 11/15, 73%). Conclusions: This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients. The observed survival outcomes might suggest potential beneficial effects. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective trial.

[Consensus recommendations on regional interdisciplinary standardization of MRI diagnostics for multiple sclerosis in the metropolitan area of Essen]. / Konsensusempfehlungen zur regionalen fächerübergreifenden Standardisierung der MRT-Diagnostik bei Multipler Sklerose im Großraum Essen.

Magnetic resonance imaging (MRI) is of exceptional importance in the diagnostics and monitoring of multiple sclerosis (MS); however, a close interdisciplinary cooperation between neurologists in private practice, (neuro)radiological practices, hospitals or specialized MS centers is only rarely established. In particular, there is a lack of standardized MRI protocols for image acquisition as well as established quality parameters, which guarantee the comparability of MRI records; however, this is a fundamental prerequisite for an effective application of MRI in the treatment of MS patients, e.g., for making the diagnosis or treatment monitoring. To address these challenges a group of neurologists and (neuro)radiologists developed a consensus proposal for standardization of image acquisition, interpretation and transmission of results and for improvement in interdisciplinary cooperation. This pilot project in the metropolitan area of Essen used a modified Delphi process and was based on the most up to date scientific knowledge. The recommendation takes the medical, economic, temporal and practical aspects of MRI in MS into consideration. The model of interdisciplinary cooperation between radiologists and neurologists with the aim of a regional standardization of MRI could serve as an example for other regions of Germany in order to optimize MRI for MS.