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Abstract Objective The postictal state is underrecognized in epilepsy. Animal models show improvement of postictal symptoms and cerebral perfusion with acetaminophen or nimodipine. We studied the effects of acetaminophen or nimodipine on postictal electroencephalographic (EEG) recovery, clinical reorientation, and hypoperfusion in patients with ECT‐induced seizures. Methods In this prospective clinical trial with three‐condition randomized crossover design, study interventions were administered orally 2 h before ECT sessions (1000 mg acetaminophen, 60 mg nimodipine, or a placebo condition). Primary outcome measure was the speed of postictal EEG recovery. Secondary outcomes were the extent of postictal EEG recovery, clinical reorientation time, and postictal cerebral blood flow as assessed by perfusion‐weighted MRI. Bayesian generalized mixed‐effects models were applied for analyses. Results We included 300 seizures, postictal EEGs, and reorientation time values, and 76 MRI perfusion measures from 33 patients (median age 53 years, 19 female). Pretreatment with acetaminophen or nimodipine was not associated with change in speed of EEG recovery compared to placebo (1.13 [95%CI 0.92, 1.40] and 1.07 [95%CI 0.87, 1.31], respectively), nor with the secondary outcomes. No patient reached full EEG recovery at 1 h post‐seizure, despite clinical recovery in 89%. Longer seizures were associated with slower EEG recovery and lower postictal perfusion. Nimodipine altered regional perfusion in the posterior cortex. Interpretation Pretreatment with acetaminophen or nimodipine did not alleviate symptoms and signs of the postictal state. Systematic study of the postictal state after ECT‐induced seizures is feasible.

Background Balloon guide catheters (BGCs) are used to prevent distal emboli during endovascular treatment for acute ischemic stroke. Although literature reports benefit of BGC, these are not universally used, and randomized head‐to‐head comparisons are lacking. This study compared functional, safety, and technical outcomes between patients treated with non‐BGC and with BGC during endovascular treatment in a nationwide prospective multicenter registry. Methods Patients from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, 2014 to 2018), who underwent endovascular treatment with a non‐BGC or BGC, were included. Primary outcome was the modified Rankin Scale score at 90 days, and secondary outcomes included procedure time and first‐attempt successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2C). Treatment‐effect modification and subgroups were analyzed according to first‐line thrombectomy technique and different sizes of non‐BGC. Results In total 2808 patients were included, and 1671 (60%) were treated with BGC. No differences in the modified Rankin Scale score at 90 days were seen between non‐BGC and BGC groups (adjusted common odds ratio [OR], 0.98 [95% CI, 0.82–1.10]). The non‐BGC was associated with faster procedure times compared with BGC (adjusted β: −2.99 [95% CI, −5.58 to −0.40]). A significant treatment effect was found between BGC use and thrombectomy technique. In subgroup analyses with stent retriever as first‐line technique, 90‐day modified Rankin Scale scores were significantly higher (more disability) in the non‐BGC group compared with the BGC group (adjusted common OR, 0.79 [95% CI, 0.65–0.96]). Direct aspiration combined with non‐BGC resulted in higher first‐attempt rates compared with BGC (adjusted OR, 1.55 [95% CI, 1.06–2.28]). Conclusions This large prospective multicenter registry showed no differences in clinical outcome between patients treated with non‐BGC and BGC. Subgroup analyses suggest that BGC outperforms the non‐BGC when stent retriever is used as first‐line technique, whereas non‐BGC outperforms the BGC when aspiration is used.

Abstract Background The goal is to estimate the additional value of ultrasonographic optic nerve sheath diameter (ONSD) measurement on days 1–3, on top of electroencephalography (EEG), pupillary light reflexes (PLR), and somatosensory evoked potentials (SSEP), for neurological outcome prediction of comatose cardiac arrest patients. We performed a prospective longitudinal cohort study in adult comatose patients after cardiac arrest. ONSD was measured on days 1–3 using ultrasound. Continuous EEG, PLR, and SSEP were acquired as standard care. Poor outcome was defined as cerebral performance categories 3–5 at 3–6 months. Logistic regression models were created for outcome prediction based on the established predictors with and without ONSD. Additional predictive value was assessed by increase in sensitivity for poor (at 100% specificity) and good outcome (at 90% specificity). Results We included 100 patients, 54 with poor outcome. Mean ONSD did not differ significantly between patients with good and poor outcome. Sensitivity for predicting poor outcome increased by adding ONSD to EEG and SSEP from 25% to 41% in all patients and from 27% to 50% after exclusion of patients with non-neurological death. Conclusions ONSD on days 1–3 after cardiac arrest holds potential to add to neurological outcome prediction. Trial registration: clinicaltrials.gov, NCT04084054. Registered 10 September 2019, https://www.clinicaltrials.gov/study/NCT04084054 .

