Introduction: The inflammatory response after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischemia, and poor functional outcome. In experimental SAH studies, complement C5 antibodies administered shortly after SAH reduced brain injury with approximately 40%. We investigated the pharmacodynamic efficacy and safety of eculizumab (a complement C5 antibody) in aSAH patients. Methods: We conducted a randomized, controlled, open-label, phase II clinical trial with blinded outcome assessment in the Netherlands. Patients were randomized (1:1) to receive eculizumab plus standard care or to standard care alone. Eculizumab (1200 mg) was administered intravenously < 12 h, on day 3 and on day 7 after ictus. Patients in the intervention group received prophylactic antibiotics for 4 weeks and prophylactic antifungal therapy if the patient had a central line or an external ventricular shunt and a positive fungal or yeast culture. The primary outcome was C5a concentration in the cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes included the occurrence of adverse events, eculizumab concentration and inflammatory parameters in the blood and CSF, cerebral infarction on magnetic resonance imaging, and clinical and cognitive outcomes. We aimed to evaluate 26 patients with CSF assessments, 13 in the intervention group and 13 in the comparator group. Results: A total of 31 patients have been included, of which 26 with CSF samples. Conclusions: Final results will be presented at the conference. Trial registration: Netherlands Trial Register: NTR6752. European Clinical Trials Database (EudraCT): 2017-004307-51.
To describe the short and long term results of neurological second opinions with regard to medical aspects and patient satisfaction. Prospective observational cohort study Data regarding medical relevance and patient satisfaction were collected for all patients referred to the neurological out-patient clinic for a second opinion over a period of 6 months. Treating neurologists were asked to fill out a questionnaire to assess the medical relevance of the consultation. Patient satisfaction was assessed using the 'Patient Satisfaction Questionnaire' which was filled out by the patient directly after the consultation and after 2 years follow-up. 183 patients were included during the study period and 78 of these patients returned the follow-up questionnaire. A neurological second opinion led to a different diagnosis in 66 patients (33%). For 42 patients (23%) the new diagnosis had treatment implications. Second opinions were nevertheless considered of low medical relevance by the treating neurologist; the psychological relevance was considered higher. Second opinions led to a short-term increase in patient satisfaction, but after 2 years satisfaction had decreased to the level seen prior to the second opinion. Only 7% of patients indicated their intention to visit another healthcare provider for the same problem directly following the consultation, whereas 2 years later it was found that 30% had done so. The benefit of second opinion consultations at an academic neurology out-patient clinic was reasonable in the short term, but limited in the long term
Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol (P<0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH.
Rationale Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth. Aim To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device). Sample size We aim to randomize 776 patients 1:1 to the intervention arm or care as usual. Design Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment. Outcomes The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by ≥ 1 mm) on repeated MR or CT angiography within 36 ± 6 months after randomization. Discussion The Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541.
We thank Dr Darsaut et al 1 for their attention paid to the PHASES score and for sharing their thinking in an opinion paper 2 years after the publication of our article.2 The authors discuss whether or not prediction modeling based on data from previous observational studies is science. Their final conclusion is that the only valid way to decide whether or not unruptured aneurysms should be treated is to compare outcomes in patients eligible for both options (ie, aneurysm occlusion …
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The natural history and optimal treatment of extracranial carotid artery aneurysms are unknown. Gadolinium enhancement of the aneurysm wall may reflect aneurysm wall inflammation and instability. In this study, we investigated the feasibility of extracranial carotid artery aneurysm wall imaging and explored a potential relationship of aneurysm wall enhancement with aneurysm growth and the presence of (silent) brain infarcts and white matter lesions.
MATERIALS AND METHODS:
Fourteen conservatively treated patients with 15 asymptomatic extracranial carotid artery aneurysms underwent gadolinium-enhanced 3T MR imaging at 2 time points with a 12-month interval. Primary outcome was growth of the aneurysm sac (≥2.0 mm); secondary outcomes were the presence of (silent) brain infarcts and white matter lesions at baseline and follow-up. MR images were reviewed by 2 independent observers, and inter- and intraobserver reproducibility was assessed.
