PET imaging of unruptured intracranial aneurysm inflammation (PET-IA) study: a feasibility study protocol.

INTRODUCTION: Positron emission tomography (PET) imaging can be used to evaluate arterial wall inflammation in extracranial vascular diseases. However, the application of PET imaging in unruptured intracranial aneurysms (UIA) remains unexplored. Our objective is to investigate feasibility of PET imaging using 18F-FDG and 68Ga-DOTANOC tracers to evaluate arterial wall inflammation in UIA. METHODS AND ANALYSIS: This PET imaging feasibility study will enrol patients scheduled for surgical treatment of UIA. The study subjects will undergo PET imaging of the intracranial arteries within 1 month before planned surgery. The imaging protocol includes 18F-FDG PET MRI, MRA with gadolinium enhancement, and 68Ga-DOTANOC PET CT. The study will also involve preoperative blood samples, intraoperative cerebrospinal fluid (CSF) samples, and aneurysm sac biopsy. Planned sample size is at least 18 patients. Primary outcome is uptake of 18F-FDG or 68Ga-DOTANOC in intracranial arterial aneurysms compared with contralateral normal vessel as maximum standardised uptake value or target-to-blood pool ratio and correlation of uptake of 18F-FDG or 68Ga-DOTANOC to aneurysm histological findings. Secondary outcomes include estimating the correlations between uptake of 18F-FDG or 68Ga-DOTANOC and histological findings with blood and CSF miRNA-levels, arterial wall enhancement in gadolinium enhanced MRA, aneurysm size and shape, smoking, hypertension, and location of the aneurysm. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committee of the Hospital District of Southwest Finland, Finnish Medicines Agency Fimea, and Turku University Hospital. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04715503.

C-reactive protein as predictor for poor outcome after aneurysmal subarachnoid haemorrhage.

BACKGROUND: Aneurysmal subarachnoid haemorrhage (SAH) is a severe disease with high case-fatality and morbidity rates. After SAH, the value of C-reactive protein (CRP)--an acute phase sensitive inflammatory marker--as a prognostic factor has been poorly studied, with conflicting results. In this prospective study, we tested whether increased CRP levels increase independently the risk for cerebral infarct and poor outcome. METHODS: Previous diseases as well as clinical, laboratory and radiological variables were recorded for 178 patients with SAH admitted within 48 h and with aneurysms occluded within 60 h after bleeding. Plasma CRP was measured, as well as computed tomography (CT) scans routinely obtained on admission, in the morning after aneurysm occlusion, and at discharge during second week after SAH. Factors predicting occurrence of cerebral infarct and poor outcome at 3 months after SAH were tested with multiple logistic regression. RESULTS: CRP levels increased significantly (p < 0.001) between hospital admission (mean ± SD, 11.4 ± 21.3 mg/l) and the postoperative morning (27.0 ± 31.0 mg/l) and then decreased (p < 0.001) during the the second week (19.8 ± 25.0 mg/l). Admission (18.0 ± 35.7 vs 8.5 ± 8.4 mg/l) and postoperative (41.0 ± 40.2 vs 21.1 ± 24.1 mg/l) CRP levels were higher (p < 0.001) in those with a poor outcome than in those with a favourable outcome, but CRP values did not predict delayed cerebral ischaemia or cerebral infarction. CRP levels did not independently predict outcome, since these correlated with admission clinical grade and occurrence of intraventricular haemorrhage. Higher increase in CRP level between admission and postoperative morning, however, independently predicted poor outcome (p = 0.004). Part of this increased risk was likely due to an appearance of early postoperative cerebral infarction. CONCLUSIONS: CRP levels correlate with outcome but do not seem to predict delayed cerebral ischaemia or infarction after SAH.

Physical exertion as a risk factor for perimesencephalic nonaneurysmal subarachnoid hemorrhage.

