Return to work after aneurysmal subarachnoid hemorrhage.

Introduction: Survivors of aneurysmal subarachnoid hemorrhage (aSAH) often recover without severe physical or cognitive deficits. However, strikingly low levels of engagement in productive employment have also been reported in aSAH patients with good or excellent outcomes. Knowledge about return to work (RTW) after aSAH and predictors of no RTW remain limited and controversial. The study aimed to delineate the return to maximum work capacity up to 5 years after the ictus in a larger number of consecutive aSAH patients from the entire aSAH severity spectrum and to identify demographic and medical predictors of no RTW. Methods: Data were acquired from a prospective institutional database. We included all 500 aSAH survivors aged > 18 years who were treated between January 2012 and March 2018. In addition to gathering data on work status and the type of work at ictus, we retrieved demographical data and assessed aSAH severity based on the quantification of subarachnoid, intraventricular, and intraparenchymal blood (ICH), as well as the World Federation of Neurological Societies (WFNS) grade. We registered the mode of aneurysm repair (endovascular or surgical) and recorded complications such as vasospasm, newly acquired cerebral infarctions, and chronic hydrocephalus. Results: Furthermore, work status and the grade of fatigue at follow-up were registered. RTW was assessed among 299 patients who were employed at ictus. Among them, 63.2% were women, and their age was 51.3 ± 9.4 (20-71) years. Return to gainful employment was 51.2%, with complete RTW accounting for 32.4%. The independent predictors of no RTW at ictus were age, the WFNS grade 3, and active smoking. The strongest independent predictor was the presence of clinically significant fatigue, which increased the risk of not returning to work by 5-fold. The chance to return to gainful employment significantly increased with the individual's years of education prior to their hemorrhage. The mode of aneurysm repair was not relevant with regard to RTW. Patients in the WFNS grades 1-2 more often returned to work than those in the WFNS grades 3-5, but our results indicate that neurological motor deficits are linked closer to no RTW than aSAH severity per se. Conclusion: Fatigue needs to be addressed as an important element on the path to return to work integration.

Appropriate treatment within 13 hours after onset may improve outcome in patients with high-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE: This retrospective study evaluated whether earlier timing of appropriate treatment of high-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as management of ruptured intracranial aneurysm (RIA) combined with required additional surgical measures for control of increased intracranial pressure (ICP), is associated with more favorable outcomes. METHODS: The study cohort comprised 253 patients with high-grade aSAH. Modified Rankin Scale score of 0-3 at 3-month follow-up after the ictus was considered as favorable outcome. RESULTS: Appropriate treatment of aSAH was completed in 205 patients (81 %), and included clipping or coiling of RIA without (64 cases) and with (141 cases) additional surgical measures for control of increased ICP (evacuation of intracranial hematoma, decompressive craniotomy, and/or cerebrospinal fluid drainage). Favorable outcome was noted significantly more often if appropriate treatment was completed within 13 h after aSAH than between 13 and 72 h (37 % vs. 17 %; adjusted P = 0.0475), which was confirmed by evaluation in the multivariate model along with other prognostic factors. Subgroup analysis revealed that completion of the appropriate treatment within 13 h was associated with more favorable outcome in those patients, who underwent management of RIA in combination with additional surgical measures for control of increased ICP (P = 0.0023), and in those, who felt into poor outcome predicting group (P = 0.0046). CONCLUSIONS: Appropriate treatment of high-grade aSAH with management of RIA in combination with required additional surgical measures for control of increased ICP, may be associated with more favorable outcomes if completed within 13 h after the ictus.

Fulminant Extra- And Intracranial Arteriovenous Thrombosis And Non-aneurysmal Subarachnoid Hemorrhage Following COVID-19 Infection.

PURPOSE: Coronavirus disease of 2019 (COVID-19) is associated with increased risk of stroke and intracranial hemorrhage. This first report of fulminant panvascular arteriovenous thrombosis with subarachnoid hemorrhage (SAH) in a post-COVID-19 infection is attributed to extensive arteriovenous inflammation leading to arterial rupture following vasculitis. CASE REPORT: We report a rare case of extensive extra- and intra-cranial cerebral arteriovenous thrombosis following COVID-19 infection, presenting as fatal non-aneurysmal subarachnoid hemorrhage. The clinical course, biochemical and radiological evaluation is discussed. The other possible etiological differentials which were analysed and ruled out during case management are also detailed. CONCLUSION: A high degree of suspicion for COVID-19 induced coagulopathy leading to extensive non- aneurysmal, non-hemispheric SAH and malignant intracranial hypertension should be entertained. Our experience and previous reports on non-aneurysmal SAH in such patients show a poor prognosis.

