Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke.

BACKGROUND AND PURPOSE: This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke. METHODS: We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0-2) at day 90 and radiographic outcomes at day 5. RESULTS: Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (P=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49-166] versus 43 [18-81] mL; P=0.006) and larger final infarct volumes (110 [61-155] versus 48 [21-99] mL; P=0.001). CONCLUSIONS: Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.

Test Accuracy of Informant-Based Cognitive Screening Tests for Diagnosis of Dementia and Multidomain Cognitive Impairment in Stroke.

BACKGROUND AND PURPOSE: Poststroke cognitive assessment can be performed using standardized questionnaires designed for family or care givers. We sought to describe the test accuracy of such informant-based assessments for diagnosis of dementia/multidomain cognitive impairment in stroke. METHODS: We performed a systematic review using a sensitive search strategy across multidisciplinary electronic databases. We created summary test accuracy metrics and described reporting and quality using STARDdem and Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tools, respectively. RESULTS: From 1432 titles, we included 11 studies. Ten papers used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Four studies described IQCODE for diagnosis of poststroke dementia (n=1197); summary sensitivity: 0.81 (95% confidence interval, 0.60-0.93); summary specificty: 0.83 (95% confidence interval, 0.64-0.93). Five studies described IQCODE as tool for predicting future dementia (n=837); summary sensitivity: 0.60 (95% confidence interval, 0.32-0.83); summary specificity: 0.97 (95% confidence interval, 0.70-1.00). All papers had issues with at least 1 aspect of study reporting or quality. CONCLUSIONS: There is a limited literature on informant cognitive assessments in stroke. IQCODE as a diagnostic tool has test properties similar to other screening tools, IQCODE as a prognostic tool is specific but insensitive. We found no papers describing test accuracy of informant tests for diagnosis of prestroke cognitive decline, few papers on poststroke dementia and all included papers had issues with potential bias.

Reperfusion of very low cerebral blood volume lesion predicts parenchymal hematoma after endovascular therapy.

BACKGROUND AND PURPOSE: Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase-induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy. METHODS: Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (Tmax <6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses. RESULTS: In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume ≥3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%; P=0.001), all of them had regional reperfusion (47% versus 0%; P=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53). CONCLUSIONS: These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice.

Comparison of magnetic resonance imaging mismatch criteria to select patients for endovascular stroke therapy.

BACKGROUND AND PURPOSE: The Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study has shown that clinical response to endovascular reperfusion differs between patients with and without perfusion-diffusion (perfusion-weighted imaging-diffusion-weighted imaging, PWI-DWI) mismatch: patients with mismatch have a favorable clinical response to reperfusion, whereas patients without mismatch do not. This study examined whether alternative mismatch criteria can also differentiate patients according to their response to reperfusion. METHODS: Patients from the DEFUSE 2 study were categorized according to vessel occlusion on magnetic resonance angiography (MRA) and DWI lesion volume criteria (MRA-DWI mismatch) and symptom severity and DWI criteria (clinical-DWI mismatch). Favorable clinical response was defined as an improvement of ≥8 points on the National Institutes of Health Stroke Scale (NIHSS) by day 30 or an NIHSS score of ≤1 at day 30. We assessed, for each set of criteria, whether the association between reperfusion and favorable clinical response differed according to mismatch status. RESULTS: A differential response to reperfusion was observed between patients with and without MRA-DWI mismatch defined as an internal carotid artery or M1 occlusion and a DWI lesion<50 mL. Reperfusion was associated with good functional outcome in patients who met these MRA-DWI mismatch criteria (odds ratio [OR], 8.5; 95% confidence interval [CI], 2.3-31.3), whereas no association was observed in patients who did not meet these criteria (OR, 0.5; 95% CI, 0.08-3.1; P for difference between the odds, 0.01). No differential response to reperfusion was observed with other variations of the MRA-DWI or clinical-DWI mismatch criteria. CONCLUSIONS: The MRA-DWI mismatch is a promising alternative to DEFUSE 2's PWI-DWI mismatch for patient selection in endovascular stroke trials.

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Prognostic biomarkers of intracerebral hemorrhage identified using targeted proteomics and machine learning algorithms.

