Endothelial NO synthase 786T/T polymorphism increases hemorrhagic transformation after endovascular thrombectomy.

BACKGROUND AND PURPOSE: This study examined whether the 786 NOS3 polymorphism is associated with the risk of hemorrhagic transformation (HT) in stroke patients with anterior large vessel occlusion (ALVO) treated using endovascular thrombectomy (EVT). METHODS: We performed an observational cohort study that included 118 patients with ALVO who underwent EVT. HT was assessed in follow-up CT and MRI. HT and non-HT patients were compared in terms of the 786 NOS3 polymorphism, flow mediated dilation (FMD) values within 3 days after the stroke, and collateral status based on three grading scales. Demographics, vascular risk factors, additional radiological data including ASPECT score, thrombus length and infarct size, and EVT procedure and outcome variables were also included. RESULTS: Radiological HT occurred in 55 (46.6%) patients and the 786T/T NOS3 polymorphism was associated with HT (unadjusted OR of 2.33, 95%CI: 1.05-5.20, adjusted OR of 3.14, 95%CI: 1.16-8.54). Collateral status and systemic endothelial function assessed by FMD were not mediators of this relationship as no differences were seen in the median FMD percentage values or collateral status between NOS3 genotypes. CONCLUSIONS: Our results suggest that genetic variations affecting the NO pathway, such as the 786 NOS3 polymorphism, may contribute to individual variability in the occurrence of HT and these results support involvement of this pathway in the pathogenesis of ischemia-reperfusion injury after EVT.

Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension.

OBJECTIVES: Some patients with deep intracerebral hemorrhage (ICH) have a transient hypertensive response and they may be erroneously classified as secondary to hypertension. We investigated frequency, risk factors, and outcomes for patients with deep ICH without hypertension. MATERIALS AND METHODS: We consecutively recruited patients with spontaneous ICH attending two Spanish stroke centers (January 2015-June 2019). Excluded were patients with lobar/infratentorial ICH and patients who died during hospitalization. We defined deep ICH without hypertension when the bleeding was in a deep structure, no requirement for antihypertensive agents during follow-up and no evident chronic hypertension markers evaluated by transthoracic echocardiography, 24 h ambulatory blood pressure monitoring and/or electrocardiography. We compared clinical, radiological, and 3-month functional outcome data for deep-ICH patients with hypertension versus those without hypertension. RESULTS: Of 759 patients with ICH, 219 (mean age 69.6 ± 15.4 years, 54.8% men) met the inclusion criteria and 36 (16.4%) did not have hypertension. Of these 36 patients, 19 (52.7%) had a transient hypertensive response. Independent predictors of deep ICH without hypertension were age (adjusted OR:0.94;95%CI:0.91-0.96) and dyslipidemia (adjusted OR:0.27;95% CI:0.08-0.85). One third of deep ICH without hypertension were secondary to vascular malformations. Favorable outcomes (modified Rankin Scale 0-2) were more frequent in patients with deep ICH without hypertension compared to those with hypertension (70.9% vs 33.8%; p < 0.001). CONCLUSION: Of patients with deep ICH, 16.4% were unrelated with hypertension, around half showed hypertensive response, and around a third had vascular malformations. We suggest studying hypertension markers and performing a follow-up brain MRI in those patients with deep ICH without prior hypertension.

Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes.

Cerebral cavernous malformations (CCMs) are dilated aberrant leaky capillaries located in the Central Nervous System. Familial CCM is an autosomal dominant inherited disorder related to mutations in KRIT1, Malcavernin or PDCD10. We show two unrelated families presenting familial CCM due to two new mutations in KRIT1 and PDCD10, producing truncated proteins. Clinical phenotype was highly variable among patients from asymptomatic individuals to diplopia, seizures or severe intracranial hemorrhage. PDCD10 patients usually show a more aggressive course and they frequently showed multiple meningiomas. This work provides evidence for the pathogenicity of two new mutations in CCM genes and supports previous findings regarding familial CCM and multiple meningiomas.

COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage.

The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation. Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations.

