The Association Between Atrial Fibrillation and Poststroke Seizures is Influenced by Ethnicity and Environmental Factors.

GOAL: Epilepsy is a major complication of stroke. There have been suggestions that patients with cardioembolic stroke are at a greater risk of developing seizures than other stroke subtypes. However, the incidence of atrial fibrillation (AF) and cardioembolic stroke varies considerably across countries, generally higher in Western populations than in Asian populations. This study assessed whether ethnicity affects the association between AF and poststroke seizure (PSS) development. We hypothesized that Royal Melbourne Hospital ([RMH] Melbourne) patients will have significantly higher incidence of AF-related PSS than in the Jinling Hospital (Nanjing) population. MATERIALS AND METHODS: This was a retrospective, multicenter cohort study including patients with anterior circulation ischemic stroke admitted between 2008 and 2015. Occurrences of PSS were ascertained by reviewing medical records or telephone follow-up. To test the hypothesis of an interaction between ethnicity and AF for PSS occurrence, a logistic regression model with AF and ethnicity together with an ethnicity-by-AF interaction term was used. FINDINGS: Of 782 patients followed-up for seizure development at RMH, 247 (31.6%) patients had AF, of whom 10 (4%) developed PSS. Of 1185 patients followed-up and included at JH, 54 (4.8%) patients with AF, of whom 4 (7.4%) developed PSS. At RMH, no significant association was found between AF and PSS; odds ratio .75, 95% confidence interval .4-1.6, (P = .4). At JH, there was a significant association between AF and increased PSS: OR 4.0, 95% CI 1.3-12.1, (P = .01), P for interaction = .03. CONCLUSION: Further understanding of genetic risks and environmental differences across ethnic populations and the role in PSS is required.

Association between different acute stroke therapies and development of post stroke seizures.

BACKGROUND: Epilepsy is a major complication of stroke. We aimed to establish whether there is an association between intravenous thrombolysis, intra-arterial thrombolysis and post stroke seizure (PSS) development. Improved understanding of the relationship between reperfusion therapies and seizure development may improve post-stroke monitoring and follow-up. METHODS: This was a retrospective, multicentre cohort study conducted at the Royal Melbourne Hospital and Jingling Hospital Nanjing. We included patients with anterior circulation ischemic stroke admitted 2008-2015. Patients were divided into four treatment groups 1. IV-tPA only, 2. Intra-arterial therapies (IAT) only, 3. IAT + IV-tPA and 4. stroke unit care only (i.e. no IV-tPA or IAT). To assess the association between type of reperfusion treatment and seizure incidence we used multivariable logistic regression models adjusted for age, stroke severity, 3-month functional outcome and prognostic factors. RESULTS: There were 1375 stroke unit care-only patients, of whom 28 (2%) developed PSS. There were 363 patients who received only IV-tPA, of whom 21 (5.8%) developed PSS. There were 93 patients who received IAT only, of whom 12 (12.9%) developed PSS and 112 that received both IV-tPA + IAT, of which 5 (4.5%) developed PSS. All reperfusion treatments were associated with seizure development compared to stroke unit care-only patients: IV-tPA only adjusted odds ratio (aOR) 3.7, 95%CI 1.8-7.4, p < 0.0001; IAT aOR 5.5, 95%CI 2.1-14.3, p < 0.0001, IAT + IV-tPA aOR 3.4, 95% CI 0.98-11.8, p = 0.05. These aORs did not differ significantly between treatment groups (IV-tPA + IAT versus IV-tPA p = 0.89, IV-tPA + IAT versus IAT, p = 0.44). CONCLUSIONS: Patients receiving thrombolytic or intra-arterial reperfusion therapies for acute ischemic stroke are at higher risk of epilepsy and may benefit from longer follow-up. No evidence for an additive or synergistic effect of treatment modality on seizure development was found.

Association between implementation of a code stroke system and poststroke epilepsy.

