Clinical Delayed Cerebral Ischemia Research Articles

414 Exploration and Validation of CSF miRNAs as Predictors of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Prospective Clinical Study

INTRODUCTION: Approximately one-third of the patients who survive Aneurysmal Subrachnoid Hemorrhage (aSAH) have delayed cerebral ischemia (DCI) which contributes to poor clinical outcome. METHODS: A prospectively maintained clinical database was utilized under IRB approval for determination of clinical DCI and collection of biological samples. CSF samples were collected at 2-time points (<24 hours and 72 hours) post-aSAH from patients treated with external ventricular drainage. miRNAs were extracted from exosomes isolated from the CSF. In the first group of patients (exploratory phase), a CSF panel containing 84 miRNAs was analyzed using quantitative real-time PCR as an exploratory phase. Using the findings from the exploratory phase, we subsequently validated 26miRNAs in a second group of patients. RESULTS: We found three miRNAs i.e., miR-150-5p (p=0.02), miR-140-3p (p=0.03), and miR-26b-5p (p=0.01) were significantly upregulated in 72 vs 24 hours in patients that developed DCI. Moreover, we observed miR-451a (p=<0.0001) and miR-106a-5p (p=0.0001) were upregulated in No DCI at 72 hours. CONCLUSIONS: Our study identifies CSF exosomal miRNAs that could be crucial in progressing aSAH to DCI, and another set of miRNAs that possibly helps in aiding protection being entered into DCI. These miRNAs could be considered as potential biomarkers for DCI progression and prevention. Specifically miR-451a and miR-106a-5p may provide a protective role by reducing inflammation mediated by Matrix Metalloproteinases genes, thus crucial in the prevention of DCI. Further validation is important in additional patient cohorts.

Laboratory biomarkers of delayed cerebral ischemia following subarachnoid hemorrhage: A systematic review.

Delayed cerebral ischemia (DCI) substantially contributes to disability and death in subarachnoid hemorrhage (SAH) patients; however, its pathophysiology is incompletely understood and diagnostic and therapeutic strategies are lacking. Biomarkers may help to elucidate the pathophysiology, optimize early diagnosis, or provide treatment targets. We systematically searched PubMed and Embase on October 13, 2021, for studies that evaluated at least one laboratory biomarker in patients with DCI, using the most up-to-date definition of DCI as proposed by a panel of experts in 2010. Quality of studies was assessed using the Newcastle-Ottawa Scale or Cochrane Collaboration's risk of bias assessment tool. Biomarkers of clinical and radiological DCI were analyzed separately. Results were meta-analyzed if possible, otherwise narratively reviewed. Biomarkers were classified as significant, inconclusive, or nonsignificant. We defined validated biomarkers as those with significant results in meta-analyses, or in at least two studies using similar methodologies within the same time interval after SAH. The search yielded 209 articles with 724 different biomarkers; 166 studies evaluated 646 biomarkers of clinical DCI, of which 141 were significant and 7 were validated biomarkers (haptoglobulin 2-1 and 2-2, ADAMTS13, vWF, NLR, P-selectin, F2-isoprostane); 78 studies evaluated 165 biomarkers of radiological DCI, of which 63 were significant and 1 was a validated biomarker (LPR). Hence, this review provides a selection of seven biomarkers of clinical DCI and one biomarker of radiological DCI as most promising biomarkers of DCI. Future research should focus on determining the exact predictive, diagnostic, and therapeutic potentials of these biomarkers.