Age- and Sex-Specific Risk Profiles and In-Hospital Mortality in 13,932 Spanish Stroke Patients.

BACKGROUND: In-hospital stroke death rate is an important sanitary issue. Despite advances in the acute phase management of stroke patients, mortality and disability rates remain high. In aging populations and with different mortality between the sexes in general, the study of sex- and age-related differences becomes increasingly relevant for optimization of post-acute clinical care of stroke patients. METHODS: We designed a cohort follow-up study with 13,932 consecutive ischemic stroke (IS) patients from 19 Spanish hospitals. Data was obtained from the Spanish Stroke Registry; transient ischemic attacks and ages <18 years were excluded. Patients were organised by age group and sex. We compared female and male patient cohorts within and across age groups univariately and used multivariable logistic regression to adjust for confounders in differential in-hospital mortality. RESULTS: The median (percentiles 2.5 and 97.5%) age was 78 (41-92) years old for women and 71 (41-92) for men. IS women were more likely to be older, to exhibit cardio-embolic aetiology, and less likely to have been admitted to a stroke unit or to have had a stroke code activated. Both pre-stroke modified Rankin Scale and National Institute of Health Stroke Scale (NIHSS) scores at admission increased significantly with age and were higher in women than those in men. Differences in distributions of common risk factors for IS and of in-hospital outcomes between women and men actually changed with patient's age. It is to be noted here that although there were no statistically significant differences (p > 0.05) between the sexes within any age group, in-hospital mortality appeared significantly higher in women than that in men when analysed overall, due to confounding. Death was more closely related to stroke in women than in men and occurred earlier. Although there were some age-specific sex differences between the predictors for in-hospital mortality, stroke severity measured by NIHSS was the main predictor of in-hospital mortality for both sexes. Topographic classifications - partial anterior circulatory infarct and total anterior circulatory infarct - were significant prognostic factors for men aged <60 years and for those in the 60-69 years range respectively. CONCLUSION: Although most of our findings were consistent with previous studies, it is important to take into account and highlight differences in in-hospital mortality between the sex and age group. Not to account for age-related differences between the sexes can give false results that may mislead management decisions. As most deaths in women were related to stroke, it is important to improve their early management, stroke code activation, access to stroke units and/or revascularisation therapies, especially in the older age groups.

Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells.

Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an 'omics' approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the body mass index. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 cytosine-guanine dinucleotides (CpG) sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of peptidase M20 domain containing 1 (PM20D1) gene was significantly hypermethylated in stroke patients. One CpG site at Caldesmon 1 (CALD1) gene showed an interaction between stroke and obesity. Two CpGs located in the genes Wilms' tumor 1 (WT1) and potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers.

Nontraditional Lipid Variables Predict Recurrent Brain Ischemia in Embolic Stroke of Undetermined Source.

OBJECTIVE: The aims of this study are, first, to calculate the risk of brain ischemia recurrence and embolic source diagnosis in the follow-up of patients with ESUS (embolic stroke of undetermined source) and, second, to identify the predictors of these events including cardiologic, laboratory, and clinical factors. METHODS: A retrospective observational cohort study of stroke patients admitted to the stroke unit in a single tertiary hospital from 2012 to 2014 was performed. Patients fulfilling ESUS criteria were identified and followed by medical history review until March 2016. Statistical analysis comprised Kaplan-Meier analysis and Cox proportional hazards multivariate analysis including clinical characteristics, cardiologic data, and blood test results. RESULTS: One hundred and thirteen patients, 8.3% of the overall stroke patients, filled ESUS criteria and they were younger, had less vascular risk factors, and suffered milder strokes than the remainder of stroke patients. Median follow-up of ESUS was 25.6 months. Risk of brain ischemia recurrence was 8.4, 10.8, and 15% at 12, 24, and 36 months, respectively, and was associated to age (HR 1.07, P = .027) and to a higher total cholesterol (TC)/high-density lipoprotein (HDL)-cholesterol (HR = 1.38, P = .002) and low-density lipoprotein (LDL)-cholesterol/HDL-cholesterol ratios (HR = 1.48, P = .001). The risk of major embolic source diagnosis was 6.7, 7.8, 13.6% at 12, 24, and 36 months, and was associated to female sex (HR = 6.05, P = .021). CONCLUSIONS: Brain ischemia recurrence increases with age and increased values of nontraditional lipid variables, TCHDLr and LDLHDLr, in ESUS patients, and women are more frequently diagnosed with a major embolic source in the follow-up.