Early prognostication of patient outcomes in intracerebral hemorrhage (ICH) is critical for patient care. We aim to investigate protein biomarkers' role in prognosticating outcomes in ICH patients. We assessed 22 protein biomarkers using targeted proteomics in serum samples obtained from the ICH patient dataset (N = 150). We defined poor outcomes as modified Rankin scale score of 3-6. We incorporated clinical variables and protein biomarkers in regression models and random forest-based machine learning algorithms to predict poor outcomes and mortality. We report Odds Ratio (OR) or Hazard Ratio (HR) with 95% Confidence Interval (CI). We used five-fold cross-validation and bootstrapping for internal validation of prediction models. We included 149 patients for 90-day and 144 patients with ICH for 180-day outcome analyses. In multivariable logistic regression, UCH-L1 (adjusted OR 9.23; 95%CI 2.41-35.33), alpha-2-macroglobulin (aOR 5.57; 95%CI 1.26-24.59), and Serpin-A11 (aOR 9.33; 95%CI 1.09-79.94) were independent predictors of 90-day poor outcome; MMP-2 (aOR 6.32; 95%CI 1.82-21.90) was independent predictor of 180-day poor outcome. In multivariable Cox regression models, IGFBP-3 (aHR 2.08; 95%CI 1.24-3.48) predicted 90-day and MMP-9 (aOR 1.98; 95%CI 1.19-3.32) predicted 180-day mortality. Machine learning identified additional predictors, including haptoglobin for poor outcomes and UCH-L1, APO-C1, and MMP-2 for mortality prediction. Overall, random forest models outperformed regression models for predicting 180-day poor outcomes (AUC 0.89), and 90-day (AUC 0.81) and 180-day mortality (AUC 0.81). Serum biomarkers independently predicted short-term poor outcomes and mortality after ICH. Further research utilizing a multi-omics platform and temporal profiling is needed to explore additional biomarkers and refine predictive models for ICH prognosis.

Thrombolysis in stroke despite contraindications or warnings?

BACKGROUND AND PURPOSE: Intravenous thrombolysis with alteplase is approved for acute ischemic stroke, but its use is limited by numerous contraindications and warnings arising from trial selection criteria or expert opinions. We examined outcomes from alteplase-treated versus untreated patients, registered in a trials archive, according to presence or absence of specified contraindications and warnings. METHODS: We analyzed 90-day modified Rankin Scale across the whole distribution of scores using the Cochran-Mantel-Haenszel test, with adjustment for age and baseline National Institutes of Health Stroke Score, followed by proportional odds logistic regression analysis to estimate the odds ratios for preferred outcome. RESULTS: We used data from 9613 ischemic stroke patients of whom 2755 were treated with thrombolysis. Adjusted odds ratios showed a broad trend of more favorable 3-month outcome associated with alteplase treatment versus no treatment in various subgroups of patients with contraindications and warnings; for example, 1.40 (95% confidence interval [CI], 1.14-1.70) in patients aged >80 (n=1805), 1.50 (95% CI, 1.03-2.18) in patients with combined history of prior stroke and diabetes mellitus (n=672), 1.42 (95% CI, 1.19-1.70) in patients on prior single antiplatelet agent (n=1626), 2.20 (95% CI, 1.12-4.32) in patients on oral anticoagulation, and International Normalized Ratio≤1.7 (n=157), 1.50 (95% CI, 1.15-1.97) in patients with baseline glucose >180 (n=879), and 1.57 (95% CI, 1.12-2.18) in patients with pretreatment National Institutes of Health Stroke Score >22 (n=620). CONCLUSIONS: This comprehensive retrospective analysis of various contraindications and warnings provides reassurance about benefits and risks of intravenous alteplase treatment in common clinical situations.

The Modified Graeb Score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome.