OBJECTIVE: We aimed to investigate the effect of a code stroke system on the development of poststroke epilepsy. METHODS: We retrospectively analyzed consecutive patients treated with IV thrombolysis under or outside the code stroke system between 2003 and 2012. Patients were followed up for at least 2 years or until death. Factors with p < 0.1 in univariate comparisons were selected for multivariable logistic and Cox regression. RESULTS: A total of 409 patients met the eligibility criteria. Their median age at stroke onset was 75 years (interquartile range 64-83 years); 220 (53.8%) were male. The median follow-up duration was 1,074 days (interquartile range 119-1,671 days). Thirty-two patients (7.8%) had poststroke seizures during follow-up, comprising 7 (1.7%) with acute symptomatic seizures and 25 (6.1%) with late-onset seizures. Twenty-six patients (6.4%) fulfilled the definition of poststroke epilepsy. Three hundred eighteen patients (77.8%) were treated with the code stroke system while 91 (22.2%) were not. After adjustment for age and stroke etiology, use of the code stroke system was associated with decreased odds of poststroke epilepsy (odds ratio = 0.36, 95% confidence interval 0.14-0.87, p = 0.024). Cox regression showed lower adjusted hazard rates for poststroke epilepsy within 5 years for patients managed under the code stroke system (hazard ratio = 0.60, 95% confidence interval 0.47-0.79, p < 0.001). CONCLUSION: The code stroke system was associated with reduced odds and instantaneous risk of poststroke epilepsy. Further studies are required to identify the contribution of the individual components and mechanisms against epileptogenesis after stroke. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for people with acute ischemic stroke, implementation of a code stroke system reduces the risk of poststroke epilepsy.

Reliability, Reproducibility and Prognostic Accuracy of the Alberta Stroke Program Early CT Score on CT Perfusion and Non-Contrast CT in Hyperacute Stroke.

BACKGROUND: Alberta Stroke Program Early CT Score (ASPECTS) assesses early ischemic change on non-contrast CT (NCCT). We hypothesised that assessing ASPECTS regions on CT Perfusion (CTP) rather than NCCT would improve inter-rater agreement and prognostic accuracy, particularly in patients presenting early after stroke onset. METHODS: Ischemic stroke patients treated with intravenous alteplase from 2009 to 2014 at our institution were included in this study. Inter-rater agreement and prognostic accuracy of ASPECTS across modalities were analysed by the time between stroke onset and initial NCCT, dichotomized 1st quartile versus quartiles 2-4, referred to as epochs. ASPECTS was assessed by 2 independent raters, blinded to stroke onset time, with agreement determined by weighted kappa (κw). Prognostic accuracy for favourable outcome (modified Rankin Scale 0-2) was assessed using the receiver-operating characteristic analysis. RESULTS: A total of 227 participants were included. There was significant time-by-CT modality interaction for ASPECTS, p < 0.0001. The inter-rater agreement of ASPECTS on NCCT significantly increased as onset to CT time increased (κw epoch 1 = 0.76 vs. κw epoch 2-4 = 0.89, p = 0.04), whereas agreement using CTP parameters was stable across epochs. Inter-rater agreement for CTP-ASPECTS was significantly higher than NCCT in early epoch: Tmax κw = 0.96, p = 0.002; cerebral blood volume (CBV) κw = 0.95, p = 0.003; cerebral blood flow (CBF) κw = 0.94, p = 0.006, with no differences in the later epochs. Prognostic accuracy of ASPECTS on NCCT in epoch 1 were (area under the ROC curves [AUC] = 0.52, 95% CI 0.48-0.56), CBV (AUC = 0.55, 95% CI 0.42-0.69, CBF (AUC = 0.58, 95% CI 0.46-0.71) and Tmax (AUC = 0.62, 95% CI 0.49-0.75), p = 0.46 between modalities. CONCLUSIONS: CTP can improve reliability when assessing the extent of ischemic changes, particularly in patients imaged early after stroke onset.

Post-Stroke Seizures Is Associated with Low Alberta Stroke Program Early CT Score.