Abstract Background Most patients show temporary impairments in clinical orientation after electroconvulsive therapy (ECT)-induced seizures. It is unclear how postictal reorientation relates to electroencephalography (EEG) restoration. This relationship may provide additional measures to quantify postictal recovery and shed light on neurophysiological aspects of reorientation after ECT. Methods We analyzed prospectively collected clinical and continuous ictal and postictal EEG data from ECT patients. Postictal EEG restoration up to 1 h was estimated by the evolution of the normalized alpha–delta ratio (ADR). Times to reorientation in the cognitive domains of person, place, and time were assessed postictally. In each cognitive domain, a linear mixed model was fitted to investigate the relationships between time to reorientation and postictal EEG restoration. Results In total, 272 pairs of ictal-postictal EEG and reorientation times of 32 patients were included. In all domains, longer time to reorientation was associated with slower postictal EEG recovery. Longer seizure duration and postictal administration of midazolam were related to longer time to reorientation in all domains. At 1-hour post-seizure, most patients were clinically reoriented, while their EEG had only partly restored. Conclusions We show a relationship between postictal EEG restoration and clinical reorientation after ECT-induced seizures. EEG was more sensitive than reorientation time in all domains to detect postictal recovery beyond 1-hour post-seizure. Our findings indicate that clinical reorientation probably depends on gradual cortical synaptic recovery, with longer seizure duration leading to longer postsynaptic suppression after ECT seizures.

Background Both aspiration and stent retriever thrombectomy are safe and effective in patients with acute ischemic stroke due to large vessel occlusion in the anterior circulation. Little is known on the outcomes of these techniques in patients with basilar artery occlusion. This study aimed to compare clinical, technical, and safety outcomes of aspiration and stent retriever thrombectomy as first‐line treatment for basilar artery occlusion in the BASICS (Basilar artery International Cooperation Study) trial. Methods For this post hoc analysis of the BASICS trial, all patients with a basilar artery occlusion who received endovascular treatment with either direct aspiration or stent retriever thrombectomy as first‐line approach were included. When both techniques were registered as first choice, patients were considered to have been treated with stent retriever. The primary outcome was favorable functional outcome, defined as a modified Rankin scale score of 0–3 at 90 days follow‐up, and analyzed using binary logistic regression analysis. Secondary outcomes included the modified Rankin scale score at 90 days (ranging from 0 to 6), procedure duration, mortality at 90 days, and symptomatic intracranial hemorrhage. Secondary outcomes were analyzed using binary, linear, or ordinal regression analyses. All analyses were adjusted for predefined variables. Results Among 158 BASICS patients treated with endovascular treatment,127 were treated with either stent retriever (N=67, 53%), or aspiration (N=60, 47%) as the first‐line treatment modality. We observed no significant difference in favorable functional outcome between patients treated with aspiration and stent retriever thrombectomy as first modality (adjusted odds ratio, 1.80; [95% CI, 0.68–4.76]). Also modified Rankin scale score at 90 days (adjusted common odds ratio, 0.62; [95% CI, 0.30–1.27]) and incidence of symptomatic intracranial hemorrhage (adjusted odds ratio, 0.61; [95% CI, 0.08–4.76]) showed no significant differences between both techniques. Procedure time was shorter with a median of 32 versus 47 minutes (26%; 95% CI, −42 to −6) and mortality rates at 90 days were lower (adjusted odds ratio, 0.36; [95% CI: 0.13–1.00]) in the direct aspiration group. Conclusions This study shows no difference in favorable functional outcome in patients with a basilar artery occlusion treated with direct aspiration compared with patients treated with stent retriever thrombectomy within the BASICS trial, despite a shorter procedure time and lower mortality rate at 90 days.

Background The optimal management of ipsilateral extracranial internal carotid artery (ICA) stenosis during endovascular treatment (EVT) is unclear. We compared the outcomes of two different strategies: EVT with vs without carotid artery stenting (CAS).Methods In this observational study, we included patients who had an acute ischaemic stroke undergoing EVT and a concomitant ipsilateral extracranial ICA stenosis of ≥50% or occlusion of presumed atherosclerotic origin, from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014–2017). The primary endpoint was a good functional outcome at 90 days, defined as a modified Rankin Scale score ≤2. Secondary endpoints were successful intracranial reperfusion, new clot in a different vascular territory, symptomatic intracranial haemorrhage, recurrent ischaemic stroke and any serious adverse event.Results Of the 433 included patients, 169 (39%) underwent EVT with CAS. In 123/168 (73%) patients, CAS was performed before intracranial thrombectomy. In 42/224 (19%) patients who underwent EVT without CAS, a deferred carotid endarterectomy or CAS was performed. EVT with and without CAS were associated with similar proportions of good functional outcome (47% vs 42%, respectively; adjusted OR (aOR), 0.90; 95% CI, 0.50 to 1.62). There were no major differences between the groups in any of the secondary endpoints, except for the increased odds of a new clot in a different vascular territory in the EVT with CAS group (aOR, 2.96; 95% CI, 1.07 to 8.21).Conclusions Functional outcomes were comparable after EVT with and without CAS. CAS during EVT might be a feasible option to treat the extracranial ICA stenosis but randomised studies are warranted to prove non-inferiority or superiority.

