Nonpharmacological interventions to improve the cognitive function among persons with traumatic brain injury: A systematic review.

PURPOSE: The systematic review aimed to evaluate the effectiveness of nonpharmacological interventions (NPIs) for improving cognitive function among persons with traumatic brain injury. DESIGN: A systematic review. METHODS: This systematic review was registered in PROSPERO and followed the PRISMA guideline. PubMed, ScienceDirect, Scopus, SpringerLink, Wiley Online Library, JSTOR, and Taylor & Francis were systematically searched for relevant articles of peer-reviewed studies published between 2008 and 2022. Two independent researchers conducted study selection, data extraction, and data quality assessment. FINDINGS: Twenty-one studies met inclusion criteria, numbering a total of 757 participants. Six groups of NPIs were effective in improving cognitive functioning among persons with traumatic brain injury, including multimodal cognitive training, technology innovation, memory training, executive function training, physical activity, and sensory stimulation programs. Pooled evidence revealed that NPIs had a large effect on memory (d = 0.80, p < 0.05 to d = 2.03, p < 0.000), processing speed (d = 1.58, p < 0.05), and cognitive behavior (d = 1.63, p < 0.001 to d = 8.91, p 0.003). There was a medium effect on executive function (d = 0.5, p < 0.01 to d = 0.62, p < 0.05), attention (d = 0.5, p < 0.01), and intelligence (d = 0.57 to d = 0.59, p = 0.000). For visuospatial function and language, there was a significant increase post-intervention. CONCLUSION: Evidence from this systematic review indicates that NPIs, specifically the use of multimodal cognitive training and sensory stimulation programs, were effective in improving cognitive function outcomes among persons with traumatic brain injury, with medium to large effect sizes. CLINICAL RELEVANCE: Nonpharmacological interventions (NPIs) can enhance cognitive function in individuals with traumatic brain injury. These findings can guide healthcare professionals in clinical settings and support the development of technology applications for cognitive rehabilitation using NPIs.

Subarachnoid Hemorrhage Outcomes in an Endovascular Right of First Refusal Neurosurgical Environment.

BACKGROUND: Randomized controlled trials demonstrate that endovascular techniques yield improved outcomes compared with microsurgical approaches. However, not all patients are suitable candidates for endovascular management. This study aimed to determine if healthy patients managed microsurgically could achieve functional outcomes comparable to patients managed endovascularly. METHODS: Patients treated for ruptured aneurysmal subarachnoid hemorrhage at 2 level 1 stroke centers from January 2012 through December 2020 were retrospectively reviewed. All cases were evaluated in an endovascular right of first refusal neurosurgical environment. We collected relevant clinical and follow-up data and created a generalized linear model to identify differences between patients treated endovascularly versus microsurgically. A propensity score model accounting for these differences was used to predict patient outcomes. Functional outcomes were independently assessed using the modified Rankin Scale (mRS) with good functional outcome defined as modified Rankin Scale score <3. RESULTS: The study included 588 patients (211 microsurgical, 377 endovascular); median age was 58 years (interquartile range: 40-86 years); in-hospital mortality was 13%. Age, aneurysm size, and aneurysm location significantly predicted treatment modality (all P < 0.05). After greedy-type matching (210 microsurgical, 210 endovascular), patients managed microsurgically were less likely to be discharged home (odds ratio = 0.6, 95% confidence interval 0.4-0.9, P = 0.01). Functional differences disappeared over time; patients in the 2 treatment arms had similar functional outcomes at 3 months (odds ratio = 1.1, 95% confidence interval 0.7-1.8, P = 0.66) and 1 year after subarachnoid hemorrhage (odds ratio = 1.3, 95% confidence interval 0.8-2.1, P = 0.38). CONCLUSIONS: In an endovascular right of first refusal neurosurgical environment, practitioners can treat patients who are not good endovascular candidates microsurgically and achieve functional outcomes comparable to patients managed endovascularly.