BACKGROUND: Perimesencephalic and nonperimesencephalic nonaneurysmal subarachnoid hemorrhage (PM-naSAH and NPM-naSAH) have a different bleeding pattern and clinical course. The etiology and risk factors for PM-naSAH and NPM-naSAH are unclear. The objective of this study was to compare risk factors and triggering events between PM-naSAH and NPM-naSAH. METHODS: We reviewed retrospectively all patients (n = 3475) who had undergone cerebral digital subtraction angiography between 2003 and 2020 at our tertiary hospital. Of these, 119 patients had 6-vessel angiography negative subarachnoid hemorrhage (47 (39%) PM-naSAH and 72 (61%) NPM-naSAH) and accurate information about the triggering event was available in 42 (89%) PM-NASAH and 64 (89%) NPM-naSAH patients. RESULTS: PM-naSAH were younger compared to NPM-naSAH (mean age [SD]; 55.3 [11.1] years vs. 59.6 [12.2] years, p = .045. PM-naSAH was triggered during the physical exertion in 79% of patients and 16% of patients with NPM-naSAH (relative risk 5.4; 95% CI, 2.9-10.1, p < .0001). There were no significant difference in sex, smoking, alcohol abuse, hypertension, diabetes, hyperlipidemia, or anticoagulation/antithrombotic usage between PM-naSAH and NMP-naSAH, p > .05. CONCLUSION: Physical exertion was a triggering factor in most of the PM-naSAH cases and the risk was five times greater than in NMP-naSAH. More studies are needed to confirm our results and to study pathophysiology of PM-naSAH and NPM-naSAH.

Risk of Rupture After Intracranial Aneurysm Growth.

Importance: Unruptured intracranial aneurysms not undergoing preventive endovascular or neurosurgical treatment are often monitored radiologically to detect aneurysm growth, which is associated with an increase in risk of rupture. However, the absolute risk of aneurysm rupture after detection of growth remains unclear. Objective: To determine the absolute risk of rupture of an aneurysm after detection of growth during follow-up and to develop a prediction model for rupture. Design, Setting, and Participants: Individual patient data were obtained from 15 international cohorts. Patients 18 years and older who had follow-up imaging for at least 1 untreated unruptured intracranial aneurysm with growth detected at follow-up imaging and with 1 day or longer of follow-up after growth were included. Fusiform or arteriovenous malformation-related aneurysms were excluded. Of the 5166 eligible patients who had follow-up imaging for intracranial aneurysms, 4827 were excluded because no aneurysm growth was detected, and 27 were excluded because they had less than 1 day follow-up after detection of growth. Exposures: All included aneurysms had growth, defined as 1 mm or greater increase in 1 direction at follow-up imaging. Main Outcomes and Measures: The primary outcome was aneurysm rupture. The absolute risk of rupture was measured with the Kaplan-Meier estimate at 3 time points (6 months, 1 year, and 2 years) after initial growth. Cox proportional hazards regression was used to identify predictors of rupture after growth detection. Results: A total of 312 patients were included (223 [71%] were women; mean [SD] age, 61 [12] years) with 329 aneurysms with growth. During 864 aneurysm-years of follow-up, 25 (7.6%) of these aneurysms ruptured. The absolute risk of rupture after growth was 2.9% (95% CI, 0.9-4.9) at 6 months, 4.3% (95% CI, 1.9-6.7) at 1 year, and 6.0% (95% CI, 2.9-9.1) at 2 years. In multivariable analyses, predictors of rupture were size (7 mm or larger hazard ratio, 3.1; 95% CI, 1.4-7.2), shape (irregular hazard ratio, 2.9; 95% CI, 1.3-6.5), and site (middle cerebral artery hazard ratio, 3.6; 95% CI, 0.8-16.3; anterior cerebral artery, posterior communicating artery, or posterior circulation hazard ratio, 2.8; 95% CI, 0.6-13.0). In the triple-S (size, site, shape) prediction model, the 1-year risk of rupture ranged from 2.1% to 10.6%. Conclusion and Relevance: Within 1 year after growth detection, rupture occurred in approximately 1 of 25 aneurysms. The triple-S risk prediction model can be used to estimate absolute risk of rupture for the initial period after detection of growth.

External Validation of the ELAPSS Score for Prediction of Unruptured Intracranial Aneurysm Growth Risk.