Abstract Background Postictal phenomena as delirium, headache, nausea, myalgia, and anterograde and retrograde amnesia are common manifestations after seizures induced by electroconvulsive therapy (ECT). Comparable postictal phenomena also contribute to the burden of patients with epilepsy. The pathophysiology of postictal phenomena is poorly understood and effective treatments are not available. Recently, seizure-induced cyclooxygenase (COX)-mediated postictal vasoconstriction, accompanied by cerebral hypoperfusion and hypoxia, has been identified as a candidate mechanism in experimentally induced seizures in rats. Vasodilatory treatment with acetaminophen or calcium antagonists reduced postictal hypoxia and postictal symptoms. The aim of this clinical trial is to study the effects of acetaminophen and nimodipine on postictal phenomena after ECT-induced seizures in patients suffering major depressive disorder. We hypothesize that (1) acetaminophen and nimodipine will reduce postictal electroencephalographic (EEG) phenomena, (2) acetaminophen and nimodipine will reduce magnetic resonance imaging (MRI) measures of postictal cerebral hypoperfusion, (3) acetaminophen and nimodipine will reduce clinical postictal phenomena, and (4) postictal phenomena will correlate with measures of postictal hypoperfusion. Methods We propose a prospective, three-condition cross-over design trial with randomized condition allocation, open-label treatment, and blinded end-point evaluation (PROBE design). Thirty-three patients (age > 17 years) suffering from a depressive episode treated with ECT will be included. Randomly and alternately, single doses of nimodipine (60 mg), acetaminophen (1000 mg), or water will be given two hours prior to each ECT session with a maximum of twelve sessions per patient. The primary outcome measure is ‘postictal EEG recovery time’, expressed and quantified as an adapted version of the temporal brain symmetry index, yielding a time constant for the duration of the postictal state on EEG. Secondary outcome measures include postictal cerebral perfusion, measured by arterial spin labelling MRI, and the postictal clinical ‘time to orientation’. Discussion With this clinical trial, we will systematically study postictal EEG, MRI and clinical phenomena after ECT-induced seizures and will test the effects of vasodilatory treatment intending to reduce postictal symptoms. If an effect is established, this will provide a novel treatment of postictal symptoms in ECT patients. Ultimately, these findings may be generalized to patients with epilepsy. Trial registration Inclusion in SYNAPSE started in December 2019. Prospective trial registration number is NCT04028596 on the international clinical trial register on July 22, 2019.

BackgroundElectroconvulsive therapy (ECT) is associated with postictal confusion and cognitive side-effects. In rats, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and calcium antagonists decreased postictal cerebral hypoperfusion along with reduction in postictal symptoms. In this study, in ECT-patients, we explore associations between use of these potentially protective medications and occurrence of postictal confusion and cognitive outcome.Materials and methodsIn this retrospective, naturalistic cohort study, patient-, treatment-, and ECT-characteristics, were collected from medical files of patients treated with ECT for major depressive disorder (MDD) or bipolar depressive episode. To test for associations of use of these medications with occurrence of postictal confusion, 295 patients could be included. Cognitive outcome data were available in a subset of 109 patients. Univariate analyses and multivariate censored regression models were used to test for associations.ResultsOccurrence of severe postictal confusion was not associated with use of acetaminophen, NSAIDs or calcium antagonists (n = 295). Regarding the cognitive outcome measure (n = 109), use of calcium antagonists was associated with higher post-ECT cognitive scores (i.e., better cognitive outcome; β = 2.23; p = 0.047), adjusted for age (β = −0.02; p = 0.23), sex (β = −0.21; p = 0.73), pre-ECT cognitive score (β = 0.47; p < 0.0001), and post-ECT depression score (β = −0.02; p = 0.62), but use of acetaminophen (β = −1.55; p = 0.07) as well as NSAIDs (β = −1.02; p = 0.23) showed no associations.ConclusionThis retrospective study does not find arguments for protective effects of acetaminophen, NSAIDs or calcium antagonists against severe postictal confusion in ECT. As a preliminary finding, the use of calcium antagonists was associated with improved cognitive outcome after ECT in this cohort. Prospective controlled studies are necessary.

