High prevalence of electroencephalographic frontal intermittent rhythmic delta activity in patients with moderately severe COVID-19.

INTRODUCTION: The aim of our study was to analyse EEG findings in patients with COVID-19 not requiring respiratory support. MATERIAL AND METHODS: We reviewed EEGs performed in patients with COVID-19 between April 2020 and May 2021 at the University Hospital in Kraków, Poland. Demographic and clinical data, including comorbid conditions, discharge disposition, survival, neuroimaging findings, laboratory results, and treatment was collected. RESULTS: The study included 44 EEGs performed in 35 patients (51.4% females), aged 65.5 ± 13.9 years. Almost all patients had at least one comorbidity, and one-third had one or more preexisting neurological conditions. Three quarters of EEGs were abnormal. The most frequent EEG finding was background slowing (16 patients; 45.7%). Frontal findings included frontally predominant rhythmic delta (FIRDA) in 10 (28.6%) patients and focal slowing in the left frontal lobe. Patients with abnormal EEG significantly more often required oxygen supplementation (p = 0.003) and were less likely to recover (p = 0.048). CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients with COVID-19 infection may frequently manifest with an abnormal EEG. FIRDA seems to be a frequent EEG pattern in less severe cases of COVID-19 infection. Future studies are needed to establish whether COVID-19 infection increases the risk for FIRDA, and to investigate its pathogenesis.

Mechanical thrombectomy in COVID-19-associated ischaemic stroke: patient characteristics and outcomes in a single-centre study.

INTRODUCTION: The aim of this study was to assess the clinical profiles and outcomes of patients with confirmed COVID-19 infection and acute ischaemic stroke (AIS) treated with mechanical thrombectomy (MT) at the Comprehensive Stroke Centre (CSC) of the University Hospital in Krakow. CLINICAL RATIONALE FOR THE STUDY: COVID-19 is a risk factor for AIS and worsens prognosis in patients with large artery occlusions. During the pandemic, the global number of MT has dropped. At the same time, studies assessing outcomes of this treatment in COVID-19-associated AIS have produced divergent results. MATERIAL AND METHODS: In this single-centre study, we retrospectively analysed and compared the clinical profiles (age, sex, presence of cardiovascular risk factors, neurological deficit at admission), stroke size (measured using postprocessing analysis of perfusion CT with RAPID software), time from stroke onset to arrival at the CSC, time from arrival at the CSC to groin puncture, treatment with intravenous thrombolysis, length of hospitalisation, laboratory test results, and short-term outcomes (measured with Thrombolysis in Cerebral Infarction scale, modified Rankin Scale and National Health Institute Stroke Scale) in patients with AIS treated with MT during the pandemic. A comparison between patients with and without concomitant SARS-CoV2 infection was then performed. RESULTS: There were no statistically significant differences between 15 COVID (+) and 167 COVID (-) AIS patients treated with AIS with respect to clinical profiles (p > 0.05), stroke size (p > 0.05) or outcomes (NIHSS at discharge, 8.1 (SD = 7.1) vs. 8.8 (SD = 9.6), p = 0.778, mRS at discharge 2.9 (SD = 2) vs. 3.1 (SD = 2.1), p = 0.817, death rate 6.7% vs. 12.6%, p = 0.699). There was a significant difference between patients with and without COVID-19 concerning time from arrival at the CSC to groin puncture [104.27 (SD = 51.47) vs. 97.63 (SD = 156.94) min., p = 0.044] and the length of hospitalisation [23.7 (SD = 11.9) vs. 10.5 (SD = 6.9) days, p < 0.001]. CONCLUSION: In AIS patients treated with MT, concomitant SARS-CoV2 infection did not affect the outcome. Our observations need to be confirmed in larger, and preferably multicentre, studies.

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.

Prognostic Significance of Stroke-Associated Infection and other Readily Available Parameters in Acute Ischemic Stroke Treated by Intravenous Thrombolysis.