BACKGROUND: Ischemic stroke is a leading cause of new-onset seizures. Cortical ischemia and large ischemic lesion size are among the most consistently reported risk factors for post-stroke seizures. Alberta Stroke Program Early CT Score (ASPECTS) is a simple and reliable tool for quantifying the extent of cerebral ischemia and may function as a screening tool for patients with high risk of seizure development. We investigated the association of post-stroke seizures with the extent of ischemia assessed by ASPECTS and with cortical involvement identified on non-contrast CT (NCCT). METHODS: This cohort study was based on a prospectively maintained clinical database of acute ischemic stroke patients who were given intravenous tissue plasminogen activator treatment. We included patients with anterior circulation stroke admitted between January 2008 and October 2014. Patients with pre-stroke seizures were excluded. Clinical data and seizure follow-up data were collected. NCCT scans acquired both on stroke admission and at 24 h were analyzed. Logistic regression and cox regression were performed in statistical analysis. RESULTS: A total of 348 patients (median age 73 years, interquartile range [IQR] 63-80, 55% male) were included. During follow-up (median duration 559 days, IQR 107.5-1188.5 days), 22 (6.3%) patients developed post-stroke seizures. Median time from stroke to seizure onset was 138 days (IQR 10-342 days). In univariate logistic regression, both ASPECTS on admission (OR 0.69 per 1-point increase; 95% CI 0.55-0.86; p = 0.001) and at 24 h (OR 0.80 per 1-point increase; 95% CI 0.70-0.92; p = 0.002) were significantly associated with post-stroke seizures. Cortical involvement at 24 h also correlated with seizure occurrence (OR 3.01; 95% CI 1.08-8.34; p = 0.03). Cox regression confirmed the higher risk of developing seizures at any time point in patients with lower ASPECTS value and cortical ischemia. Of note, ASPECTS was the only independent predictor for post-stroke seizures in multivariate logistic regression. CONCLUSION: The extent of ischemia assessed by ASPECTS and cortical involvement identified on NCCT were associated with the development of post-stroke seizures.

Computed tomography perfusion as a diagnostic tool for seizures after ischemic stroke.

INTRODUCTION: Cerebral cortical ischemia is a risk factor for post-stroke seizures. However, the optimal imaging method is unclear. We investigated CT perfusion (CTP) in detecting cortical ischemia and its correlation with post-stroke seizures compared with non-contrast CT (NCCT). METHODS: We included patients with acute ischemic stroke admitted to the Royal Melbourne Hospital between 2009 and 2014. Post-stroke seizure information was collected. Cortical involvement was determined on acute NCCT and CTP (T max, cerebral blood volume [CBV], and cerebral blood flow [CBF]). The association between cortical involvement detected by different imaging modalities and post-stroke seizures was examined. RESULTS: Three-hundred fifty-two patients were included for analysis. Fifty-nine percent were male, and median age was 73 years (inter-quartile range 61-82). Follow-up was available for 96 %; median follow-up duration was 377 days (inter-quartile range 91-1018 days). Thirteen patients had post-stroke seizures (3.9 %). Cortical involvement was significantly associated with post-stroke seizures across all modalities. CBV had the highest hazard ratio (11.3, 95 % confidence interval (CI) 1.1-41.2), followed by NCCT (5.3, 95 % CI 1.5-18.0) and CBF (4.2, 95 % CI 1.1-15.2). Sensitivity was highest for T max (100 %), followed by CBV and CBF (both 76.9 %) and NCCT (63.6 %). Specificity was highest for CBV (77.8 %), then NCCT (75.6 %), CBF (54.0 %), and T max (29.1 %). Receiver-operating characteristic area under the curve was significantly different between imaging modalities (p < 0.001), CBV 0.77, NCCT 0.70, CBF 0.65, and T max 0.65. CONCLUSION: CTP may improve sensitivity and specificity of cortical involvement for post-stroke seizures compared to NCCT.

The effects of dexamethasone on post-asphyxial cerebral oxygenation in the preterm fetal sheep.