Hunt-Hess Score at 48 Hours Improves Prognostication in Grade 5 Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with Hunt-Hess (HH)5 aneurysmal subarachnoid hemorrhage (SAH) have high mortality rates. Despite an initial moribund exam, a subset of patients progress to favorable outcomes. OBJECTIVE: To evaluate the utility of delayed HH grading to improve prognostication. METHODS: We retrospectively reviewed patients undergoing treatment of ruptured aneurysms at two level 1 stroke centers from January 2012 through December 2020. We collected relevant clinical information and developed a multivariate cox regression model to identify independent predictors of mortality. To evaluate the utility of delayed examinations in predicting outcomes, we re-assessed the HH grade at 48 hours post admission and constructed a logistic regression model with potential confounders to predict mortality. RESULTS: From 2012 to 2020, 621 patients underwent treatment for aneurysmal SAH. We identified 63 HH5 patients (10%) with a mean age of 58 years. Among these patients, the median length of stay was 14 days, with 3 patients passing away within 48 hours. The overall mortality rate was 63% at 24 months. To predict mortality, our cox regression model found only age to be significant (P = 0.002). Delayed HH grading improved prognostication at 48 hours and remained significant on multivariate analysis as a predictor of mortality (P = 0.0001). We observed a significant difference in mortality between patients HH5 and patients HH4 or lower at 48 hours (P = 0.0003). CONCLUSIONS: Delayed reassessment of HH grade 48 hours postadmission is a predictor of mortality, suggesting reassessment at 48 hours in high grade SAH leads to better prognostication.

Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1-3] and death) patient outcomes after aSAH. RESULTS: Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n = 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based on p-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR = 11.7, p = 0.0006 and OR = 15.6, p = 0.0018, respectively) and death at 3 and 12 months (OR = 19.1, p = 0.0093 and OR = 12.8, p = 0.0041, respectively). These results were replicated in an independent sample (n = 100 participants) observing significant associations with GOS at 3 and 12 months (OR = 8.2, p = 0.001 and OR = 6.3, p = 0.0.0047, respectively) and death at 3 months (OR = 2.3, p = 0.008) and a suggestive association (i.e., p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR = 2.0, p = 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups. CONCLUSION: Our results support a role for DNAm of cg25713625/STEAP3 in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3 as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.

ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients.

Background: Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. Results: EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. Conclusions: We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

Methylation Data Processing Protocol and Comparison of Blood and Cerebral Spinal Fluid Following Aneurysmal Subarachnoid Hemorrhage.

One challenge in conducting DNA methylation-based epigenome-wide association study (EWAS) is the appropriate cleaning and quality-checking of data to minimize biases and experimental artifacts, while simultaneously retaining potential biological signals. These issues are compounded in studies that include multiple tissue types, and/or tissues for which reference data are unavailable to assist in adjusting for cell-type mixture, for example cerebral spinal fluid (CSF). For our study that evaluated blood and CSF taken from aneurysmal subarachnoid hemorrhage (aSAH) patients, we developed a protocol to clean and quality-check genome-wide methylation levels and compared the methylomic profiles of the two tissues to determine whether blood is a suitable surrogate for CSF. CSF samples were collected from 279 aSAH patients longitudinally during the first 14 days of hospitalization, and a subset of 88 of these patients also provided blood samples within the first 2 days. Quality control (QC) procedures included identification and exclusion of poor performing samples and low-quality probes, functional normalization, and correction for cell-type heterogeneity via surrogate variable analysis (SVA). Significant differences in rates of poor sample performance was observed between blood (1.1% failing QC) and CSF (9.12% failing QC; p = 0.003). Functional normalization increased the concordance of methylation values among technical replicates in both CSF and blood. SVA improved the asymptotic behavior of the test of association in a simulated EWAS under the null hypothesis. To determine the suitability of blood as a surrogate for CSF, we calculated the correlations of adjusted methylation values at each CpG between blood and CSF globally and by genomic regions. Overall, mean within-CpG correlation was low (r < 0.26), suggesting that blood is not a suitable surrogate for global methylation in CSF. However, differences in the magnitude of the correlation were observed by genomic region (CpG island, shore, shelf, open sea; p < 0.001 for all) and orientation with respect to nearby genes (3' UTR, transcription start site, exon, body, 5' UTR; p < 0.01 for all). In conclusion, the correlation analysis and QC pipelines indicated that DNA extracted from blood was not, overall, a suitable surrogate for DNA from CSF in aSAH methylomic studies.

Psychometric Properties of the Patient Assessment of Own Functioning Inventory Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the psychometric properties of the Patient Assessment of Own Functioning Inventory (PAOFI) following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The PAOFI was completed by 182 participants 3 months after verified aSAH. Exploratory factor analysis was used to evaluate the underlying factor structure of the PAOFI and reliability and concurrent validity were evaluated for each subscale. RESULTS: A three-factor structure accounted for 58.9% of the extracted variance. Cronbach's alpha coefficients for extracted factors ranged from .867 to .924. The PAOFI subscales demonstrated concurrent validity with neuropsychological tests measuring similar constructs. CONCLUSION: There is evidence of reliability and validity of the PAOFI following aSAH. Further studies are needed to confirm these results.

Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Iron can be detrimental to most tissues both in excess and in deficiency. The brain in particular is highly susceptible to the consequences of excessive iron, especially during blood brain barrier disruption after injury. Preliminary evidence suggests that iron homeostasis is important during recovery after neurologic injury; therefore, the exploration of genetic variability in genes involved in iron homeostasis is an important area of patient outcomes research. The purpose of this study was to examine the relationship between tagging single nucleotide polymorphisms (SNPs) in candidate genes related to iron homeostasis and acute and long-term patient outcomes after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This study was a longitudinal, observational, candidate gene association study of participants with aSAH that used a two-tier design including tier 1 (discovery, n = 197) and tier 2 (replication, n = 277). Participants were followed during the acute outcome phase for development of cerebral vasospasm and delayed cerebral ischemia (DCI) and during the long-term outcome phase for death and gross functional outcome using the Glasgow Outcome Scale (GOS; poor = 1-3). Genetic association analyses were performed using a logistic regression model adjusted for age, sex, and Fisher grade. Approximate Bayes factors (ABF) and Bayesian false discovery probabilities (BFDP) were used to prioritize and interpret results. RESULTS: In tier 1, 235 tagging SNPs in 28 candidate genes were available for analysis and 26 associations (20 unique SNPs in 12 genes) were nominated for replication in tier 2. In tier 2, we observed an increase in evidence of association for three associations in the ceruloplasmin (CP) and cubilin (CUBN) genes. We observed an association of rs17838831 (CP) with GOS at 3 months (tier 2 results, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.14-3.86, p = 0.018, ABF = 0.52, and BFDP = 70.8%) and GOS at 12 months (tier 2 results, OR = 1.86, 95% CI 0.98-3.52, p = 0.058, ABF = 0.72, and BFDP = 77.3%) as well as rs10904850 (CUBN) with DCI (tier 2 results, OR = 0.70, 95% CI 0.48-1.02, p = 0.064, ABF = 0.59, and BFDP = 71.8%). CONCLUSIONS: Among the genes examined, our findings support a role for CP and CUBN in patient outcomes after aSAH. In an effort to translate these findings into clinical utility and improve outcomes after aSAH, additional research is needed to examine the functional roles of these genes after aSAH.

Neurocardiac Injury Assessed by Strain Imaging Is Associated With In-Hospital Mortality in Patients With Subarachnoid Hemorrhage.

OBJECTIVES: This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. BACKGROUND: SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. METHODS: A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as <17% and <23% (absolute values), respectively. RESULTS: Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p < 0.001). A reverse Takotsubo pattern of segmental strain was observed in 49% of patients (apical sparing and reduced basal strain). Importantly, LV GLS was more strongly associated with in-hospital mortality than left ventricular ejection fraction (LVEF), even after adjusting for clinical severity (odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.12 to 8.63; p = 0.029). RV strain was measured in 159 subjects (72%); abnormal RV strain was added to LV GLS for predicting in-hospital mortality (p = 0.007). CONCLUSIONS: Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility.