OBJECTIVES: The impact of contracting stroke-associate infection (SAI) that requires antibiotic treatment after an acute ischemic stroke (AIS) treated with alteplase remains unclear. We studied the profiles of SAI in patients with AIS treated with alteplase toward identifying predictive factors and prognostic implications at 90 days post-stroke. METHODS: We analyzed 33 parameters readily available within 24 hours after AIS: demographics, risk factors, and several clinical and biochemical parameters. Outcome measures were mRS ≤ 2 and mortality 90 days post-stroke. RESULTS: 83 (23.6%) of 352 patients developed SAI. Multivariate logistic regression analysis showed that atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS (the difference between NIHSS score measured upon admission and 24 hours after later), CRP≥10 mg/L, and elevated WBC count affected SAI risk (model including CRP levels and WBC count) and atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS, HT, and elevated fibrinogen levels affected SAI risk (model excluding CRP levels and WBC count). 231 patients (74.1%) had mRS ≤ 2 at day 90. Multivariate logistic regression analysis showed that younger age, no hypertension, mRS=0 pre-stroke, higher delta NIHSS, no HT, no SAI, and CRP<10 mg/L, were associated with mRS≤2 at day 90. 54 (15.3%) patients died within 90 days. Multivariate logistic regression analysis showed that pre-stroke mRS>0, lower delta NIHSS, HT, CRP≥10 mg/L, lower triglyceride levels affected the risk of death within 90 days. CONCLUSIONS: Several markers available within 24 hours post-stroke were predictive of SAI that requires antibiotic treatment. SAI affects long-term outcome but not mortality.

4C Mortality Score correlates with in-hospital functional outcome after COVID-19-associated ischaemic stroke.

AIM OF THE STUDY: The 4C Mortality Score was created to predict mortality in hospitalised patients with COVID-19 and has to date been evaluated only in respiratory system disorders. The aim of this study was to investigate its application in patients with COVID-19-associated acute ischaemic stroke (AIS). CLINICAL RATIONALE FOR STUDY: COVID-19 is a risk factor for AIS. COVID-19-associated AIS results in higher mortality and worse functional outcome. Predictors of functional outcome in COVID-19-associated AIS are required. MATERIALS AND METHODS: This was a retrospective observational study of patients with AIS hospitalised in seven neurological wards in Malopolska Voivodship (Poland) between August and December 2020. We gathered data concerning the patients' age, sex, presence of cardiovascular risk factors, type of treatment received, and the presence of stroke-associated infections (including pneumonia, urinary tract infection and infection of unknown source). We calculated 4C Mortality Score at stroke onset, and investigated whether there was a correlation with neurological deficit measured using the National Health Institute Stroke Scale (NIHSS) and functional outcome assessed using the modified Rankin Scale (mRS) at discharge. RESULTS: The study included 52 patients with COVID-19-associated AIS. The 4C Mortality Score at stroke onset correlated with mRS (rs = 0.565, p < 0.01) at discharge. There was also a statistically significant difference in the mean 4C Mortality Score between patients who died and patients who survived the stroke (13.08 ± 2.71 vs. 9.85 ± 3.47, p = 0.04). CONCLUSIONS AND CLINICAL IMPLICATIONS: 4C Mortality Score predicts functional outcome at discharge in COVID-19-associated AIS patients.

Neurological symptoms in hospitalised patients with COVID-19 and their association with in-hospital mortality.

OBJECTIVES: To evaluate the spectrum of neurological symptoms in patients with COVID-19 during the first 14 days of hospitalisation and its association with in-hospital mortality. MATERIAL AND METHODS: We included 200 patients with RT-PCR-confirmed COVID-19 admitted to University Hospital in Krakow, Poland. In 164 patients, a detailed questionnaire concerning neurological symptoms and signs was performed prospectively within 14 days of hospitalisation. In the remaining 36 patients, such questionnaires were completed retrospectively based on daily observations in the Department of Neurology. RESULTS: During hospitalisation, 169 patients (84.5%) experienced neurological symptoms; the most common were: fatigue (62.5%), decreased mood (45.5%), myalgia (43.5%), and muscle weakness (42.5%). Patients who died during hospitalisation compared to the remainder were older (79 [70.5-88.5] vs. 63.5 [51-77] years, p = 0.001), and more often had decreased level of consciousness (50.0% vs. 9.3%, p < 0.001), delirium (33.3% vs. 4.4%, p < 0.001), arterial hypotension (50.0% vs. 19.6%, p = 0.005) or stroke during (18.8% vs. 3.3%, p = 0.026) or before hospitalisation (50.0% vs. 7.1, p < 0.001), whereas those who survived more often suffered from headache (42.1% vs. 0%, p = 0.012) or decreased mood (51.7% vs. 0%, p = 0.003). CONCLUSIONS: Most hospitalised patients with COVID-19 experience neurological symptoms. Decreased level of consciousness, delirium, arterial hypotension, and stroke during or before hospitalisation increase the risk of in-hospital mortality.