Systemic Inflammatory Response in Spontaneous Subarachnoid Hemorrhage from Aneurysmal Rupture versus Subarachnoid Hemorrhage of Unknown Origin.

Objective: It is well known that spontaneous non-aneurysmal subarachnoid hemorrhage (SAH), also known as sine materia SAH (smSAH), has usually a better course and prognosis than its aneurysmal counterpart (aSAH). This might depend on different inflammatory mechanisms initiated by bleeding events of different origins. The aim of the present study was to explore the systemic inflammatory response in spontaneous SAH, comparing aSAH and smSAH. Methods: We performed a prospective observational study over a consecutive series of patients with SAH. For these patients, we collected all clinical data and, furthermore, performed venous blood sampling over six time points to analyze blood cells. We further performed the analysis of lymphocytes and monocytes by means of flow cytometry to quantify common subtypes. Statistical analysis included a t-student test, Chi-square test, multivariate logistic regression, and ROC analysis. Results: 48 patients were included: six (12.5%) with a diagnosis of spontaneous smSAH, and forty-two patients (87.5%) with aSAH. Significant differences on Day 0 were found for neutrophils and a systemic neuro-inflammatory index, namely, systemic inflammatory response index (SIRI). At the ROC analysis, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and SIRI exhibited satisfactory predictive power on day 0. At the multivariable logistic regression analysis, the combined index (NLR, LMR, SIRI at day 0) yielded an OR of 0.59 (95% CI 0.29-1.21]). LMR at day 0 yielded an OR of 1.25 ([95% CI 0.94-1.68]), NLR at day 0 exhibited an OR of 0.68 ([95% CI 0.42-1.09]), and SIRI at day 0 displayed an OR of 0.31 ([95% CI 0.06-1.49]). Conclusion: This preliminary study indicated a possible role of some inflammatory indices that point out the importance of innate and adaptive immunity in the etiopathogenetic mechanisms. Drugs modulating these responses could eventually counteract or, at least, reduce secondary damage associated with SAH.

Near Infrared Spectroscopy for Poor Grade Aneurysmal Subarachnoid Hemorrhage-A Concise Review.

Delayed cerebral ischemia (DCI) disproportionately affects poor grade aneurysmal subarachnoid hemorrhage (aSAH) patients. An unreliable neurological exam and the lack of appropriate monitoring leads to unrecognized DCI, which in turn is associated with severe long-term deficits and higher mortality. Near Infrared Spectroscopy (NIRS) offers simple, continuous, real time, non-invasive cerebral monitoring. It provides regional cerebral oxygen saturation (c-rSO2), which reflects the balance between cerebral oxygen consumption and supply. Reports have demonstrated a good correlation with other cerebral oxygen and blood flow monitoring, and credible cerebrovascular reactivity indices were also derived from NIRS signals. Multiple critical c-rSO2 values have been reported in aSAH patients, based on various thresholds, duration, variation from baseline or cerebrovascular reactivity indices. Some were associated with vasospasm, some with DCI and others with clinical outcomes. However, the poor grade aSAH population has not been specifically studied and no randomized clinical trial has been published. The available literature does not support a specific NIRS-based intervention threshold to guide diagnostic or treatment in aSAH patients. We review herein the fundamental basic concepts behind NIRS technology, relationship of c-rSO2 to other brain monitoring values and their potential clinical interpretation. We follow with a critical evaluation of the use of NIRS in the aSAH population, more specifically its ability to diagnose vasospasm, to predict DCI and its association to outcome. In summary, NIRS might offer significant potential for poor grade aSAH in the future. However, current evidence does not support its use in clinical decision-making, and proper technology evaluation is required.

Non-aneurysmal subarachnoid hemorrhage: Is the deep venous system the hidden culprit?

AIM: The exact cause of bleeding in non-aneurysmal sub-arachnoid hemorrhage (SAH) is yet to be established. The present study intends to evaluate the morphological variants of deep cerebral venous drainage, especially basal veins of Rosenthal (BVR), and to correlate if such a venous anomaly is associated with increased incidence of non-aneurysmal SAH. METHODS: A prospective analysis of all the patients of age more than 12 years with spontaneous non-aneurysmal SAH and undergone 4-vessel DSA for the diagnosis of the source of bleeding was included in the study (n = 59). The anatomy of the basal venous distribution was evaluated and was divided into 3 different types, namely normal (Type A), normal variant (Type B), and primitive (Type C), based on DSA findings. The follow-up of these cases was noted. The three groups were compared with one another. RESULTS: The median age of presentation was 51 years with slight male predominance (52%). Primitive venous drainage was associated with a poorer grade at presentation (p = 0.002), more severe bleed (p = 0.001), vasospasm (p = 0.045), and a poorer outcome at 6 months (p = 0.019). Hydrocephalous and vasospasm were seen in patients with primitive venous drainage. On multivariate regression analysis for poorer outcome, it was observed that a worse grade at presentation, extensive bleed, primitive venous drainage are independent predictors of an adverse outcome. CONCLUSION: The presence of primitive venous drainage has a linear relationship with the development of non-aneurysmal SAH with multi-cisternal hemorrhage, worse grade at presentation, and unfavorable outcome.