Prognostic value of plasma ß-amyloid levels in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: It has been proposed that the deposition of the ß-amyloid peptide (Aß) in the brain parenchyma and brain blood vessels has deleterious effects. We tested the hypothesis that the levels of plasma Aß are related to the outcome in patients with intracerebral hemorrhage. METHODS: In a multicenter study, we prospectively included patients with spontaneous intracerebral hemorrhage within the first 24 hours after onset. At admission, we measured plasma Aß40 and Aß42 levels using ELISA techniques. Also, we recorded age, sex, vascular risk factors, National Institutes of Health Stroke Scale score, presence of intraventricular hemorrhage, localization, cause, and volume of the hematoma. We obtained the modified Rankin scale and defined a unfavorable outcome as modified Rankin scale >2 at 3 months. Bivariate and multivariate regression analyses were performed. RESULTS: We studied 160 patients (mean age, 73.8±11.3 years; 59.4% of them were men). A favorable outcome was observed in 64 (40%) of the patients. In the bivariate analyses, unfavorable outcome was associated with high age, female sex, diabetes mellitus, presence of intraventricular hemorrhage, high blood glucose, high National Institutes of Health Stroke Scale score, high volume, and high plasma levels of Aß42 and Aß40. The multivariate analysis showed that increased age (odds ratio, 1.07; 95% confidence interval, 1.035-1.21; P<0.0001), high admission National Institutes of Health Stroke Scale score (odds ratio, 1.29, 95% confidence interval, 1.17-1.42; P<0.0001), presence of diabetes mellitus (odds ratio, 4.15; 95% confidence interval, 1.21-14.1; P=0.02), and Aß42 levels >9.7 pg/mL (odds ratio, 4.11; 95% confidence interval, 1.65-10.1; P=0.02) were independently associated with an increased likelihood of an unfavorable outcome. CONCLUSIONS: High levels of plasma Aß42 in patients with acute intracerebral hemorrhage are associated with a poor functional prognosis.

Microbleed burden and hematoma expansion in acute intracerebral hemorrhage.

BACKGROUND: Intracranial amyloid and hypertensive angiopathy have been related to impaired blood vessel function and the etiology of intracerebral hemorrhage (ICH). Microbleeds (MBs) are surrogate radiological markers that are associated with these underlying angiopathies. We assessed the hypothesis that MBs are associated with hematoma expansion (HE) in patients with hyperacute ICH. METHODS: We studied patients with spontaneous supratentorial ICH within the first 6 h after onset. HE was defined as an increase≥33% in the volume of hematoma on the follow-up CT in comparison with the admission CT. The volume was calculated using the ABC/2 formula. MBs were detected by specific magnetic resonance sequences (gradient-echo). The presence, number and distribution of MBs were analyzed. RESULTS: Our study included 44 patients. Their mean age was 68.9±11.1 years, and 70.5% of them were men. HE was observed in 14 of the patients (31.8%). HE was more prevalent in patients with more than 10 MBs compared with patients with 1-10 MBs (60 vs 12.5%; p=0.03). CONCLUSION: A high burden of MBs is associated with an increased risk of HE in patients with ICH. This is probably a marker of a more severe underlying angiopathy.

Impact on functional outcome of an adaptive Stroke Unit based system of care for patients undergoing endovascular treatment during pandemic times.