The prognostic significance of large vessel occlusion in stroke patients treated by intravenous thrombolysis.

PURPOSE: According to guidelines, to shorten the treatment window, acute ischaemic stroke (AIS) treatment by intravenous thrombolysis (IVT) can be done based on the results of head computed tomography (CT) without contrast. The impact of large vessel occlusion (LVO) on computed tomography angiography (CTA) in stroke prognosis in patients treated IVT or IVT and mechanical thrombectomy (MT), where indicated, has not yet been studied systematically. We investigated the influence of LVO in consecutive AIS patients on haemorrhagic transformation (HT) on CT 24 h after treatment, mRS < 2 on discharge (unfavourable outcome), and in-hospital mortality. MATERIAL AND METHODS: We analysed several parameters within 24 h after AIS: demographics, risk factors, mRS score pre-stroke, NIHSS upon admission and 24 h later, several clinical and biochemical parameters, and chronic treatment. RESULTS: We registered 1209 patients, of whom 362 (29.9%) received IVT and 108 had MT, where indicated. Admission CTA showed LVO in 197 patients (54.4%). Multivariate regression analysis showed that the presence of LVO and lower delta NIHSS (NIHSS on admission minus NIHSS 24 hours later) were independent parameters affecting HT risk. Multivariate analysis showed that the presence LVO and also older age, female sex, lower delta NIHSS, HT, stroke-associated infection, CRP levels ≥ 10 mg/L, and higher WBC count affected unfavourable outcome on discharge. LVO did not affect in-hospital mortality. CONCLUSIONS: LVO in AIS patients treated by IVT or IVT and MT affects the risk of HT and unfavourable short-term outcome but not in-hospital mortality.

Fasting Hyperglycemia and Long-term Outcome in Patients with Acute Ischemic Stroke Treated with Mechanical Thrombectomy.

BACKGROUND: Little is known about the prognostic role of fasting glucose after mechanical thrombectomy (MT). AIMS: We investigated whether fasting glucose on the next day after MT was associated with long-term outcome in acute ischemic stroke patients according to diabetes. METHODS: We retrospectively analyzed 181 consecutive patients with acute anterior circulation ischemic stroke who underwent MT in 2 comprehensive stroke centers in Poland. Glucose levels were evaluated on admission and on the next day after MT. Fasting hyperglycemia (FHG) was defined as the glucose level above 5.5 mmol/L. Unfavorable outcome was defined as modified Rankin scale (mRS) of 3-6 at day 90 from stroke onset. RESULTS: Patients with FHG had higher mRS at 3-month follow-up compared with those without FHG (3.71 ± 2.56 versus 1.87 ± 2.22, P < .001). In the subgroup analyses, FHG was associated with poor neurological outcome in the group without diabetes (3.74 ± 2.52 versus 1.81 ± 3.74, P < .001) but not with diabetes (3.64 ± 2.67 versus 2.30 ± 3.74, P= .11). Patients without diabetes who had FHG were older, had higher glucose on admission, higher prevalence of atrial fibrillation, cardioembolic stroke etiology and bleeding brain complications compared with the group with normal fasting glucose. After adjustment for potential confounders, fasting glucose (odds ratio [OR] 1.46; 95% CI 1.19-1.79, P < .001), age (OR 1.06; 95% CI 1.02-1.10, P = .001), successful reperfusion (OR 0.09; 95% CI 0.04-0.22, P < .001) and baseline NIHSS score (OR 1.18; 95% CI 1.08-1.29, P < .001) were predictors of mRS 3-6 at 3-month follow-up in the whole group. In the subgroup without diabetes, fasting glucose (OR 1.57; 95% CI 1.17-2.11, P = .002), age (OR 1.05; 95% CI 1.01-1.08, P = .008), successful reperfusion (OR 0.11; 95% CI 0.04-0.30, P < .001) and baseline NIHSS score (OR 1.14; 95% CI 1.04-1.26, P = .011) were independent predictors of unfavorable 3-month outcome. CONCLUSIONS: Fasting glucose on the next day after MT in patients with acute ischemic stroke is an independent risk factor for worse 3-month outcome.