Genetic Variability and Trajectories of DNA Methylation May Support a Role for HAMP in Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Preclinical evidence suggests that iron homeostasis is an important biological mechanism following aneurysmal subarachnoid hemorrhage (aSAH); however, this concept is underexplored in humans. This study examined the relationship between patient outcomes following aSAH and genetic variants and DNA methylation in the hepcidin gene (HAMP), a key regulator of iron homeostasis. METHODS: In this exploratory, longitudinal observational study, participants with verified aSAH were monitored for acute outcomes including cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) and evaluated post-discharge at 3 and 12 months for long-term outcomes of death and functional status using the Modified Rankin Scale (mRS; poor = 3-6) and Glasgow Outcome Scale (GOS; poor = 1-3). Participants were genotyped for two genetic variants, and DNA methylation data were collected from serial cerebrospinal fluid over 14 days post-aSAH at eight methylation sites within HAMP. Participants were grouped based on their site-specific DNA methylation trajectory, with and without correcting for cell-type heterogeneity (CTH), and the associations between genetic variants and inferred DNA methylation trajectory groups and patient outcomes were tested. To correct for multiple testing, an empirical significance threshold was computed using permutation testing. RESULTS: Genotype data for rs10421768 and rs7251432 were available for 241 and 371 participants, respectively, and serial DNA methylation data were available for 260 participants. Acute outcome prevalence included CV in 45% and DCI in 37.1% of the overall sample. Long-term outcome prevalence at 3 and 12 months included poor GOS in 23% and 21%, poor mRS in 31.6% and 27.3%, and mortality in 15.1% and 18.2%, respectively, in the overall sample. Being homozygous for the rs7251432 variant allele was significantly associated with death at 3 months (p = 0.003) and was the only association identified that passed adjustment for multiple testing mentioned above. Suggestive associations (defined as trending toward significance, p value < 0.05, but not meeting empirical significance thresholds) were identified between the homozygous variant allele for rs7251432 and poor GOS and mRS at 3 months (both p = 0.04) and death at 12 months (p = 0.02). For methylation trajectory groups, no associations remained significant after correction for multiple testing. However, for methylation trajectory groups not adjusted for CTH, suggestive associations were identified between cg18149657 and poor GOS and mRS at 3 months (p = 0.003 and p = 0.04, respectively) and death at 3 months (p = 0.04), and between cg26283059 and DCI (p = 0.01). For methylation trajectory groups adjusted for CTH, suggestive associations were identified between cg02131995 and good mRS at 12 months (p = 0.02), and between cg26283059 and DCI (p = 0.01). CONCLUSIONS: This exploratory pilot study offers preliminary evidence that HAMP may play a role in patient outcomes after aSAH. Replication of this study and mechanistic investigation of the role of HAMP in patient outcomes after aSAH are needed.

The Relationships Between BNP and Neurocardiac Injury Severity, Noninvasive Cardiac Output, and Outcomes After Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Neurocardiac injury, a type of myocardial dysfunction associated with neurological insult to the brain, occurs in 31-48% of aneurysmal subarachnoid hemorrhage (aSAH) patients. Cardiac troponin I (cTnI) is commonly used to diagnose neurocardiac injury. Brain natriuretic peptide (BNP), another cardiac marker, is more often used to evaluate degree of heart failure. The purpose of this study was to examine the relationships between BNP and (a) neurocardiac injury severity according to cTnI, (b) noninvasive continuous cardiac output (NCCO), and (c) outcomes in aSAH patients. METHOD: This descriptive longitudinal study enrolled 30 adult aSAH patients. Data collected included BNP and cTnI levels and NCCO parameters for 14 days and outcomes (modified Rankin Scale [mRS] and mortality) at discharge and 3 months. Generalized estimating equations were used to evaluate associations between BNP and cTnI, NCCO, and outcomes. RESULTS: BNP was significantly associated with cTnI. For every 1 unit increase in log BNP, cTnI increased by 0.05 ng/ml ( p = .001). Among NCCO parameters, BNP was significantly associated with thoracic fluid content ( p = .0003). On multivariable analyses, significant associations were found between BNP and poor mRS. For every 1 unit increase in log BNP, patients were 3.16 times more likely to have a poor mRS at discharge ( p = .021) and 5.40 times more likely at 3 months ( p < .0001). CONCLUSION: There were significant relationships between BNP and cTnI and poor outcomes after aSAH. BNP may have utility as a marker of neurocardiac injury and outcomes after aSAH.

Impaired Work Productivity After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a sudden debilitating condition affecting individuals during the most productive times of their lives. Treatment advances have reduced mortality rates but increased the number of survivors facing deficits in physical and neuropsychological function. OBJECTIVE: This study examined associations between neuropsychological function and work productivity after aSAH. METHODS: Fifty-two patients with aSAH, employed before hemorrhage, were recruited from an ongoing National Institutes of Health study. Work Limitations Questionnaire (WLQ), neuropsychological tests (executive function, psychomotor speed, attention and mental flexibility, memory), and Patient Assessment of Own Function were completed at 3 and 12 months after aSAH. RESULTS: Subjects in this analysis reported some level of difficulty in work productivity at 3 and 12 months (35% and 30%, respectively) after hemorrhage. Lower WLQ scores in time management and mental/interpersonal subscales were associated with poorer performance in psychomotor function (r = .5, p = .04 and r = .42, p = .09). Poorer mental flexibility and working memory correlated with time management difficulty at 3 months (r = -.4, p = .09 and r = .54, p = .02). Patients performing poorly on story recall tests were more likely to report difficulty with job physical performance (r = -.42, p = .09) and completing work effectively (r = .61, p = .009). Poorer working memory performance was associated with lower scores on mental/interpersonal WLQ subscales (r = .45, p = .05) and overall health-related work productivity loss (r = .47, p = .04). WLQ areas also correlated with participants' perception of their neuropsychological function after aSAH. CONCLUSIONS: These results suggest that neuropsychological deficits impact work quality after hemorrhage and provide strong impetus for future studies so that domain-specific interventions can be implemented to improve outcomes that affect quality of life including work productivity.

