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Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. Among 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 μg/ml per one SD, 95% CI [3.45, 8.11]). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal pleiotropy. In an independent cohort of 1,241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per one SD 0.77, 95% CI: [0.61, 0.97]). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.

4D PC MRI of the aorta has become a routinely available examination, and a multitude of single parameters have been suggested for the quantitative assessment of relevant flow features for clinical studies and diagnosis. However, clinically applicable assessment of complex flow patterns is still challenging. We present a concept for applying radiomics for the quantitative characterization of flow patterns in the aorta. To this end, we derive cross-sectional scalar parameter maps related to parameters suggested in literature such as throughflow, flow direction, vorticity, and normalized helicity. Derived radiomics features are selected with regard to their inter-scanner and inter-observer reproducibility, as well as their performance in the differentiation of sex-, age- and disease-related flow properties. The reproducible features were tested on user-selected examples with respect to their suitability for characterizing flow profile types. In future work, such signatures could be applied for quantitative flow assessment in clinical studies or disease phenotyping., Competing Interests: The 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., (© 2023 Huellebrand, Jarmatz, Manini, Laube, Ivantsits, Schulz-Menger, Nordmeyer, Harloff, Hansmann, Kelle and Hennemuth.)

Background: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment., Methods: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation., Results: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P <0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P <0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy., Conclusions: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

Objective . This study assesses age-related differences of thoracic aorta blood flow profiles and provides age- and sex-specific reference values using 4D flow cardiovascular magnetic resonance (CMR) data. Approach . 126 volunteers (age 20-80 years, female 51%) underwent 4D flow CMR and 12 perpendicular analysis planes in the thoracic aorta were specified. For these planes the following parameters were evaluated: body surface area-adjusted aortic area ( A '), normalized flow displacement (NFD), the degree of wall parallelism (WPD), the minimal relative cross-sectional area through which 80% of the volume flow passes (A80) and the angle between flow direction and centerline ( α ). Main results . Age-related differences in blood flow parameters were seen in the ascending aorta with higher values for NFD and angle and lower values for WPD and A80 in older subjects. All parameters describing blood flow patterns correlated with the cross-sectional area in the ascending aorta. No relevant sex-differences regarding blood flow profiles were found. Significance . These age- and sex-specific reference values for quantitative parameters describing blood flow within the aorta might help to study the clinical relevance of flow profiles in the future., (Creative Commons Attribution license.)