Exposure to clinical doses of the glucocorticoid dexamethasone increases brain activity and causes seizures in normoxic preterm fetal sheep without causing brain injury. In contrast, the same treatment after asphyxia increased brain injury. We hypothesised that increased injury was in part mediated by a mismatch between oxygen demand and oxygen supply. In preterm fetal sheep at 0.7 gestation we measured cerebral oxygenation using near-infrared spectroscopy, electroencephalographic (EEG) activity, and carotid blood flow (CaBF) from 24 h before until 72 h after asphyxia induced by 25 min of umbilical cord occlusion. Ewes received dexamethasone intramuscularly (12 mg 3 ml(-1)) or saline 15 min after the end of asphyxia. Fetuses were studied for 3 days after occlusion. During the first 6 h of recovery after asphyxia, dexamethasone treatment was associated with a significantly greater fall in CaBF (P < 0.05), increased carotid vascular resistance (P < 0.001) and a greater fall in cerebral oxygenation as measured by the difference between oxygenated and deoxygenated haemoglobin (delta haemoglobin; P < 0.05). EEG activity was similarly suppressed in both groups. From 6 to 10 h onward, dexamethasone treatment was associated with a return of CaBF to saline control levels, increased EEG power (P < 0.005), greater epileptiform transient activity (P < 0.001), increased oxidised cytochrome oxidase (P < 0.05) and an attenuated increase in [delta haemoglobin] (P < 0.05). In conclusion, dexamethasone treatment after asphyxia is associated with greater hypoperfusion in the critical latent phase, leading to impaired intracerebral oxygenation that may exacerbate neural injury after asphyxia.

Ontogeny and control of the heart rate power spectrum in the last third of gestation in fetal sheep.

Power spectral analysis of fetal heart rate variability has been proposed to provide a non-invasive estimate of autonomic balance. However, there are few systematic data before birth. We therefore examined developmental changes in the frequency power spectrum at very low (0-0.04 Hz), low (0.04-0.15 Hz) and high frequencies (0.15-0.4 Hz), as well as the ratio of low- to high-frequency power (LF/HF), in chronically catheterized, healthy fetal sheep at 0.6 (n = 8), 0.7 (n = 7) and 0.8 gestational age (ga; n = 11). In a second study, 0.8 ga fetuses received either atropine (4.8 mg bolus, then 4.8 mg h(-1) for 30 min, n = 6) or 6-hydroxydopamine (20 mg ml(-1) at 2.5 ml h(-1) for 3 h; n = 9). Data were analysed by sleep state, defined by low-voltage-high-frequency (LV) or high-voltage-low-frequency (HV) EEG. Total spectral power increased with gestational age (P < 0.05), while LF/HF decreased from 0.6 to 0.7 ga. At 0.8 ga, heart rate and LF/HF were significantly higher during HV than LV sleep (P < 0.05). Consistent with this, although total spectral power was not significantly greater during HV sleep, there was a significant interaction between sleep state and frequency band (P = 0.02). Both atropine (P = 0.05) and 6-hydroxydopamine (P < 0.05) were associated with an overall reduction in spectral power but no significant effect on the LF/HF ratio. This study does not support substantial, consistent differences between the frequencies of sympathetic and parasympathetic activity in late-gestation fetal sheep.

Antenatal dexamethasone after asphyxia increases neural injury in preterm fetal sheep.

BACKGROUND AND PURPOSE: Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain. METHODS: Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach. RESULTS: Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290 ± 76 vs 484 ± 98 neurons/mm(2), mean ± SEM, P<0.05) and basal ganglia (putamen, 538 ± 112 vs 814 ± 34 neurons/mm(2), P<0.05) compared to asphyxia-saline, and with greater loss of both total (913 ± 77 vs 1201 ± 75/mm(2), P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66 ± 8 vs 114 ± 12/mm(2), P<0.05, vs sham controls 165 ± 10/mm(2), P<0.001). This was associated with transient hyperglycemia (peak 3.5 ± 0.2 vs. 1.4 ± 0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum -1.5 ± 1.2 dB vs. -5.0 ± 1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures. CONCLUSIONS: In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.

Glucocorticoids and preterm hypoxic-ischemic brain injury: the good and the bad.

Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.