External Validation of an Extreme Gradient Boosting Model for Prediction of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Delayed cerebral ischemia (DCI) may significantly worsen the functional status of patients with aneurysmal subarachnoid hemorrhage (aSAH). Several authors have designed predictive models for early identification of patients at risk of post-aSAH DCI. In this study, we externally validate an extreme gradient boosting (EGB) forecasting model for post-aSAH DCI prediction. A 9-year institutional retrospective review of patients with aSAH was performed. Patients were included if they underwent surgical or endovascular treatment and had available follow-up data. DCI was diagnosed as new-onset neurologic deficits at 4-12 days after aneurysm rupture, defined as worsening Glasgow Coma Scale score for ≥2 points, and new ischemic infarcts at imaging. We collected 267 patients with aSAH. At admission, median Hunt-Hess score was 2 (range, 1-5), median Fisher score 3 (range, 1-4), and median modified Fisher score 3 (range, 1-4). One-hundred and forty-five patients underwent external ventricular drainage placement for hydrocephalus (54.3%). The ruptured aneurysms were treated with clipping (64%), coiling (34.8%), and stent-assisted coiling (1.1%). Fifty-eight patients (21.7%) were diagnosed with clinical DCI and 82 (30.7%) with asymptomatic imaging vasospasm. The EGB classifier correctly predicted 19 cases of DCI (7.1%) and 154 cases of no-DCI (57.7%), achieving sensitivity of 32.76% and specificity of 73.68%. The calculated F1 score and accuracy were 0.288% and 64.8%, respectively. We validated that the EGB model is a potential assistant tool to predict post-aSAH DCI in clinical practice, finding moderate-high specificity but low sensitivity. Future research should investigate the underlying pathophysiology of DCI to allow the development of high-performing forecasting models.

Predictive Relevance of Early Temperature Elevation on the Risk of Delayed Cerebral Ischemia Development Following Aneurysmal Subarachnoid Hemorrhage

Fever in aneurysmal subarachnoid hemorrhage (aSAH) has been associated with delayed cerebral ischemia (DCI), but its relevance in risk stratification has not been explored. This study investigated whether early temperature elevation following aSAH predicts impending clinical deterioration caused by DCI. Relevant cases were identified from a prospectively maintained database for consecutive patients with aSAH treated at our center between July 2015 and January 2020. Temperature readings obtained every 2 hours for individual patients from admission through day 14 were recorded and analyzed. Demographic, clinical, treatment, and angiographic data were extracted from the electronic medical record. The primary end point was the occurrence of DCI (clinical and radiographic vasospasm). Multivariate logistic regression analyses were performed to account forpatient age, smoking status, and VASOGRADE classification. The study included 175 patients (124 women) with aSAH. The median age at diagnosis was 55.4 years (range, 20.5-87.2 years). Clinical DCI occurred in 58 patients; 2 (1.1%) responded to hemodynamic augmentation, and 56 (32.0%) required intra-arterial therapy. Temperature graphs showed a marked divergence on day 4 between clinical DCI and non-DCI groups (1.12°C ± 0.15°C and 0.76°C ± 0.08°C, respectively, P= 0.007). Patients with temperature elevation ≥2.5°C on day 4 or 5 compared with their admission temperature were more likely to clinically deteriorate owing to DCI (odds ratio 4.55, 95% confidence interval 1.31-15.77, P= 0.017). Temperature elevation of ≥2.5°C on day 4 or 5 compared with baseline suggests a greater risk of clinical deterioration owing to DCI.

Abstract 65: Intrathecal Nicardipine for Cerebral Vasospasm Post Subarachnoid Hemorrhage - A Single Center Experience

Introduction: Cerebral vasospasm leading to delayed cerebral ischemia (DCI) is one of the most significant factors impacting functional outcome in patients diagnosed with non-traumatic subarachnoid hemorrhage (SAH). Effective treatment in this setting is lacking. We now report a single center retrospective cohort experience with intrathecal (IT) Nicardipine for this indication. Methods: All patients discharged between 2013-2017 diagnosed with non-traumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Demographics, risk factors, clinical courses, radiological DCI, and functional outcomes were analyzed. Results: 1,085 patients were admitted with aneurysmal (n=796) or idiopathic (n=289) SAH. The mean age was 54.5±14.1 and 67.7% were women. Low grade hemorrhage (WFNS 1) was found in 42.4%, medium (WFNS 2-3) in 26.9%, and high grade (WFNS 4-5) in 30.7%. Cerebral vasospasm was diagnosed in 36.6% of the patients, and 85.4% of those received IT Nicardipine (n=339). Only 8.4% of all patients required angiography to treat vasospasm. TCD data was available for 159 patients who received IT Nicardipine. Treatment reduced mean velocities in all arteries within one day by 15.4% on average (p<0.01). This reduction was sustained for the duration of treatment. Nineteen patients (1.8%) suffered from bacterial ventriculitis, and no statistically significant correlation was noted between IT treatment and infection (OR 1.06 95%CI[0.42-2.7]). The incidence of radiological DCI, identified by blinded assement of imaging, was 9.4% and clinical DCI was 5.7%. In this cohort, 65.5% had a favorable functional outcome (mRS≤2) at 90 days. Conclusions: In a retrospective analysis, off-label IT Nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent cerebral ischemia. Being the largest of its kind, this cohort could serve as a baseline for future clinical trial designs assessing IT Nicardipine safety and efficacy in a prospective, controlled fashion.