20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients.

Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. Patients with CND and unfavorable 3-month MRS had 2.2- and 2.7-fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20-HETE trajectory groups (35.7%) were 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH.

Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage.

Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8*4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels (P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND (P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2*7, CYP2C8*1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8*2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2*7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.

Plasma Estrogen Levels Are Associated With Severity of Injury and Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Biochemical mediators alter cerebral perfusion and have been implicated in delayed cerebral ischemia (DCI) and poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Estrogens (estrone [E1] and estradiol [E2]) are mediators with neuroprotective properties that could play a role in DCI. This study explored associations between plasma estrogen levels and outcomes following aSAH. METHODS: Plasma samples from 1-4, 4-6, and 7-10 days after hemorrhage from 99 adult aSAH patients were analyzed for estrogen levels using liquid chromatography tandem mass spectrometry. DCI was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. Outcomes were assessed using the Modified Rankin Scale at 3 and 12 months after hemorrhage. Statistical analysis included correlation, regression, and group-based trajectory. RESULTS: Higher E1 and E2 levels were associated with higher Hunt and Hess grade (E1, p = .01; E2, p = .03), the presence of DCI (E1, p = .02; E2, p = .02), and poor 3-month outcomes (E1, p = .002; E2, p = .002). Trajectory analysis identified distinct populations over time for E1 (61% E1 high) and E2 (68% E2 high). Patients in higher trajectory groups had higher Fisher grades (E1, p = .008; E2, p = .01), more frequent DCI (E1, p = .04; E2, p = .08), and worse 3-month outcomes (E1, p = .01; E2, p = .004) than low groups. CONCLUSIONS: These results provide the first clinical evidence that plasma E1 and E2 concentrations are associated with severity of injury and outcomes after aSAH.

Transcranial regional cerebral oxygen desaturation predicts delayed cerebral ischaemia and poor outcomes after subarachnoid haemorrhage: a correlational study.

OBJECTIVES: To examine the relationship between regional cerebral oxygen saturation (rSO2), delayed cerebral ischaemia (DCI), and outcomes after aneurysmal subarachnoid haemorrhage (aSAH). RESEARCH METHODOLOGY: Subjects (n = 163) with aSAH, age 21-75 years, and Fisher grade >1 were included in the study. Continuous rSO2 monitoring was performed for 5-10 days after injury using near-infrared spectroscopy with sensors over the frontal/temporal cortex. rSO2<50 indicated desaturation. DCI was defined as neurological deterioration due to impaired cerebral blood flow. Three- and 12-month functional outcomes were assessed by the modified Rankin scale (MRS) as good (0-3) and poor (4-6). RESULTS: DCI occurred in 57% of patients; of these 66% had rSO2<50. Overall, 56% had rSO2<50 on either side, 21% and 16% had poor MRS at 3 and 12 months. Subjects with rSO2 <50 were 3.25 times more likely to have DCI compared to those with rSO2 >50 (OR 3.25, 95%CI 1.58-6.69), positive predictive value (PPV) = 70%. Subjects with rSO2 <50 were 2.7 times more likely to have poor 3-month MRS compared to those with rSO2 >50 (OR 2.7, 95%CI 1.1-7.2), PPV = 70%. CONCLUSIONS: These results suggest that NIRS has the potential for detecting DCI after aSAH. This potential needs to be further explored in a larger prospective study.