Background and PURPOSE: Prediction of intracranial aneurysm growth risk can assist physicians in planning of follow-up imaging of conservatively managed unruptured intracranial aneurysms. We therefore aimed to externally validate the ELAPSS (Earlier subarachnoid hemorrhage, aneurysm Location, Age, Population, aneurysm Size and Shape) score for prediction of the risk of unruptured intracranial aneurysm growth. METHODS: From 11 international cohorts of patients ≥18 years with ≥1 unruptured intracranial aneurysm and ≥6 months of radiological follow-up, we collected data on the predictors of the ELAPSS score, and calculated 3- and 5-year absolute growth risks according to the score. Model performance was assessed in terms of calibration (predicted versus observed risk) and discrimination (c-statistic). RESULTS: We included 1,072 patients with a total of 1,452 aneurysms. During 4,268 aneurysm-years of follow-up, 199 (14%) aneurysms enlarged. Calibration was comparable to that of the development cohort with the overall observed risks within the range of the expected risks. The c-statistic was 0.69 (95% confidence interval [CI], 0.64 to 0.73) at 3 years, compared to 0.72 (95% CI, 0.68 to 0.76) in the development cohort. At 5 years, the c-statistic was 0.68 (95% CI, 0.64 to 0.72), compared to 0.72 (95% CI, 0.68 to 0.75) in the development cohort. CONCLUSION: s The ELAPSS score showed accurate calibration for 3- and 5-year risks of aneurysm growth and modest discrimination in our external validation cohort. This indicates that the score is externally valid and could assist patients and physicians in predicting growth of unruptured intracranial aneurysms and plan follow-up imaging accordingly.

Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and cerebral infarction after aneurysmal subarachnoid hemorrhage.

OBJECT: Stress-induced hyperglycemia has been shown to be associated with poor outcome after aneurysmal subarachnoid hemorrhage (SAH). The authors prospectively tested whether hyperglycemia, independent of other factors, affects patient outcomes and the occurrence of cerebral infarction after SAH. METHODS: Previous diseases, health habits, medications, clinical condition, and neuroimaging variables were recorded for 175 patients with SAH who were admitted to the hospital within 48 hours after bleeding. The plasma level of glucose was measured at admission and the fasting value of glucose was measured in the morning after aneurysm occlusion. Factors found to be independently predictive of patient outcomes at 3 months after SAH onset and the appearance of cerebral infarction were tested by performing multiple logistic regression. Plasma glucose values at admission were found to be associated with patient age, body mass index (BMI), history of hypertension, clinical condition, amount of subarachnoid or intraventricular blood, shunt-dependent hydrocephalus, outcome variables, and the appearance of cerebral infarction. When considered independently of age, clinical condition, or amount of subarachnoid, intraventricular, or intracerebral blood, the plasma glucose values at admission predicted poor outcome (per millimole/liter the odds ratio [OR] was 1.24 with a 95% confidence interval [CI] of 1.02-1.51). After an adjustment was made for the amount of subarachnoid blood, the clinical condition, and the duration of temporary artery occlusion during surgery, the BMI was found to be a significant predictor (per kilogram/square meter the OR was 1.15 with a 95% CI of 1.02-1.29) for the finding of cerebral infarction on the follow-up computerized tomography scan. Hypertension (OR 3.11, 95% CI 1.11-8.73)--but not plasma glucose (OR 1.06, 95% CI 0.87-1.29)--also predicted the occurrence of infarction when tested instead of the BMI. CONCLUSIONS: Independent of the severity of bleeding, hyperglycemia at admission seems to impair outcome, and excess weight and hypertension appear to elevate the risk of cerebral infarction after SAH.

Diazepam does not reduce infarct size in rats subjected to transient occlusion of the middle cerebral artery when normothermia is maintained.

Activation of the gamma-amino butyric acid (GABA)-ergic system might protect against the damage that occurs after cerebral ischaemia. We examined this hypothesis by administering diazepam to rats subjected to transient middle cerebral artery occlusion (MCAO) using the intraluminal thread method. Diffusion MRI (DWI) and perfusion imaging (PI) were acquired during MCAO to assess brain tissue status and haemodynamics, respectively. Rats were intraperitoneally injected with either 10 mg kg(-1) diazepam (n = 5) or vehicle (n = 5) both 30 min and 90 min after the onset of MCAO. To exclude the possibility that neuroprotection was due to the hypothermic action of the drug, body temperature was maintained at 37-38 degrees C for up to 7 h postischaemia with a feed-back controlled thermoregulatory unit. Infarct volumes quantified 2 days after MCAO from T(2)-weighted images were similar in ischaemic control rats and in ischaemic rats treated with diazepam. We conclude that diazepam-induced enhancement of GABA(A) activity does not effectively protect against neuronal damage that occurs after transient MCAO in normothermic rats.