BACKGROUND AND PURPOSE: Simple and rapid measures of intraventricular hemorrhage (IVH) volume are lacking. We developed and validated a modification of the original Graeb scale to facilitate rapid assessment of IVH over time. METHODS: We explored the relationship between the modified Graeb scale (mGS), original Graeb scale, measured IVH volume, and outcome using data from the Clot Lysis: Evaluating Accelerated Resolution of Hemorrhage with rtPA B (CLEAR B) study. We also explored its reliability. We then evaluated the relationship between mGS and outcome in a large sample of participants with IVH using data contained within the Virtual International Stroke Trials Archive (VISTA). We defined outcome using the modified Rankin scale (>3 signifying poor outcome). RESULTS: The CLEAR B study included 360 scans from 36 subjects. The mGS score and IVH volume were highly correlated (R = 0.80, P<0.0001, R(2) 0.65). Baseline mGS was predictive of poor outcome (area under receiving operating characteristic curve 0.74, 95% confidence interval, 0.57-0.91), whereas the original Graeb scale was not. The VISTA study included 399 participants. Each unit increase in the mGS led to a 12% increase in the odds of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.05-1.19). Measures of reliability (intra- and inter- reader) were good in both studies. CONCLUSIONS: The mGS, a semiquantitative scale for IVH volume measurement, is a reliable measure with prognostic validity suitable for rapid use in clinical practice and in research.

Comparison of Sex-Based In-Hospital Procedural Outcomes and Hospital Readmission Frequency After Patent Foramen Ovale Occluder Device Placement: A Propensity Matched National Cohort.

Patent foramen ovale (PFO) occluder device has been shown to reduce the chance of recurrent stroke. Per guidelines, stroke is higher in females but procedural efficacy and complications based on sex difference is understudied. The nationwide readmission database (NRD) was used to create sex cohorts using ICD-10 Procedural code for elective PFO occluder device placement performed during the years 2016-2019. The 2 groups were compared using propensity score matching (PSM) and multivariate regression models that matched for confounders to report multivariate odds ratio (mOR) for primary and secondary cardiovascular outcomes. Outcomes included in-hospital mortality, acute kidney injury (AKI), acute ischemic stroke, postprocedure bleeding, and cardiac tamponade. Statistical analysis was performed using STATA v. 17. A total of 5818 patients who underwent PFO occluder device placement were identified, of which 3144 (54.0%) were females, and 2673 (46.0%) were males. There was no difference in periprocedural in-hospital mortality, new onset acute ischemic stroke, postprocedural bleeding, or cardiac tamponade between both sexes undergoing occluder device placement. AKI incidence was higher in males compared to females after matching for CKD (mOR = 0.66; 95% CI [0.48-0.92]; P = 0.016) this can be procedural or can be secondary to volume status or nephrotoxins. Males also had a higher length of stay (LOS) at their index hospitalization (2 days vs 1 day) which led to slightly higher total hospitalization cost ($26,585 vs $24,265). Our data did not show a statistically significant difference in the readmission LOS trends between the 2 groups at 30, 90, and 180 days. This national retrospective cohort study of PFO occluder outcomes shows similar efficacy and complication rates between sexes, with the exception of AKI incidence which was higher in males. AKI occurrence was high in males that can be limited due to unavailability of data about hydration status and nephrotoxic medications.

Polygenic Risk of Epilepsy and Post-Stroke Epilepsy.

Background and Aims: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivor's risk of Post-Stroke Epilepsy (PSE). Methods: We conducted a three-stage genetic analysis. First, we identified independent epilepsy-associated ( p <5x10 -8 ) genetic variants from public data. Second, we estimated PSE-specific variant weights in stroke/TIA survivors from the UK Biobank. Third, we tested for an association between a polygenic risk score (PRS) and PSE risk in stroke/TIA survivors from the All of Us Research Program. Primary analysis included all ancestries, while a secondary analysis was restricted to European ancestry only. A sensitivity analysis excluded TIA survivors. Association testing was conducted via multivariable logistic regression, adjusting for age, sex, and genetic ancestry. Results: Among 19,708 UK Biobank participants with stroke/TIA, 805 (4.1%) developed PSE. Likewise, among 12,251 All of Us participants with stroke/TIA, 394 (3.2%) developed PSE. After establishing PSE-specific weights for 39 epilepsy-linked genetic variants in the UK Biobank, the resultant PRS was associated with elevated odds of PSE development in All of Us (OR:1.16[1.02-1.32]). A similar result was obtained when restricting to participants of European ancestry (OR:1.23[1.02-1.49]) and when excluding participants with a TIA history (OR:1.18[1.02-1.38]). Conclusions: Our findings suggest that akin to other forms of epilepsy, genetic predisposition plays an essential role in PSE. Because the PSE data were sparse, our results should be interpreted cautiously.

Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy. METHODS: We searched articles until January 25, 2022, in MEDLINE, Embase, PsycInfo, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker's pooled standardized mean difference (SMD) and 95% CI. Molecular interaction network and enrichment analyses were conducted in Cytoscape (PROSPERO CRD42021297110). RESULTS: We included 22 studies with 1,499 cases with post-brain injury epilepsy and 7,929 controls without post-brain injury epilepsy. Forty-five biomarkers in the blood or CSF were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most of the biomarkers (28/45) were investigated in single studies; only 9 provided validation data, and studies used variable definitions for early-onset and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in 4 studies were significantly higher in patients with poststroke epilepsy (PSE) than those without PSE (SMD 0.44; CI 0.19-0.69). From individual studies, 15 biomarkers in the blood and 7 in the CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (interleukin [IL]-6, IL-1ß]) were predominantly inflammation related. DISCUSSION: We cannot yet recommend using the reported biomarkers for designing antiepileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Although our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual's genetic susceptibilities might contribute to his/her risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted.

Outcomes in Patients With Poststroke Seizures: A Systematic Review and Meta-Analysis.

Importance: Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors' knowledge. Objective: To investigate outcomes in people with PSS compared with people without PSS. Data Sources: MEDLINE, Embase, PsycInfo, Cochrane, LILACS, LIPECS, and Web of Science, with years searched from 1951 to January 30, 2023. Study Selection: Observational studies that reported PSS outcomes. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used for abstracting data, and the Joanna Briggs Institute tool was used for risk-of-bias assessment. Data were reported as odds ratio (OR) and standardized mean difference (SMD) with a 95% CI using a random-effects meta-analysis. Publication bias was assessed using funnel plots and the Egger test. Outlier and meta-regression analyses were performed to explore the source of heterogeneity. Data were analyzed from November 2022 to January 2023. Main Outcomes and Measures: Measured outcomes were mortality, poor functional outcome (modified Rankin scale [mRS] score 3-6), disability (mean mRS score), recurrent stroke, and dementia at patient follow-up. Results: The search yielded 71 eligible articles, including 20 110 patients with PSS and 1 166 085 patients without PSS. Of the participants with PSS, 1967 (9.8%) had early seizures, and 10 605 (52.7%) had late seizures. The risk of bias was high in 5 studies (7.0%), moderate in 35 (49.3%), and low in 31 (43.7%). PSSs were associated with mortality risk (OR, 2.1; 95% CI, 1.8-2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8-2.8), greater disability (SMD, 0.6; 95% CI, 0.4-0.7), and increased dementia risk (OR, 3.1; 95% CI, 1.3-7.7) compared with patients without PSS. In subgroup analyses, early seizures but not late seizures were associated with mortality (OR, 2.4; 95% CI, 1.9-2.9 vs OR, 1.2; 95% CI, 0.8-2.0) and both ischemic and hemorrhagic stroke subtypes were associated with mortality (OR, 2.2; 95% CI, 1.8-2.7 vs OR, 1.4; 95% CI, 1.0-1.8). In addition, early and late seizures (OR, 2.4; 95% CI, 1.6-3.4 vs OR, 2.7; 95% CI, 1.8-4.1) and stroke subtypes were associated with poor outcomes (OR, 2.6; 95% CI, 1.9-3.7 vs OR, 1.9; 95% CI, 1.0-3.6). Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that PSSs were associated with significantly increased mortality and severe disability in patients with history of stroke. Unraveling these associations is a high clinical and research priority. Trials of interventions to prevent seizures may be warranted.

Clinical characteristics and outcomes of patients with post-stroke epilepsy: protocol for an individual patient data meta-analysis from the International Post-stroke Epilepsy Research Repository (IPSERR).