Cerebrospinal fluid 20-HETE is associated with delayed cerebral ischemia and poor outcomes after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a major complication after aneurysmal subarachnoid hemorrhage (aSAH); it is manifested by changes in cerebral blood flow accompanied by neurological decline, and it results in long-term functional and neuropsychological impairment. Preclinical evidence has demonstrated that the arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), affects cerebral microvascular tone and cerebral blood flow after aSAH. The purpose of this study was to determine whether cerebrospinal fluid 20-HETE levels were associated with DCI and long-term neuropsychological outcomes in aSAH patients. METHODS: Cerebrospinal fluid samples were collected twice daily through 14 days after hemorrhage on 108 acute, adult, aSAH patients. Samples were analyzed for 20-HETE via HPLC MSQ single quadrupole mass spectrometry. DCI was defined as the presence of impaired cerebral blood flow (angiographic vasospasm, elevated transcranial Dopplers, abnormal computed tomography or magnetic resonance perfusion scans) accompanied by neurological deterioration. Outcomes, including death and neuropsychological testing, were completed at 3 months after hemorrhage. RESULTS: Detectable 20-HETE levels were observed in 31% of patient samples and were associated with severity of hemorrhage (Hunt & Hess [HH], P=0.04; Fisher, P=0.05). Detection of 20-HETE was not associated with angiographic vasospasm (P=0.34); however, detectable 20-HETE was significantly associated with DCI (P=0.016). Our data also suggest that detectable 20-HETE was associated with decreased performance in 5 neuropsychological domains. CONCLUSIONS: These results provide the first clinical evidence that cerebrospinal fluid 20-HETE concentrations are associated with DCI and poor outcomes, and this provides impetus for future studies to elucidate the clinical utility of inhibiting 20-HETE formation as a novel therapeutic intervention in patients with aSAH.

Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. The aim of this study was to investigate the relationship between cerebrospinal fluid (CSF) ET-1 levels and angiographic vasospasm and DCI. METHODS: Patients with aSAH were consented (n = 106). Cerebral vasospasm was determined by angiography. DCI was determined by transcranial Doppler (TCD) results and/or angiogram results with corresponding clinical deterioration. CSF ET-1 levels over 14 days after the initial insult was quantified by ELISA. ET-1 analysis included a group-based trajectory analysis and ET-1 exposure rate during 24, 48, and 72 h prior to, as well as 72 h post angiography, or clinical deterioration. RESULTS: Trajectory analysis revealed two distinct groups of subjects with 56% of patients in the low ET-1 trajectory group (mean at day 1 = 0.31 pg/ml; SE = 0.04; mean at day 14 = 0.41 pg/ml; SE = 0.15) and 44% of patients in the high ET-1 trajectory group (mean at day 1 = 0.65 pg/ml; SE = 0.08; mean at day 14 = 0.61 pg/ml; SE = 0.06). Furthermore, we observed that ET-1 exposure rate 72 h before angiography and clinical spasm was a significant predictor of both angiographic vasospasm and DCI, whereas, ET-1 exposure after angiography and clinical spasm was not associated with either angiographic vasospasm or DCI. CONCLUSION: Based on these results we conclude that ET-1 concentrations are elevated in a sub-group of patients and that the acute (72 h prior to angiography and clinical neurological deterioration), but not chronic, elevations in CSF ET-1 concentrations are indicative of the pathogenic alterations of vasospasm and DCI in aSAH patients.

Elevated cardiac troponin I and functional recovery and disability in patients after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage experience myocardial injury at the time of rupture, but its effect on functional recovery and disability is unclear. OBJECTIVE: To describe the prevalence of myocardial injury, as indicated by high serum levels of cardiac troponin I (≥0.3 ng/mL), within the first 5 days after aneurysmal subarachnoid hemorrhage and the effect of the injury on 3-month functional recovery and disability. METHODS: In a prospective longitudinal study, 239 patients with Hunt/Hess grade 3 or greater and/or Fisher grade 2 or greater at admission had serum level of troponin I measured on days 0 to 5. Patients were interviewed at 3 months to evaluate functional recovery (Glasgow Outcome Scale) and functional disability (Modified Rankin Scale). Statistics included χ² analysis, t tests, and binary logistic regression. RESULTS: Troponin values were elevated in 33.5% of the patients, and few patients in either group had a history of coronary artery disease (7.4% with troponin levels ≥0.3 ng/mL vs 2.7% with levels <0.3 ng/mL, P = .12). Higher troponin levels were significantly related to age and Hunt/Hess and Fisher grades, but not race, and were significantly associated with poorer functional recovery (P < .001) and more functional disability (P < .001). Even after controls for age, race, and more severe Hunt/Hess grades, higher levels remained a significant predictor of poorer functional recovery (P = .04) and disability (P = .01). CONCLUSION Elevated levels of cardiac troponin I after aneurysmal subarachnoid hemorrhage are common in patients with no cardiac history, are associated with severity of the hemorrhage, and are independently predictive of poorer functional recovery and increased disability.