Objectives: The aim of this study was to compare outcomes of routine shunting to near-infrared spectroscopy (NIRS)-guided shunting in patients undergoing eversion endarterectomy (EEA) under general anaesthesia., Methods: We retrospectively evaluated data of all patients undergoing EEA of the internal carotid artery (ICA) in our department from January 2011 until January 2019. Included were patients with EEA of the ICA and the patients were divided into 2 groups: selective-shunting group and routine-shunting group. Patients (i) with patch angioplasty during the surgery, (ii) undergoing surgery for restenosis and (ii) stenosis after radiation therapy, (iii) without recorded regional cerebral oxygen saturation trends, (iv) presenting with an emergency treatment indication and (v) operated upon by residents were excluded. In all patients, EEA was performed in general anaesthesia and under NIRS monitoring. One-to-one propensity score matching was used to compare EEA outcomes after routine shunting to NIRS-guided shunting. Primary end points were defined as perioperative stroke and in-hospital mortality after EEA., Results: Routine and NIRS-guided selective shunting were applied in 340 (34.0%) and 661 (66.0%) patients, respectively. A total of 277 pairs were generated via propensity score matching. Fifty-eight (20.1%) from the selective-shunting group were intraoperatively shunted. Concomitant procedures were more frequently performed in the routine-shunting group [170 (61.4%) vs 47 (17.0%), 180 (65%) vs 101 (36.5%), and 60 (21.7%) vs 6 (2.2%), P < 0.001]. The perioperative stroke rate in the routine-shunting group was higher as well [11 (4.0%) vs 3 (1.1%), P = 0.022]. In-hospital death was overall 0.2% (n = 1). Multivariable logistic regression in the matched patient indicated age (odds ratio 1.050, 95% confidence interval 1.002-1.104, P = 0.046) and routine shunting (odds ratio 2.788, confidence interval 1.119-7.428, P = 0.032) as risk factors for perioperative stroke during EEA of the ICA., Conclusions: We found that, during EEA of the ICA, under general anaesthesia, NIRS-guided selective shunting was associated with a lower incidence of perioperative stroke than routine shunting., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The Rydel Seiffer tuning fork (RSTF) can be easily applied to evaluate deficits of vibration perception. Standard normative data as stated in textbooks (6/8-thresholds among the "elderly") is not suitable for an informed decision-making process., Objective: To reevaluate the range of vibration detection thresholds (VDT) based on assessments in healthy Caucasians stratified for age and gender using the RSTF and on a short-review of literature on normative data on PubMed., Methods: Monocentric, prospective assessment of VDT at the dorsal 1st metatarsophalangeal joint of both sides in 77 healthy volunteers. Participants were grouped according to age: 20-39 years (group I, n = 24), 40-59 years (group II, n = 29), 60-79 years (group III, n = 24). Data was stratified for gender. Means were compared via Mann-Whitney U-test; correlations were rated via Pearson correlation coefficient. A short-review of literature was performed on PubMed., Results: Aging related to declined vibration perception (r = -0.446, p < 0.001). Women aged 60 years and older showed better vibration perception compared to men (men: 6.5 ± 1.3, women: 7.5 ± 0.9, p = 0.003). All VDT-limits were higher compared to results gathered in literature (I: 7.9 ± 0.3, II: 7.7 ± 0.5, III: 7.1 ± 1.1). Formerly reported VDT-limits at the lower limbs were scattered (e.g., >4.5/8 to ≥6.6/8 at age 18-29). Current data, especially VDT of participants aged 50 years and older, were largely in line with data reported by Hilz et al. 1998: 18-29 years: ≥ 6.6/8, 30-39 years: ≥ 5.5/8, 40-49 years: ≥ 5.7/8, 50-59 years: ≥ 5.4/8, 60-69 years ≥ 5.2/8, > 70 years ≥ 5.3/8, alternative: 30-39 years ≥ 6.2/8 Magerl et al. 2010. Data on diagnostic sensitivity by Xirou et al. 2020 supported a VDT-limit of 5.9/8 across all ages to aim for high sensitivity. A better vibration perception among elder women compared to men has been described by many studies., Discussion: The current data and literature underline, that higher VDT-limits stratified for age and gender should be considered in a clinical setting. Until further validation within larger samples, we propose to consider the limits as reported by Hilz et al. 1998. Furthermore, women at age 60 + years presenting with borderline thresholds should be considered for further diagnostic workup., Competing Interests: Declaration of interests All authors confirm that there are no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Aortic stiffness is associated with a higher incidence of cardiovascular events including stroke. The primary aim of this study was to evaluate whether increased pulse wave velocity (PWV), a marker of stiffness, is an independent predictor of aortic atheroma. The secondary aim was to test whether increased PWV reinforces retrograde blood flow from the descending aorta (DAo), a mechanism of stroke., Methods: We performed a cross-sectional case-control study with prospective data acquisition. In all, 40 stroke and 60 ophthalmic patients matched for age and cardiovascular risk factors were included. Multicontrast magnetic resonance imaging (MRI) protocol of the aorta tailored to allow a detailed plaque analysis using 3-dimensional (D) T1-weighted bright blood, T2-weighted and proton density-weighted black blood, and hemodynamic assessment using 4D flow MRI was applied. Individual PWV was calculated based on 4D flow MRI data using the time-to-foot of the blood flow waveform. The extent of maximum retrograde blood flow from the proximal DAo into the arch was quantified., Results: PWV was higher in stroke patients compared with controls (7.62±2.59 vs. 5.96±2.49 m/s; P=0.005) and in patients with plaques (irrespective of thickness) compared with patients without plaques (7.47±2.89 vs. 5.62±1.89 m/s; P=0.002). Increased PWV was an independent predictor of plaque prevalence and contributed significantly to a predictor model explaining 36.5% (Nagelkerke R2) of the variance in plaque presence. Maximum retrograde flow extent from the proximal DAo was not correlated with PWV., Conclusions: Aortic stiffness was higher in stroke patients and associated with a higher prevalence of plaques. Increased PWV was an independent predictor of plaque presence. Accordingly, regional PWV seems to be a valuable biomarker for the assessment and management of aortic atherosclerosis. However, no association was found for increased retrograde flow extent from the DAo., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: This study aims to assess the number of patients with acute ischemic cerebrovascular events seeking in-patient medical emergency care since the implementation of social distancing measures in the coronavirus disease 2019 (COVID-19) pandemic., Methods: In this retrospective multicenter study, data on the number of hospital admissions due to acute ischemic stroke or transient ischemic attack and numbers of reperfusion therapies performed in weeks 1 to 15 of 2020 and 2019 were collected in 4 German academic stroke centers. Poisson regression was used to test for a change in admission rates before and after the implementation of extensive social distancing measures in week 12 of 2020. The analysis of anonymized regional mobility data allowed for correlations between changes in public mobility as measured by the number and length of trips taken and hospital admission for stroke/transient ischemic attack., Results: Only little variation of admission rates was observed before and after week 11 in 2019 and between the weeks 1 and 11 of 2019 and 2020. However, reflecting the impact of the COVID-19 pandemic, a significant decrease in the number of admissions for transient ischemic attack was observed (-85%, -46%, -42%) in 3 of 4 centers, while in 2 of 4 centers, stroke admission rates decreased significantly by 40% and 46% after week 12 in 2020. A relevant effect on reperfusion therapies was found for 1 center only (thrombolysis, -60%; thrombectomy, -61%). Positive correlations between number of ischemic events and mobility measures in the corresponding cities were identified for 3 of 4 centers., Conclusions: These data demonstrate and quantify decreasing hospital admissions due to ischemic cerebrovascular events and suggest that this may be a consequence of social distancing measures, in particular because hospital resources for acute stroke care were not limited during this period. Hence, raising public awareness is necessary to avoid serious healthcare and economic consequences of undiagnosed and untreated strokes and transient ischemic attacks.