Introduction: The COVID19 pandemic collapsed intensive care units (ICUs) all around the world, conditioning systems of care (SOC) for other critical conditions such as severe ischemic stroke requiring endovascular treatment (EVT). Our aim was to evaluate the impact of an adaptive Stroke Unit (SU) based SOC on functional outcomes, with the goal of avoiding both general anesthesia (GA) and ICU admission in stroke patients treated with EVT. Material and methods: We performed an observational study comparing data from our traditional ICU-GA based SOC and the adaptive SU-Conscious Sedation (CS) based SOC (consecutive patients undergoing EVT 1 year prior and after onset of the pandemic). Primary outcome was 90-days modified Rankin Scale (mRS), and secondary outcomes included, among others, in-hospital complications, and hospital length of stay (LOS). Results: A total of 210 EVT were performed during the study period (107 under the traditional-SOC and 103 under the adaptive-SOC). A significantly greater proportion of patient was treated under CS (15.9% vs 57.3%; p < 0.001) and admitted for post-procedural care at SU (15% vs 66%; p < 0.001) in the adaptive SOC. Rates of in-hospital complications were similar in both periods, with reduced hospital LOS in the adaptive SOC (10 (7-15) vs 8 (6-12); p = 0.005). The adaptive SOC was associated with higher odds for 90 days favorable outcome (mRS 0-2) (aOR 3.15 (1.34-7.39); p = 0.008). Conclusion: In our case, an adaptive SOC that combined both preference for CS and postprocedural care in SU was associated with better functional outcomes and reduced healthcare resource use for patients undergoing EVT.

Progression of carotid near-occlusion to complete occlusion: related factors and clinical implications.

BACKGROUND: The clinical consequences and factors related to the progression from a carotid near-occlusion (CNO) to a complete occlusion are not well established. Our aim is to describe the rate, predictive factors and clinical implications of the progression to complete carotid occlusion (PCCO) in a population of patients with symptomatic CNO. METHODS: We conducted a multicenter, nationwide, prospective study from January 2010 to May 2016. Patients with angiography-confirmed CNO were included. We collected information on demographic data, clinical manifestations, radiological and hemodynamic findings, and treatment modalities. A 24 month carotid-imaging follow-up of the CNO was performed. RESULTS: 141 patients were included in the study, and carotid-imaging follow-up was performed in 122 patients. PCCO occurred in 40 patients (32.8%), and was more frequent in medically-treated patients (34 out of 61; 55.7%) compared with patients treated with revascularization (6 out of 61; 9.8%) (p<0.001). 7 of the 40 patients with PCCO (17.5%) suffered ipsilateral symptoms. Factors independently related with PCCO in the multivariate analysis were: age ≥75 years (OR 2.93, 95% CI 1.05 to 8.13), revascularization (OR 0.07, 95% CI 0.02 to 0.20), and collateral circulation through the ipsilateral ophthalmic artery (OR 3.25, 95% CI 1.01 to 10.48). CONCLUSIONS: PCCO occurred within 24 months in more than half of the patients under medical treatment. Most episodes of PCCO were not associated with ipsilateral symptoms. Revascularization reduces the risk of PCCO.

Prevalence of dementia and major dementia subtypes in Spanish populations: a reanalysis of dementia prevalence surveys, 1990-2008.

BACKGROUND: This study describes the prevalence of dementia and major dementia subtypes in Spanish elderly. METHODS: We identified screening surveys, both published and unpublished, in Spanish populations, which fulfilled specific quality criteria and targeted prevalence of dementia in populations aged 70 years and above. Surveys covering 13 geographically different populations were selected (prevalence period: 1990-2008). Authors of original surveys provided methodological details of their studies through a systematic questionnaire and also raw age-specific data. Prevalence data were compared using direct adjustment and logistic regression. RESULTS: The reanalyzed study population (aged 70 year and above) was composed of Central and North-Eastern Spanish sub-populations obtained from 9 surveys and totaled 12,232 persons and 1,194 cases of dementia (707 of Alzheimer's disease, 238 of vascular dementia). Results showed high variation in age- and sex-specific prevalence across studies. The reanalyzed prevalence of dementia was significantly higher in women; increased with age, particularly for Alzheimer's disease; and displayed a significant geographical variation among men. Prevalence was lowest in surveys reporting participation below 85%, studies referred to urban-mixed populations and populations diagnosed by psychiatrists. CONCLUSION: Prevalence of dementia and Alzheimer's disease in Central and North-Eastern Spain is higher in females, increases with age, and displays considerable geographic variation that may be method-related. People suffering from dementia and Alzheimer's disease in Spain may approach 600,000 and 400,000 respectively. However, existing studies may not be completely appropriate to infer prevalence of dementia and its subtypes in Spain until surveys in Southern Spain are conducted.