Impairments of memory, attention, and executive functioning are frequently reported after acute onset brain injury. MRI markers hold potential to contribute to identification of patients at risk for cognitive impairments and clarification of mechanisms. The aim of this systematic review was to summarize and value the evidence on MRI markers of memory, attention, and executive functioning after acute onset brain injury. We included ninety-eight studies, on six classes of MRI factors (location and severity of damage (n = 15), volume/atrophy (n = 36), signs of small vessel disease (n = 15), diffusion-weighted imaging measures (n = 36), resting-state functional MRI measures (n = 13), and arterial spin labeling measures (n = 1)). Three measures showed consistent results regarding their association with cognition. Smaller hippocampal volume was associated with worse memory in fourteen studies (pooled correlation 0.58 [95% CI: 0.46–0.68] for whole, 0.11 [95% CI: 0.04–0.19] for left, and 0.34 [95% CI: 0.17–0.49] for right hippocampus). Lower fractional anisotropy in cingulum and fornix was associated with worse memory in six and five studies (pooled correlation 0.20 [95% CI: 0.08–0.32] and 0.29 [95% CI: 0.20–0.37], respectively). Lower functional connectivity within the default-mode network was associated with worse cognition in four studies. In conclusion, hippocampal volume, fractional anisotropy in cingulum and fornix, and functional connectivity within the default-mode network showed consistent associations with cognitive performance in all types of acute onset brain injury. External validation and cut off values for predicting cognitive impairments are needed for clinical implementation.

Objective: International guidelines recommend early screening for identification of patients who are at risk of long-term cognitive impairments after cardiac arrest. However, information about predictors is not provided. A systematic review of the literature was performed to identify early predictors of long-term cognitive outcome after cardiac arrest. Methods: Scopus and PubMed were systematically searched to identify studies on early predictors of long-term cognitive outcome in patients after cardiac arrest. The population included adult cardiac arrest survivors and potential early predictors were demographics, early cognitive screening scores, imaging measures, electroencephalographic measures, and levels of blood biomarkers. Two investigators reviewed studies for relevance, extracted data and assessed risk of bias. Results: Five articles were included. Risk of bias was assessed as low or moderate. Most detected longterm cognitive impairments were in the domain of memory. Coma duration (2 studies), early cognitive impairments by the self-developed clinical Bedside Neuropsychological Test Battery (BNTB) screener (2 studies), and high S-100B levels on day 3 (2 studies) were the most prominent identified determinants of cognitive impairment on the group level. On the individual patient level, a score on the BNTB of ≤ 94.5 predicted cognitive impairments at 6 months after cardiac arrest (1 study without external validation). Studies on brain imaging and electroencephalography are lacking. Conclusion: Early bedside cognitive screening can contribute to prediction of long-term cognitive impairment after cardiac arrest. Evidence is scarce for S-100B levels and coma duration and absent for measures derived from brain imaging and electroencephalography. LAY ABSTRACT Survival rates of patients after cardiac arrest have increased significantly over the past decades. However, many cardiac arrest survivors have impairments in different domains of thinking (memory, attention, and executive functions, such as planning). Early identification of survivors at risk of such impairments could guide personalized rehabilitation. However, such predictors are currently unavailable. This study reviewed the literature to identify possible early predictors for patients at risk of long-term impairments in thinking. A short, early, bedside test to screen domains of thinking during hospital admission may help to predict long-term impairments. Certain blood markers and a long duration of coma have also been associated with long-term impairments of thinking, but the evidence is weak. There are no studies on brain imaging and electroencephalography in this context.

Abstract Objective Standardized investigation of epileptic seizures and the postictal state may contribute to a better understanding of ictal and postictal phenomena. This comparative case study aims to assess whether electrically induced seizures in electroconvulsive therapy (ECT) show sufficient similarities with spontaneous seizures to serve as a human epilepsy model. Methods We compared six EEG recordings, three ECT‐induced seizures and three generalized tonic‐clonic seizures, using quantitative electroencephalography (EEG) analyses. EEG recordings during and after ECT sessions (under general anesthesia and muscle paralysis) were collected prospectively, whereas epilepsy data were selected retrospectively. Time‐frequency representations, dominant ictal frequencies, and postictal alpha‐delta ratios were calculated. Results In all EEG recordings, a decrease in dominant ictal frequency was observed, as well as postictal suppression. Postictal alpha‐delta ratio indicated the same trend for all: a gradual increase from predominantly delta to alpha frequencies on timescales of hours after the seizure. Postictal spectral representation was similar. Muscle artifacts were absent in ECT‐induced seizures and present in spontaneous seizures. Ictal amplitude was higher in epileptic than in ECT‐induced seizures. Temporospectral ictal dynamics varied slightly between groups. Significance We show that ictal and postictal characteristics in ECT and patients with generalized tonic‐clonic seizures are essentially similar. ECT‐induced seizures may be used to investigate aspects of ictal and postictal states in a highly predictable manner and well‐controlled environment. This suggests that clinical and electrophysiological observations during ECT may be extrapolated to epilepsy with generalized tonic‐clonic seizures.