External Cerebrospinal Fluid Drainage in the Management of Nonaneurysmal Subarachnoid Hemorrhage.

Distinguishing the aneurysmal from nonaneurysmal subarachnoid hemorrhage (SAH) may be difficult as acute bleeding in the subarachnoid space is a common denominator. It is believed that toxic effects of breakdown products of acute bleed, including hemoglobin, contribute to the morbidity and mortality of this condition; and that early drainage will potentially reduce them. This series focuses on our local experience with the application of external cerebrospinal fluid (CSF) drainage in the management of a series of cases confirmed to be nonaneurysmal SAH and its effects on the outcome. The objective of this report is to observe the usefulness of external CSF drainage in the management of nonaneurysmal SAH. Five consecutive cases over four years were reviewed and reported as a case series. The main points we focused on were presentation, diagnostic findings on imaging, CSF drainage, and outcome up to six months. All the patients presented with headaches described as sudden, and only one had significant impairment of consciousness Glasgow Coma Scale (GCS) 10/15. Three out of the five patients had a premorbid hypertensive condition of unclear control status. We also observed that three out of the five had a low-pressure pretruncal/perimesencephalic pattern of bleed, whereas two had the typical high-pressure SAH pattern. CT angiography (CTA) was negative in all. Four had lumbar drainage, while one had external ventricular drainage. All were discharged within three weeks and functioned optimally at six months. CSF drainage in managing nonaneurysmal SAH is achievable with minimal access procedures, including lumbar drain (LD) and external ventricular drainage (EVD), which may have further reduced the low morbidity normally associated with this condition.

Factors Affecting Time to Emergence From General Anesthesia Following Clipping of Ruptured Aneurysms: A Prospective Observational Study.

INTRODUCTION: Early emergence from anesthesia is valuable, especially among neurosurgical patients for postoperative neurological evaluation and appropriate interventions. However, the factors affecting the emergence in patients undergoing clipping of ruptured aneurysms have not been studied. MATERIALS AND METHODS: This was a prospective observational study on patients of aneurysmal subarachnoid hemorrhage with World Federation of Neurological Surgeons (WFNS) Grades I to III, undergoing surgical clipping. All relevant preoperative and intraoperative details were collected and analyzed to assess the factors affecting emergence time. RESULTS: A total of 67 patients with a median age of 46 years were included in the study. The number of patients with Fisher Grades I, II, III, and IV was 6, 20, 25, and 16, respectively. The median time to emergence was 17 minutes (interquartile range 10-240 minutes). On univariate analysis, the factors that were found to have a significant relationship with time to emergence were preoperative Glasgow Coma Score (GCS; P = 0.02), WFNS grade (P = 0.005, temporary clipping time (P = 0.03), and the temperature at the end of surgery (P < 0.001) In the multivariate analysis using generalized linear model, preinduction GCS (P < 0.001), patient's temperature at the end of surgery (P < 0.001), and temporary clipping time (P = 0.01) had a significant impact on the emergence time, independent of age, American Society of Anesthesiologists grade, Fisher grade, duration of anesthesia and of each other, with GCS and temperature having the maximum impact. ROC curve for temperature had a cutoff value at 35.3°C with an 83% probability of awakening beyond 15 minutes if the temperature decreased below 35.3°C. CONCLUSION: The preinduction GCS, the temperature of patients at the end of surgery, and the duration of temporary clipping have a significant independent impact on the time to emergence from neurosurgical anesthesia, in the order of the strength of the association.