RESULTS:
Seven (50%) patients were men; the median age was 55 years (range, 40–69 years). Eleven extracranial carotid artery aneurysms (73%) were saccular (median size, 11 mm; range, 5.0–38.5 mm), and 4 were fusiform (median size, 21.5 mm; range, 10.0–40.0 mm). Eleven of 15 aneurysms (73%) exhibited gadolinium enhancement at baseline. Four aneurysms (27%) showed growth at follow-up imaging, 2 gadolinium-positive (+) and 2 gadolinium-negative (–) (P = .245). Three patients (21%) had ipsilateral brain infarcts at baseline; 1 of them showed a new silent brain infarct at follow-up imaging (gadolinium+). Nine patients (64%) showed bilateral white matter lesions at baseline. In 3 patients, increased white matter lesion severity was observed at follow-up (2 gadolinium+). All observations showed excellent inter- and intraobserver reproducibility.
CONCLUSIONS:
In this explorative study, we demonstrated that extracranial carotid artery aneurysm wall imaging was feasible. Future well-powered studies are needed to investigate whether extracranial carotid artery aneurysm gadolinium enhancement predicts aneurysm growth and thromboembolic complications.
Delayed cerebral ischemia (DCI) is a major contributor to the high morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarizations may play a role in DCI pathophysiology. Because patients with migraine are probably more susceptible to spreading depolarizations, we investigated whether patients with aneurysmal subarachnoid hemorrhage with migraine are at increased risk for DCI.We included patients with aneurysmal subarachnoid hemorrhage from 3 hospitals in the Netherlands. We assessed lifetime migraine history with a short screener. DCI was defined as neurological deterioration lasting >1 hour not attributable to other causes by diagnostic work-up. Adjustments were made for possible confounders in multivariable Cox regression analyses and adjusted hazard ratios (aHR) were calculated. We assessed the interaction effects of age and sex.We included 582 patients (mean age 57 years, 71% women) mostly with mild to moderate aneurysmal subarachnoid hemorrhage of whom 108 (19%) had a history of migraine (57 with aura). Patients with migraine were not at increased risk of developing DCI compared with patients without migraine (22% versus 24%, aHR, 0.89 [95% CI, 0.56-1.43]). Additionally, no increased risk was found in patients with migraine with possible aura (aHR, 0.74 [95% CI, 0.39-1.43]), in women (aHR, 0.88 [95% CI, 0.53-1.45], Pinteraction=0.859), or in young patients aged <50 years (aHR, 1.59 [95% CI, 0.72-3.49]), although numbers in these subgroups were limited. We found an interaction between migraine and age with an increased risk of DCI among young patients with migraine (Pinteraction=0.075).Patients with migraine are in general not at increased risk of DCI. Future studies should focus in particular on young SAH patients, in whom there might be an association between migraine history and development of DCI.
Background Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. Aims To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007–2014. Hospitals were categorized by annual case-volume (low volume: <41/year; intermediate: 41–70/year; high: >70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. Results We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high-volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2–11.7%), for intermediate volume 7.0% (95% CI 6.2–7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47–0.85)) and for high volume 5.4% (95% CI 4.6–6.3%; adjusted OR 0.50 (95% CI 0.33–0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30–0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25–0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55–1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36–0.87) with high case-volume. Conclusions Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers.
Abstract BACKGROUND Seizure is a significant complication in patients under acute admission for aneurysmal SAH and could result in poor outcomes. Treatment strategies to optimize management will benefit from methods to better identify at-risk patients. OBJECTIVE To develop and validate a risk score for convulsive seizure during acute admission for SAH. METHODS A risk score was developed in 1500 patients from a single tertiary hospital and externally validated in 852 patients. Candidate predictors were identified by systematic review of the literature and were included in a backward stepwise logistic regression model with in-hospital seizure as a dependent variable. The risk score was assessed for discrimination using the area under the receiver operator characteristics curve (AUC) and for calibration using a goodness-of-fit test. RESULTS The SAFARI score, based on 4 items (age ≥ 60 yr, seizure occurrence before hospitalization, ruptured aneurysm in the anterior circulation, and hydrocephalus requiring cerebrospinal fluid diversion), had AUC = 0.77, 95% confidence interval (CI): 0.73-0.82 in the development cohort. The validation cohort had AUC = 0.65, 95% CI 0.56-0.73. A calibrated increase in the risk of seizure was noted with increasing SAFARI score points. CONCLUSION The SAFARI score is a simple tool that adequately stratified SAH patients according to their risk for seizure using a few readily derived predictor items. It may contribute to a more individualized management of seizure following SAH.