Time from stroke onset to groin puncture affects rate of recanalisation after mechanical thrombectomy: a real-life single centre experience.

AIM OF THE STUDY: We investigated whether the time elapsed between stroke onset and groin puncture (SO-GP) affects the rate of recanalisation as measured by the Thrombolysis in Cerebral Infarction (TICI) scale. CLINICAL RATIONALE FOR THE STUDY: There is no doubt that the effectiveness of thrombolysis in acute ischaemic stroke (AIS) is time-dependent. There is growing evidence that there is a correlation between SO-GP time and rate of recanalisation in patients treated by mechanical thrombectomy (MT). MATERIALS AND METHODS: This study was performed in patients treated in the Comprehensive Stroke Centre in Krakow that covers 3.5 million inhabitants. The following data was collected for this study: demographics, stroke risk factors, transportation (directly from home or via another hospital), admission NIHSS, IV rt-PA administration prior to MT, the number of passes used during MT, and SO-GP time. The favourable outcome measure was TICI 2b or 3. RESULTS: 223 patients (48.4% females; mean age: 66.0 ± 16.6 years) with anterior circulation strokes were treated by MT; 64.6% arrived directly from home. Mean admission NIHSS was 15.6 ± 5.3. IV rtPA was administered in 68.6% of patients. At least two thrombectomy passes were required in 20.6% of cases. Median SO-GP time was 240 minutes (IQR range: 180-305 minutes). Grade 3 or 2b TICI scores were obtained in 70.4% of patients. Univariate logistic regression showed that among all studied parameters, only NIHSS affected the rate of recanalisation, but in a multivariate logistic regression model, the only parameter that affected the rate of recanalisation was the SO-GP time (OR = 0.76; 95% CI: 0.60-0.98, p = 0.03). CONCLUSIONS AND CLINICAL IMPLICATIONS: We suggest that SO-GP time affects the rate of recanalisation in patients with MT.

Mechanical thrombectomy for acute ischaemic stroke during therapeutic anticoagulation: long-term outcomes.

AIM OF STUDY: Mechanical thrombectomy (MT) is one of the aetiological treatment options recommended for anticoagulated patients with acute ischaemic stroke (AIS). We analysed its long-term outcomes using the modified Rankin Score (mRS) or mortality on day 90. CLINICAL RATIONALE FOR THE STUDY: Data describing the anticoagulant efficacy and safety of MT in patients with AIS is limited. MATERIALS AND METHODS: This study included 291 patients with AIS (49% women, mean [SD] age 66 [15] years) who underwent MT in the Comprehensive Stroke Centre in Krakow, Poland. Data describing demographics, stroke risk factors, NIHSS on admission, postprocedural thrombolysis in cerebral infarction score, 24-hour postprocedural haemorrhagic transformation (ECASS-2) as seen on computed tomography, and time between stroke onset and groin puncture was collected. The outcome measure was the mRS on day 90 after stroke onset (a favourable outcome was defined as an mRS not exceeding 2 points; an unfavourable outcome was death). RESULTS: Thirty-seven patients (13%) were on therapeutic anticoagulation during MT. Univariate analysis showed that anticoagulated patients were older and more likely to have been diagnosed with hypertension, ischaemic heart disease, or atrial fibrillation. The patient groups did not differ in terms of clot location, postprocedural thrombolysis in cerebral infarction score, haemorrhagic transformation on computed tomography, or mRS on day 90. Multivariate logistic regression analysis showed that younger age, male sex, no history of diabetes mellitus, lower NIHSS score on admission, shorter time between stroke onset and groin puncture, and better recanalisation were associated with favourable outcomes at day 90, and that therapeutic anticoagulation was not (OR, 1.00; 95%CI, 0.46-2.15; p = 0.99). Anticoagulation did not affect mortality at day 90 (OR, 1.28; 95%CI, 0.56-2.92; p = 0.55). CONCLUSION AND CLINICAL IMPLICATIONS: In anticoagulated patients with AIS, MT does not affect long-term outcomes.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Genetic variants in CETP increase risk of intracerebral hemorrhage.

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

The FGA Thr312Ala polymorphism and risk of intracerebral haemorrhage in Polish and Greek populations.