Background: A considerable proportion of acute ischemic stroke patients treated with endovascular thrombectomy (EVT) are dead or severely disabled at 3 months despite successful reperfusion. Ischemic core imaging biomarkers may help to identify patients who are more likely to have a poor outcome after endovascular thrombectomy (EVT) despite successful reperfusion. We studied the association of CT perfusion-(CTP), CT angiography-(CTA), and non-contrast CT-(NCCT) based imaging markers with poor outcome in patients who underwent EVT in daily clinical practice.Methods: We included EVT-treated patients (July 2016–November 2017) with an anterior circulation occlusion from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry with available baseline CTP, CTA, and NCCT. We used multivariable binary and ordinal logistic regression to analyze the association of CTP ischemic core volume, CTA-Collateral Score (CTA-CS), and Alberta Stroke Program Early CT Score (ASPECTS) with poor outcome (modified Rankin Scale score (mRS) 5-6) and likelihood of having a lower score on the mRS at 90 days.Results: In 201 patients, median core volume was 13 (IQR 5-41) mL. Median ASPECTS was 9 (IQR 8-10). Most patients had grade 2 (83/201; 42%) or grade 3 (28/201; 14%) collaterals. CTP ischemic core volume was associated with poor outcome [aOR per 10 mL 1.02 (95%CI 1.01–1.04)] and lower likelihood of having a lower score on the mRS at 90 days [aOR per 10 mL 0.85 (95% CI 0.78–0.93)]. In multivariable analysis, neither CTA-CS nor ASPECTS were significantly associated with poor outcome or the likelihood of having a lower mRS.Conclusion: In our population of patients treated with EVT in daily clinical practice, CTP ischemic core volume is associated with poor outcome and lower likelihood of shift toward better outcome in contrast to either CTA-CS or ASPECTS.

Background Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in time to reperfusion can be guided by between‐hospital and within‐hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door‐to‐reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. Methods and Results We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door‐to‐reperfusion time was subdivided into time intervals, separately for direct patients (door‐to‐computed tomography, computed tomography‐to‐computed tomography angiography [CTA], CTA‐to‐groin, and groin‐to‐reperfusion times) and for transferred patients (door‐to‐groin and groin‐to‐reperfusion times). We used linear mixed models to distinguish the variation in door‐to‐reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between‐hospital variation in door‐to‐reperfusion time was 9%, and the within‐hospital variation was 91%. The contribution of case‐mix variables on the variation in door‐to‐reperfusion time was marginal (2%–7%). Of the between‐hospital variation, CTA‐to‐groin time explained 83%, whereas groin‐to‐reperfusion time explained 15%. Within‐hospital variation was mostly explained by CTA‐to‐groin time (33%) and groin‐to‐reperfusion time (42%). Similar results were found for transferred patients. Conclusions Door‐to‐reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between‐hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA‐to‐groin time and groin‐to‐reperfusion time.

Aim: Current multimodal approaches leave approximately half of the comatose patients after cardiac arrest with an indeterminate prognosis. Here we investigated whether early MRI markers of brain network integrity can distinguish between comatose patients with a good versus poor neurological outcome six months later. Methods: We performed a prospective cohort study in 48 patients after cardiac arrest submitted in a comatose state to the Intensive Care Unit of two Dutch hospitals. MRI was performed at three days after cardiac arrest, including resting state functional MRI and diffusion-tensor imaging (DTI). Resting state fMRI was used to quantify functional connectivity within ten resting-state networks, and DTI to assess mean diffusivity (MD) in these same networks. We contrasted two groups of patients, those with good (n = 29, cerebral performance category 1–2) versus poor (n = 19, cerebral performance category 3–5) outcome at six months. Mutual associations between functional connectivity, MD, and clinical outcome were studied. Results: Patients with good outcome show higher within-network functional connectivity (fMRI) and higher MD (DTI) than patients with poor outcome across 8/10 networks, most prominent in the default mode network, salience network, and visual network. While the anatomical distribution of outcome-related changes was similar for functional connectivity and MD, the pattern of inter-individual differences was very different: functional connectivity showed larger inter-individual variability in good versus poor outcome, while the opposite was observed for MD. Exploratory analyses suggested that it is possible to define network-specific cut-off values that could help in outcome prediction: (1) high functional connectivity and high MD, associated with good outcome; (2) low functional connectivity and low MD, associated with poor outcome; (3) low functional connectivity and high MD, associated with uncertain outcome. Discussion: Resting-state functional connectivity and mean diffusivity-three days after cardiac arrest are strongly associated with neurological recovery-six months later in a complementary fashion. The combination of fMRI and MD holds potential to improve prediction of outcome.