Burden of cerebral hypoperfusion in patients with delayed cerebral ischemia after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden. Sixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7-10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres. Twenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%-23%, vs 12%, 9%-16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049). The burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions.

Predictors of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage with Asymptomatic Angiographic Vasospasm on Admission

Risk of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) with asymptomatic angiographic vasospasm on admission is unclear in the literature. The goal of this study is to identify predictors of clinical DCI in this group of patients. An exploratory subgroup analysis was conducted in the SAHIT (Subarachnoid Hemorrhage International Trialists) data repository to identify predictors of clinical DCI in patients with good-grade aSAH (World Federation of Neurological Surgeons grade I and II) with angiographic vasospasm on admission. Predictors considered include age, sex, systolic blood pressure at presentation, World Federation of Neurological Surgeon grade, Fisher grade, aneurysm size and location, treatment modality, hydrocephalus requiring external ventricular drain insertion, and severity of vasospasm. The predictors were ranked based on dominance analysis with R2 as fit statistics and assessed in a set of logistic regression analysis models. Four data sets out of 16 studies in the SAHIT database were analyzed, with a total of 4125 patients. One hundred and ninety-one patients (4.6%) had asymptomatic angiographic vasospasm at admission. Of those, 78 patients (40.8%) developed clinical DCI. Univariate analysis showed significant associations between severe vasospasm on admission and development of clinical DCI (odds ratio, 9.5, 95% confidence interval, 2.07-43.50; P= 0.004). None of the studied predictors was associated with the development of clinical DCI on multivariate analysis. Asymptomatic angiographic vasospasm in patients with good-grade aSAH on admission is uncommon. Further studies are needed to identify high-risk patients for the development of DCI in the context of asymptomatic early vasospasm.

Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study.

Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62% with IQR -87 to -39%) compared to the control group (median +27% with IQR -32 to +104%, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95% CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI.

Effectiveness of diagnostic strategies in suspected delayed cerebral ischemia: a decision analysis.

Delayed cerebral ischemia (DCI) is a serious complication after aneurysmal subarachnoid hemorrhage. If DCI is suspected clinically, imaging methods designed to detect angiographic vasospasm or regional hypoperfusion are often used before instituting therapy. Uncertainty in the strength of the relationship between imaged vasospasm or perfusion deficits and DCI-related outcomes raises the question of whether imaging to select patients for therapy improves outcomes in clinical DCI. Decision analysis was performed using Markov models. Strategies were either to treat all patients immediately or to first undergo diagnostic testing by digital subtraction angiography or computed tomography angiography to assess for angiographic vasospasm, or computed tomography perfusion to assess for perfusion deficits. According to current practice guidelines, treatment consisted of induced hypertension. Outcomes were survival in terms of life-years and quality-adjusted life-years. When treatment was assumed to be ineffective in nonvasospasm patients, Treat All and digital subtraction angiography were equivalent strategies; when a moderate treatment effect was assumed in nonvasospasm patients, Treat All became the superior strategy. Treating all patients was also superior to selecting patients for treatment via computed tomography perfusion. One-way sensitivity analyses demonstrated that the models were robust; 2- and 3-way sensitivity analyses with variation of disease and treatment parameters reinforced dominance of the Treat All strategy. Imaging studies to test for the presence of angiographic vasospasm or perfusion deficits in patients with clinical DCI do not seem helpful in selecting which patients should undergo treatment and may not improve outcomes. Future directions include validating these results in prospective cohort studies.