BACKGROUND AND PURPOSE: Spontaneous intracerebral haemorrhage (ICH) is the most fatal form of stroke with the highest morbidity and disability rate of all stroke types. Recent data suggest that the genetic background has a sizeable and mostly undiscovered effect on the brain haemorrhage risk. Since the coagulation system is crucial to ICH pathology, we studied the significance of the FGA Thr312Ala polymorphism in two European populations. MATERIALS AND METHODS: We genotyped 550 and 224 controls as well as 261 and 242 stroke patients in Polish and Greek populations, respectively. The ICH diagnosis was confirmed by computed tomography. The FGA Thr312Ala polymorphism was analysed using real-time polymorphism chain reaction. RESULTS: Both crude and multivariable regression analyses showed that the studied polymorphism is a protective factor in the Polish population under the dominant and additive models of inheritance. Those results did not replicate in the Greek population. The meta-analysis of results from the Polish and the Greek populations proved that FGA Thr312Ala polymorphism affects the risk of ICH in the dominant model of inheritance. CONCLUSIONS: The FGA Thr312Ala polymorphism affects a risk for ICH in the Polish but not in the Greek population. An advanced meta-analysis of well-designed studies with a significant number of cases might provide useful information of novel polymorphisms, including the FGA Thr312Ala polymorphism, and their role in ICH pathology.

Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. METHODS: We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. RESULTS: ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOEloci and at 12% (SE, 4%) for APOE. CONCLUSIONS: Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.

The ß-fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population.

BACKGROUND AND PURPOSE: Ischaemic stroke is considered to be multifactorial and interactions between environmental and genetic factors play an important role. Although vascular risk factors are well known, the genetic ones are still undiscovered. In the present study, we assessed the significance of the ß-fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population. MATERIAL AND METHODS: 426 ischaemic stroke patients classified according to stroke aetiologies (small vessel disease, large vessel disease or cardioembolic stroke) and 234 controls were included in the study. The association of the ß-fibrinogen genotypes with ischaemic stroke was tested using logistic regression analysis under dominant, recessive or additive models of inheritance. RESULTS: The allele and genotype distributions of the ß-fibrinogen -455G/A gene polymorphism did not differ significantly between patients and controls (patients: G - 75%, GG - 56.6%, GA - 36.8%, AA - 6.6%; controls: G - 73.7%, GG - 57.3%, GA - 32.9%, AA - 9.8%; p > 0.05, χ2). In addition, logistic regression analysis adjusted for the known risk factors, i.e. hypertension, ischaemic heart disease, myocardial infarction, hypercholesterolaemia, diabetes mellitus and smoking, did not show a role of the studied polymorphism in ischaemic stroke. CONCLUSIONS: The ß-fibrinogen -455G/A gene polymorphism is not a risk factor for ischaemic stroke in a Polish population.

Fibrin clot properties in acute stroke: what differs cerebral hemorrhage from cerebral ischemia?

BACKGROUND AND PURPOSE: Fibrin clot formation is important in acute intracerebral hemorrhage (ICH). We investigated plasma fibrin clot characteristics in acute ICH compared with acute ischemic stroke (IS) and nonstroke conditions. METHODS: In the 3 studied groups, we analyzed plasma fibrin clot phenotype and its association with clinical stroke presentation. RESULTS: Compared with controls, in patients with acute strokes, fibrin clots presented with lower clot permeability, longer lysis time, and higher maximum clot absorbance (for all, P<0.001). In ICH patients compared with IS patients, only lysis time was shorter by 13% (P<0.001). In the ICH group, neurological deficit correlated significantly (P<0.05) with clot compaction, and the rate of increase in d-dimers released from clots, whereas initial hematoma volume correlated with lag phase of fibrin formation on turbidimetry and compaction (P<0.05). CONCLUSIONS: In both types of acute strokes, fibrin clot properties are altered: denser fibrin clots are relatively resistant to lysis. In acute ICH, fibrin clots are more susceptible to tissue plasminogen activator-mediated lysis compared with in IS, which might affect ICH pathogenesis.

Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. METHODS: We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. RESULTS: No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. CONCLUSIONS: Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.

Common mitochondrial sequence variants in ischemic stroke.

OBJECTIVE: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV). METHODS: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke. RESULTS: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037). INTERPRETATION: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.