The biological pathways involved in lesion formation after an acute ischemic stroke (AIS) are poorly understood. Despite successful reperfusion treatment, up to two thirds of patients with large vessel occlusion remain functionally dependent. Imaging characteristics extracted from DWI and T2-FLAIR follow-up MR sequences could aid in providing a better understanding of the lesion constituents. We built a fully automated pipeline based on a tree ensemble machine learning model to predict poor long-term functional outcome in patients from the MR CLEAN-NO IV trial. Several feature sets were compared, considering only imaging, only clinical, or both types of features. Nested cross-validation with grid search and a feature selection procedure based on SHapley Additive exPlanations (SHAP) was used to train and validate the models. Considering features from both imaging modalities in combination with clinical characteristics led to the best prognostic model (AUC = 0.85, 95%CI [0.81, 0.89]). Moreover, SHAP values showed that imaging features from both sequences have a relevant impact on the final classification, with texture heterogeneity being the most predictive imaging biomarker. This study suggests the prognostic value of both DWI and T2-FLAIR follow-up sequences for AIS patients. If combined with clinical characteristics, they could lead to better understanding of lesion pathophysiology and improved long-term functional outcome prediction.

Abstract Background Some studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable outcome after ischaemic stroke or intracerebral haemorrhage, possibly through an increase in intracranial collateral blood flow and a reduction in blood pressure. The Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP) aims to assess the effect of transdermal GTN, started within 3 h after stroke onset in the prehospital setting, on functional outcome at 90 days in patients with acute ischaemic stroke or intracerebral haemorrhage. Methods MR ASAP is a phase III, multicentre, randomised, open-label clinical trial with a blinded outcome assessment. A total of 1400 adult patients with suspected stroke and a systolic blood pressure ≥ 140 mmHg will be randomised to transdermal GTN (5 mg/day), administered as a transdermal patch by paramedics in the prehospital setting within 3 h of stroke onset and continued for 24 h or to standard care. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days, analysed with ordinal logistic regression. Secondary outcomes include blood pressure and collateral circulation at hospital admission, neurological deficit measured with the National Institutes of Health Stroke Scale at 24 h, and mortality and poor outcome (mRS score 3 to 6) at 90 days. This trial will be conducted in the Netherlands and will use a deferred consent procedure. The trial is part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) programme. Discussion MR ASAP will assess whether very early administration of GTN improves outcome after stroke in a setting where rates of intravenous thrombolysis and endovascular treatment for acute ischaemic stroke are high. The deferred consent procedure facilitates prompt GTN treatment and will prevent delay to revascularisation therapies. If early transdermal GTN treatment proves to be effective, this low-cost treatment can be readily implemented into daily clinical practice. Trial registration ISRCTN Registry, ISRCTN99503308. Registered on 2 January 2018.

Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.

Objective: We present relations of SSEP amplitude with neurological outcome and of SSEP amplitude with EEG amplitude in comatose patients after cardiac arrest.Methods: This is a post hoc analysis of a prospective cohort study in comatose patients after cardiac arrest. Amplitude of SSEP recordings obtained within 48–72 h, and EEG patterns obtained at 12 and 24h after cardiac arrest were related to good (CPC 1-2) or poor (CPC 3-5) outcome at 6 months. In 39% of the study population multiple SSEP measurements were performed. Additionally, SSEP amplitude was related to mean EEG amplitude.Results: We included 138 patients (77% poor outcome). Absent SSEP responses, a N20 amplitude