Isokinetic assessment of shoulder complex strength in adolescent elite synchronized swimmers.

Children and adolescent participation in sport has increased in recent years. Synchronized swimming requires correct muscle balance in the shoulder complex. The purpose of this study was to establish isokinetic strength profiles and peak torque ratios of shoulder internal and external rotator muscles in a female high-level synchronized swimming team. Twenty-six adolescent female high-level synchronized swimmers, aged 12-14, participated in this study. Maximal bilateral shoulder concentric external and internal rotation force was measured at 60°/s (5 repetitions) and 180°/s (15 repetitions). The isokinetic concentric strength generated by the internal rotator muscles was significantly higher (p < 0.05) than by the external rotators in both limbs and at both velocities. Significant bilateral differences in the external rotation (ER):internal rotation (IR) strength ratio were noted at 60°/s. Isokinetic assessment is essential in sports medicine, since it is the only test capable of diagnosing any shoulder strength deficit.

Stroke prevalence among the Spanish elderly: an analysis based on screening surveys.

BACKGROUND: This study sought to describe stroke prevalence in Spanish elderly populations and compare it against that of other European countries. METHODS: We identified screening surveys--both published and unpublished--in Spanish populations, which fulfilled specific quality requirements and targeted prevalence of stroke in populations aged 70 years and over. Surveys covering seven geographically different populations with prevalence years in the period 1991-2002 were selected, and the respective authors were then asked to provide descriptions of the methodology and raw age-specific data by completing a questionnaire. In addition, five reported screening surveys in European populations furnished useful data for comparison purposes. Prevalence data were combined, using direct adjustment and logistic regression. RESULTS: The overall study population, resident in central and north-eastern Spain, totalled 10,647 persons and yielded 715 cases. Age-adjusted prevalences, using the European standard population, were 7.3% for men, 5.6% for women, and 6.4% for both sexes. Prevalence was significantly lower in women, OR 0.79 95% CI 0.68-0.93, increased with age, particularly among women, and displayed a threefold spatial variation with statistically significant differences. Prevalences were highest, 8.7%, in suburban, and lowest, 3.8%, in rural populations. Compared to pooled Spanish populations, statistically significant differences were seen in eight Italian populations, OR 1.39 95% CI (1.18-1.64), and in Kungsholmen, Sweden, OR 0.40 95% CI (0.27-0.58). CONCLUSION: Prevalence in central and north-eastern Spain is higher in males and in suburban areas, and displays a threefold geographic variation, with women constituting the majority of elderly stroke sufferers. Compared to reported European data, stroke prevalence in Spain can be said to be medium and presents similar age- and sex-specific traits.

Epigenetic Changes in the Methylation Patterns of KCNQ1 and WT1 after a Weight Loss Intervention Program in Obese Stroke Patients.

Ischemic stroke patients often show high concentrations of circulating inflammatory markers that are associated with increased risk of recurrence. Epigenetic mechanisms could be involved in obesity, inflammation and stroke. The objective of this research was to investigate, in obese patients suffering a previous stroke, the effects of a nutritional program on anthropometric and biochemical variables, and on the methylation patterns of two stroke-related genes (KCNQ1: potassium channel, voltage gated KQT-like subfamily Q, member 1; and WT1: Wilms tumor 1). Twenty-two ischemic stroke patients were compared with a control group composed of eighteen obese subjects with similar age and body mass index ranges. Both groups followed a 20-week nutritional program based on an energy-restricted balanced diet with high adherence to the Mediterranean dietary pattern. The intervention significantly improved anthropometric and metabolic variables, such as the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein concentration, in ischemic stroke patients, and was accompanied by changes in the methylation patterns of both stroke-related genes, which correlated with anthropometric and biochemical variables.