INTRODUCTION: Despite significant advances in managing acute stroke and reducing stroke mortality, preventing complications like post-stroke epilepsy (PSE) has seen limited progress. PSE research has been scattered worldwide with varying methodologies and data reporting. To address this, we established the International Post-stroke Epilepsy Research Consortium (IPSERC) to integrate global PSE research efforts. This protocol outlines an individual patient data meta-analysis (IPD-MA) to determine outcomes in patients with post-stroke seizures (PSS) and develop/validate PSE prediction models, comparing them with existing models. This protocol informs about creating the International Post-stroke Epilepsy Research Repository (IPSERR) to support future collaborative research. METHODS AND ANALYSIS: We utilised a comprehensive search strategy and searched MEDLINE, Embase, PsycInfo, Cochrane, and Web of Science databases until 30 January 2023. We extracted observational studies of stroke patients aged ≥18 years, presenting early or late PSS with data on patient outcome measures, and conducted the risk of bias assessment. We did not apply any restriction based on the date or language of publication. We will invite these study authors and the IPSERC collaborators to contribute IPD to IPSERR. We will review the IPD lodged within IPSERR to identify patients who developed epileptic seizures and those who did not. We will merge the IPD files of individual data and standardise the variables where possible for consistency. We will conduct an IPD-MA to estimate the prognostic value of clinical characteristics in predicting PSE. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. The results will be published in peer-reviewed journals. This study will contribute to IPSERR, which will be available to researchers for future PSE research projects. It will also serve as a platform to anchor future clinical trials. TRIAL REGISTRATION NUMBER: NCT06108102.

Low body temperature does not compromise the treatment effect of alteplase.

BACKGROUND AND PURPOSE: Hypothermia is neuroprotective in ischemic stroke models. The influence of baseline body temperature on outcomes after thrombolytic therapy is unclear. We examined outcomes after alteplase treatment across baseline body temperature for patients with ischemic stroke in data held within the Virtual International Stroke Trials Archive (VISTA; 1998 to 2007). METHODS: We collated data on age, baseline severity (National Institutes of Health Stroke Scale), and 90-day modified Rankin Scale score on patients presenting with acute ischemic stroke. We compared 90-day modified Rankin Scale score between thrombolyzed and nonthrombolyzed comparators across baseline body temperature. We report age and baseline National Institutes of Health Stroke Scale-adjusted Cochran-Mantel-Haenszel probability value and proportional OR with 95% CI for improved modified Rankin Scale distribution. We report temperature profiles over 72 hours after stroke by treatment group. RESULTS: Rankin data were available for 5586 patients with acute ischemic stroke in VISTA (1980 received alteplase). Age and baseline severity were similar (age 68.0±13.0 years versus 69.9±12.3 years, National Institutes of Health Stroke Scale 14.2±5.2 versus 13.0±5.6). Alteplase was associated with improved outcome (OR, 1.49; 95% CI, 1.35 to 1.65, P<0.0001). Alteplase treatment effect was not associated with baseline temperature (P=0.14). Point estimates showed benefit of alteplase treatment across 35.5°C to 37.5°C but showed a negative trend >37.5°C. Alteplase did not influence temperature profiles over 72 hours after stroke. CONCLUSIONS: There is no evidence of influence of body temperature on alteplase treatment response. These results are reassuring that low temperatures across a physiological range do not compromise therapeutic effect of alteplase.

Home time is extended in patients with ischemic stroke who receive thrombolytic therapy: a validation study of home time as an outcome measure.

BACKGROUND AND PURPOSE: "Home time" (HT) refers to the number of days over the first 90 after stroke onset that a patient spends residing in their own home or a relative's home versus any institutional care. It is an accessible and objective parameter, free from subjective bias, with potential as an outcome measure in acute stroke trials. We sought to validate HT and assess treatment responsiveness using independent data. METHODS: We estimated HT in the Stroke Acute Ischemic NXY Treatment (SAINT) I neuroprotection trial. We compared outcomes between thrombolyzed (T) and nonthrombolyzed comparators (C) using HT and the modified Rankin Scale. For our primary analysis, we adjusted for baseline covariates that significantly influence HT and in sensitivity analyses considered all variables that differed between groups at baseline. We report ordinal logistic regression and analysis of covariance with 95% CIs. We describe the relationship of HT with baseline National Institutes of Health Stroke Scale and its components and with Day 90 modified Rankin Scale and Barthel Index. RESULTS: SAINT I included 1699 patients from 23 countries, of whom 28.7% received alteplase. HT correlated with age, baseline severity, alteplase use, side of ischemic lesion, presence of diabetes, and country of patient enrollment (each P<0.05). We found an association between use of alteplase with better adjusted outcomes by either measure (OR for extended HT, 1.36; 95% CI, 1.08 to 1.72; P=0.009; analysis of covariance P=0.007 with a 5.5-day advantage; OR for more favorable modified Rankin Scale, 1.6; 95% CI, 1.28 to 2.00; P<0.0001; Cochran-Mantel-Haenszel P=0.046). HT was significantly associated with baseline National Institutes of Health Stroke Scale and each component of the National Institutes of Health Stroke Scale except level of consciousness, dysarthria, and ataxia. HT was significantly associated with Day 90 modified Rankin Scale and Barthel Index. CONCLUSIONS: HT is a responsive measure for use in multinational acute stroke trials. Its inclusion as a complementary outcome is reasonable. We propose treatment effects are adjusted for age, baseline National Institutes of Health Stroke Scale, side of stroke lesion, country of enrollment, and the presence of diabetes.