Abstract Background We recently showed that electroencephalography (EEG) patterns within the first 24 hours robustly contribute to multimodal prediction of poor or good neurological outcome of comatose patients after cardiac arrest. Here, we confirm these results and present a cost-minimization analysis. Early prognosis contributes to communication between doctors and family, and may prevent inappropriate treatment. Methods A prospective cohort study including 430 subsequent comatose patients after cardiac arrest was conducted at intensive care units of two teaching hospitals. Continuous EEG was started within 12 hours after cardiac arrest and continued up to 3 days. EEG patterns were visually classified as unfavorable (isoelectric, low-voltage, or burst suppression with identical bursts) or favorable (continuous patterns) at 12 and 24 hours after cardiac arrest. Outcome at 6 months was classified as good (cerebral performance category (CPC) 1 or 2) or poor (CPC 3, 4, or 5). Predictive values of EEG measures and cost-consequences from a hospital perspective were investigated, assuming EEG-based decision- making about withdrawal of life-sustaining treatment in the case of a poor predicted outcome. Results Poor outcome occurred in 197 patients (51% of those included in the analyses). Unfavorable EEG patterns at 24 hours predicted a poor outcome with specificity of 100% (95% CI 98–100%) and sensitivity of 29% (95% CI 22–36%). Favorable patterns at 12 hours predicted good outcome with specificity of 88% (95% CI 81–93%) and sensitivity of 51% (95% CI 42–60%). Treatment withdrawal based on an unfavorable EEG pattern at 24 hours resulted in a reduced mean ICU length of stay without increased mortality in the long term. This gave small cost reductions, depending on the timing of withdrawal. Conclusions Early EEG contributes to reliable prediction of good or poor outcome of postanoxic coma and may lead to reduced length of ICU stay. In turn, this may bring small cost reductions.

Introduction: Previous studies revealed a high prevalence of sleep-wake disturbances in subacute and chronic stroke. We analyzed sleep quantity and quality in patients with hyperacute ischemic stroke on stroke units.Methods: We categorized sleep stages as N1, N2, N3, and REM according to the 2017 criteria of the American Academy of Sleep Medicine in 23 continuous, overnight EEG registrations from 18 patients, starting within 48 h since the onset of cortical ischemic stroke. Associations between presence and duration of sleep stages, and secondary deterioration or functional outcome were analyzed.Results: Physiological sleep cycles were seen in none of the patients. Otherwise, sleep stages alternated chaotically, both during day- and during nighttime, with a sleep efficiency of 30% and 10.5 ± 4.4 (mean ± SD) awakenings per hour of sleep. We cannot differentiate between stroke related and external factors. Only few interruptions could be related to planned nightly wake up calls, but turbulence on stroke units may have played a role. Six patients (seven nights) did not reach deep sleep (N3), 10 patients (13 nights) did not reach REM sleep. If reached, the mean durations of deep and REM sleep were short, with 37 (standard deviation (SD) 25) and 18 (SD15) minutes, respectively. Patients with secondary deterioration more often lacked deep sleep (N3) than patients without secondary deterioration [4 (57%) vs. 2 (25%)], but without statistical significance (p = 0.12).Conclusion: We show that sleep is severely disturbed in patients with acute ischemic stroke admitted to stroke units. Larger studies are needed to clarify associations between deprivation of deep sleep and secondary deterioration.

In the core of a brain infarct, neuronal death occurs within minutes after loss of perfusion. In the penumbra, a surrounding area with some residual perfusion, neurons initially remain structurally intact, but hypoxia-induced synaptic failure impedes neuronal activity. Penumbral activity may recover or further deteriorate, reflecting cell death. Mechanisms leading to either outcome remain ill-understood, but may involve changes in the excitation to inhibition (E/I) ratio. The E/I ratio is determined by structural (relative densities of excitatory and inhibitory synapses) and functional factors (synaptic strengths). Clinical studies demonstrated excitability alterations in regions surrounding the infarct core. These may be related to structural E/I changes, but the effects of hypoxia /ischemia on structural connectivity have not yet been investigated, and the role of structural connectivity changes in excitability alterations remains unclear. We investigated the evolution of the structural E/I ratio and associated network excitability in cortical cultures exposed to severe hypoxia of varying duration. 6–12 h of hypoxia reduced the total synaptic density. In particular, the inhibitory synaptic density dropped significantly, resulting in an elevated E/I ratio. Initially, this does not lead to increased excitability due to hypoxia-induced synaptic failure. Increased excitability becomes apparent upon reoxygenation after 6 or 12 h, but not after 24 h. After 24 h of hypoxia, structural patterns of vesicular glutamate stainings change. This possibly reflects disassembly of excitatory synapses, and may account for the irreversible reduction of activity and stimulus responses seen after 24 h.