Background: To analyze the outcome of near-infrared spectroscopy (NIRS)-guided selective shunting during carotid endarterectomy and the procedural outcome., Methods: In this retrospective single-center study, patients undergoing carotid endarterectomy in general anesthesia and receiving bihemispheric NIRS as single neuromonitoring tool between January 2009 and January 2014 were included. Shunting was applied if the reduction in the NIRS values after cross-clamping on the ipsilateral side exceeded 15%. Patients with contralateral occlusion of the internal carotid artery (ICA) were excluded, as were patients operated on by surgeons performing routine shunting. All patients underwent intraoperative angiography after vessel recanalization., Results: NIRS trend was available in 441 patients. Twenty-eight were excluded from this study (14 due to preference for general shunting, 13 due to contralateral ICA occlusion, and 1 due to intraoperative ICA occlusion), resulting in a final sample of 413 patients. We observed a >15% drop in NIRS values on the ipsilateral side in 29 (7%) patients. Accordingly, an intraluminal shunt was placed into the ICA. Shunting was not performed in 384 patients (<15% drop in NIRS values). Interestingly, the NIRS values on the contralateral side were significantly elevated after cross-clamping compared with baseline in the group without shunt (P < 0.0001). On the contrary, patients requiring an ICA shunt revealed a statistically significant reduction in the rSO 2 on the contralateral side compared with the baseline (after ipsilateral clamping) (P = 0.047). Three patients overall suffered a stroke, all of whom were in the no-shunt group (combined stroke rate of 0.8% [3/384] with no significant intergroup difference). There was no difference in morbidity factors between the two groups. However, surgical revision after intraoperative angiography was significantly more frequent in the shunt group (17.2%, 5/29) versus the no-shunt group (6%, 23/384), (P < 0.037)., Conclusions: An NIRS-guided selective shunting strategy was associated with excellent clinical outcomes and has the potential to identify patients at risk for hypoperfusion during the clamping period. However, a potentially shunt-associated higher rate of requiring local revisions (due to flaps, twisting, stenosis, and kinking) in ICA was observed. Additional studies are needed to further refine cut-off values for NIRS, indicating the need for shunting., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Retrograde blood flow from complex atheroma in the descending aorta (DAo) has only recently been described as a potential mechanism of stroke. However, prevalence of this mechanism in the general population and the exact factors influencing stroke risk are unclear., Methods: One hundred twenty-six consecutively recruited inhabitants of Freiburg, Germany, between 20 and 80 years of age prospectively underwent 3-T MRI. Aortic plaque location and thickness were determined by 3D T1 MRI (1 mm 3 ). 4D flow MRI (spatial/temporal resolution 2 mm 3 /20 ms) and dedicated software were used to determine prevalence and extent of flow reversal and potential embolization from DAo plaques. Flow was correlated with baseline characteristics and echocardiographic and MRI parameters (aortic diameter, wall thickness, and pulse wave velocity)., Results: The maximum length of retrograde blood flow connecting the DAo with the left subclavian artery (LSA) increased from 16.1 ± 8.3 mm in 20-29-year-old to 24.7 ± 11.7 mm in 70-80-year-old subjects, correlated with age (r = 0.37; p < 0.001), and was lower in females (p = 0.003). Age was the only independent predictor of increased flow reversal. Complex DAo plaques ≥ 4-mm thickness were found in eight subjects (6.3%) and were connected with the LSA, left common carotid artery, and brachiocephalic trunk in 8 (100%), 1 (12.5%), and 0 (0%) cases, respectively., Conclusions: Retrograde blood flow from the DAo was very frequent. However, potential retrograde embolization was rare due to the low incidence of complex DAo plaques. The magnitude of flow reversal and prevalence of complex atheroma increased with age. Thus, older patients with aortic atherosclerosis are especially vulnerable to this stroke mechanism., Key Points: • 4D flow MRI allows in vivo visualization and quantification of individual and three-dimensional blood flow patterns within the thoracic aorta including retrograde components. • This population-based study showed that blood flow reversal from the proximal descending aorta to the brain-supplying great arteries is very frequent and able to reach all brain territories. The extent of such flow reversal increases with age and with the extent of aortic atherosclerosis. • The combination of blood flow reversal with plaque rupture in the proximal descending aorta constitutes a potential stroke mechanism that should be considered in future trials and in the management of stroke patients in clinical routine.

Dabigatran is a direct thrombin inhibitor and a non-vitamin-K-antagonizing oral anticoagulant, approved for the prevention of stroke and systemic embolization in atrial fibrillation. Idarucizumab is a humanized monoclonal antibody that was recently approved for antagonizing the anticoagulant effects of dabigatran. Here, we report the use of idarucizumab in four acute stroke patients treated with dabigatran in order to enable intravenous thrombolysis in three patients and emergent trepanation in one patient with space occupying subdural hematoma. Since experience on the optimal management of acute stroke patients under medication with dabigatran and on the use of idarucizumab is currently limited, we propose an approach for laboratory testing and fast administration of intravenous thrombolysis and neurosurgery based on our experience.