Mutism and amnesia following high-voltage electrical injury: psychogenic symptomatology triggered by organic dysfunction?

BACKGROUND: Mutism and dense retrograde amnesia are found both in organic and dissociative contexts. Moreover, dissociative symptoms may be modulated by right prefrontal activity. A single case, M.R., developed left hemiparesis, mutism and retrograde amnesia after a high-voltage electric shock without evidence of lasting brain lesions. M.R. suddenly recovered from his mutism following a mild brain trauma 2 years later. METHODS: M.R.'s neuropsychological pattern and anatomoclinical correlations were studied through (i) language and memory assessment to characterize his deficits, (ii) functional neuroimaging during a standard language paradigm, and (iii) assessment of frontal and left insular connectivity through diffusion tractography imaging and transcranial magnetic stimulation. A control evaluation was repeated after recovery. FINDINGS: M.R. recovered from the left hemiparesis within 90 days of the accident, which indicated a transient right brain impairment. One year later, neurobehavioral, language and memory evaluations strongly suggested a dissociative component in the mutism and retrograde amnesia. Investigations (including MRI, fMRI, diffusion tensor imaging, EEG and r-TMS) were normal. Twenty-seven months after the electrical injury, M.R. had a very mild head injury which was followed by a rapid recovery of speech. However, the retrograde amnesia persisted. DISCUSSION: This case indicates an interaction of both organic and dissociative mechanisms in order to explain the patient's symptoms. The study also illustrates dissociation in the time course of the two different dissociative symptoms in the same patient.

Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the Virtual International Stroke Trials Archive (VISTA).

BACKGROUND AND PURPOSE: Baseline stroke severity predicts outcomes among thrombolysed patients. The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrollment, or both. Using data lodged with Virtual International Stroke Trials Archive, we compared adjusted outcomes between thrombolysed and nonthrombolysed patients enrolled in neuroprotection trials (1998-2007) to assess the influence of various levels of baseline NIHSS. Method-We assessed the association of treatment with outcome, measured across the modified Rankin scale score distribution, in patients categorized by baseline NIHSS in increments of 4. We used an age and baseline NIHSS adjusted Cochran-Mantel-Haenszel test followed by proportional odds logistic regression analysis. We report the Cochran-Mantel-Haenszel P values and estimated odds ratios (OR) for improved modified Rankin scale score distribution with treatment for patients within each baseline NIHSS category. RESULTS: Data were available for 5817 patients (1585 thrombolysed and 4232 nonthrombolysed). Baseline severity was greater among thrombolysed than nonthrombolysed (median baseline NIHSS, 14 vs 13; P < 0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0-1.6; N = 278/934 thrombolysed/nonthrombolysed), 9 to 12 (P = 0.01; OR, 1.3; 95% CI, 1.1-1.6; N = 404/942), 13 to 16 (P < 0.05; OR, 1.6; 95% CI, 1.3-2.1; N = 342/814), 17 to 20 (P < 0.05; OR, 1.7; 95% CI, 1.3-2.1; N = 311/736), and 21 to 24 (P < 0.05; OR, 1.6; 95% CI, 1.1-2.1; N = 178/466). No association was observed within baseline NIHSS categories 1 to 4 (P = 0.8; OR, 1.1; 95% CI, 0.3-4.4; N = 8/161) or ≥ 25 (P = 0.08; OR, 1.1; 95% CI, 0.7-1.9; N = 64/179). CONCLUSIONS: In this nonrandomized comparison, outcomes after thrombolysis were significantly better than in untreated comparators across baseline NIHSS 5 to 24. The significant association was lost only at extremes of baseline NIHSS when sample sizes were small and confidence limits were wide.