IntroductionThere is strong evidence suggesting detrimental effects of cortical spreading depolarization (CSD) in patients with acute ischemic stroke and severe traumatic brain injury. Previous studies implicated scalp electroencephalography (EEG) features to be correlates of CSD based on retrospective analysis of EEG epochs after having detected “CSD” in time aligned electrocorticography. We studied the feasibility of CSD detection in a prospective cohort study with continuous EEG in 18 patients with acute ischemic stroke and 18 with acute severe traumatic brain injury.MethodsFull band EEG with 21 silver/silver chloride electrodes was started within 48 h since symptom onset. Five additional electrodes were used above the infarct. We visually analyzed all raw EEG data in epochs of 1 h. Inspection was directed at detection of the typical combination of CSD characteristics, i.e., (i) a large slow potential change (SPC) accompanied by a simultaneous amplitude depression of >1Hz activity, (ii) focal presentation, and (iii) spread reflected as appearance on neighboring electrodes with a delay.ResultsIn 3,035 one-hour EEG epochs, infraslow activity (ISA) was present in half to three quarters of the registration time. Typically, activity was intermittent with amplitudes of 40–220 µV, approximately half was oscillatory. There was no specific spatial distribution. Relevant changes of ISA were always visible in multiple electrodes, and not focal, as expected in CSD. ISA appearing as “SPC” was mostly associated with an amplitude increase of faster activities, and never with suppression. In all patients, depressions of spontaneous brain activity occurred. However, these were not accompanied by simultaneous SPC, occurred simultaneously on all channels, and were not focal, let alone spread, as expected in CSD.ConclusionWith full band scalp EEG in patients with cortical ischemic stroke or traumatic brain injury, we observed various ISA, probably modulating cortical excitability. However, we were unable to identify unambiguous characteristics of CSD.

Improvement of neuronal recovery in the ischemic penumbra around a brain infarct has a large potential to advance clinical recovery of patients with acute ischemic stroke. However, pathophysiological mechanisms leading to either recovery or secondary damage in the penumbra are not completely understood. We studied neuronal dynamics in a model system of the penumbra consisting of networks of cultured cortical neurons exposed to controlled levels and durations of hypoxia. Short periods of hypoxia (pO2≈20mmHg) reduced spontaneous activity, due to impeded synaptic function. After ≈6 hours, activity and connectivity partially recovered, even during continuing hypoxia. If the oxygen supply was restored within 12 hours, changes in network connectivity were completely reversible. For longer periods of hypoxia (12-30 h), activity levels initially increased, but eventually decreased and connectivity changes became partially irreversible. After ≈30 hours, all functional connections disappeared and no activity remained. Since this complete silence seemed unrelated to hypoxic depths, but always followed an extended period of low activity, we speculate that irreversible damage (at least partly) results from insufficient neuronal activation. This opens avenues for therapies to improve recovery by neuronal activation.

OBJECTIVE: In common peripheral neuropathies, sensory symptoms usually prevail over motor symptoms. This predominance of sensory symptoms may result from higher sensitivity of sensory axons to ischemia. METHODS: We measured median nerve compound sensory action potentials (CSAPs), compound muscle action potentials (CMAPs), and excitability indices in five healthy subjects during forearm ischemia lasting up to disappearance of both CSAPs and CMAPs. RESULTS: ISCHEMIA INDUCED: (1) earlier disappearance of CSAPs than CMAPs (mean ± standard deviation 30±5 vs. 46±6 minutes), (2) initial changes compatible with axonal depolarization on excitability testing (decrease in threshold, increase in strength duration time constant (SDTC) and refractory period, and decrease in absolute superexcitability) which were all more prominent in sensory than in motor axons, and (3) a subsequent decrease of SDTC reflecting a decrease in persistent Na(+) conductance during continuing depolarisation. INTERPRETATION: Our study shows that peripheral sensory axons are more vulnerable for ischemia than motor axons, with faster inexcitability during ischemia. Excitability studies during ischemia showed that this was associated with faster depolarization and faster persistent Na(+) channel inactivation in sensory than in motor axons. These findings might be attributed to differences in ion channel composition between sensory and motor axons and may contribute to the predominance of sensory over motor symptoms in common peripheral neuropathies.

Background Randomised controlled trials with perfusion selection have shown benefit of endovascular treatment (EVT) for ischaemic stroke between 6 and 24 hours after symptom onset or time last seen well. However, outcomes after EVT in these late window patients without perfusion imaging are largely unknown. We assessed their characteristics and outcomes in routine clinical practice.Methods The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective, multicentre study in the Netherlands, included patients with an anterior circulation occlusion who underwent EVT between 2014 and 2017. CT perfusion was no standard imaging modality. We used adjusted ordinal logistic regression analysis to compare patients treated within versus beyond 6.5 hours after propensity score matching on age, prestroke modified Rankin Scale (mRS), National Institutes of Health Stroke Scale, Alberta Stroke Programme Early CT Score (ASPECTS), collateral status, location of occlusion and treatment with intravenous thrombolysis. Outcomes included 3-month mRS score, functional independence (defined as mRS 0–2), and death.Results Of 3264 patients who underwent EVT, 106 (3.2%) were treated beyond 6.5 hours (median 8.5, IQR 6.9–10.6), of whom 93 (87.7%) had unknown time of stroke onset. CT perfusion was not performed in 87/106 (80.2%) late window patients. Late window patients were younger (mean 67 vs 70 years, p