Long-Term Medical Resource Consumption between Surgical Clipping and Endovascular Coiling for Aneurysmal Subarachnoid Hemorrhage: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

PURPOSE: To estimate long-term medical resource consumption in patients with subarachnoid aneurysmal hemorrhage (SAH) receiving surgical clipping or endovascular coiling. PATIENTS AND METHODS: From Taiwan's National Health Insurance Research Database, we enrolled patients with aneurysmal SAH who received clipping or coiling. After propensity score matching and adjustment for confounders, a generalized linear mixed model was used to determine significant differences in the accumulative hospital stay (days), intensive care unit (ICU) stay, and total medical cost for aneurysmal SAH, as well as possible subsequent surgical complications and recurrence. RESULTS: The matching process yielded a final cohort of 8102 patients (4051 and 4051 in endovascular coil embolization and surgical clipping, respectively) who were eligible for further analysis. The mean accumulative hospital stay significantly differed between coiling (31.2 days) and clipping (46.8 days; p < 0.0001). After the generalized linear model adjustment of gamma distribution with a log link, compared with the surgical clipping procedure, the adjusted odds ratios (aOR; 95% confidence interval [CI]) of the medical cost of accumulative hospital stay for the endovascular coil embolization procedure was 0.63 (0.60, 0.66; p < 0·0001). The mean accumulative ICU stay significantly differed between the coiling and clipping groups (9.4 vs. 14.9 days; p < 0.0001). The aORs (95% CI) of the medical cost of accumulative ICU stay in the endovascular coil embolization group was 0.61 (0.58, 0.64; p < 0.0001). The aOR (95% CI) of the total medical cost of index hospitalization in the endovascular coil embolization group was 0·85 (0.82, 0.87; p < 0.0001). CONCLUSIONS: Medical resource consumption in the coiling group was lower than that in the clipping group.

Statins Improve Clinical Outcome After Non-aneurysmal Subarachnoid Hemorrhage: A Translational Insight From a Systematic Review of Experimental Studies.

The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.

Urea-Creatinine Ratio (UCR) After Aneurysmal Subarachnoid Hemorrhage: Association of Protein Catabolism with Complication Rate and Outcome.

OBJECTIVE: The urea-creatinine ratio (UCR) has been proposed as potential biomarker for critical illness-associated catabolism. Its role in the context of aneurysmal subarachnoid hemorrhage (aSAH) remains to be elucidated, which was the aim of the present study. METHODS: We enrolled 66 patients with aSAH with normal renal function and 36 patients undergoing elective cardiac surgery as a control group for the effects of surgery. In patients with aSAH, the predictive or diagnostic value of early (day 0-2) and critical (day 5-7) UCRs was assessed with regard to delayed cerebral ischemia (DCI), DCI-related infarction, and clinical outcome after 12 months. RESULTS: Preoperatively, UCR was similar both groups. Within 2 days postoperatively, UCRs increased significantly in patients in the elective cardiac surgery group (P < 0.001) but decreased back to baseline on day 5-7 (P = 0.245), whereas UCRs in patients with aSAH increased to significantly greater levels on day 5-7 (P = 0.028). Greater early or critical UCRs were associated with poor clinical outcomes (P = 0.015) or DCI (P = 0.011), DCI-related infarction (P = 0.006), and poor clinical outcomes (P < 0.001) respectively. In multivariate analysis, there was an independent association between greater early UCRs and poor clinical outcomes (P = 0.026). CONCLUSIONS: In this exploratory study of UCR in the context of aSAH, greater early values were predictive for a poor clinical outcome after 12 months, whereas greater critical values were associated with DCI, DCI-related infarctions, and poor clinical outcomes. The clinical implications as well as the pathophysiologic relevance of protein catabolism should be explored further in the context of aSAH.

Circulatory dipeptidyl peptidase 3 (cDPP3) is a potential biomarker for early detection of secondary brain injury after aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) that can culminate in secondary brain damage. Although it remains one of the main preventable causes of aSAH-related morbidity, there is still a lack of prognostic criteria for identification of patients at risk of developing DCI. Because elevated circulatory levels of the enzyme dipeptidyl peptidase 3 (cDPP3) were recently identified as a potential biomarker for outcome prediction in critically ill patients, we evaluated the time-course of changes in cDPP3 levels after aSAH. MATERIALS AND METHODS: cDPP3 levels were quantified in serum obtained from 96 confirmed aSAH patients during the early (EP: d1-4), critical (CP: d5-8, d9-12, d13-15) and late (LP: d16-21) phase after aSAH onset. Associations between cDPP3 levels and demographic or clinical parameters were evaluated. The relations between cDPP3 levels and DCI, DCI-related infarctions and long-term clinical outcomes were examined by receiver operating characteristics (ROC) curve analysis and multivariate logistic regression. RESULTS: Significantly higher cDPP3 levels during CP (d5-8, d9-12, d13-15) were observed in patients with poor clinical (p < 0.001 to p = 0.033) or radiological (p = 0.012 to p = 0.039) status on admission, DCI (p < 0.001 to p = 0.001), DCI-related infarctions (p = 0.002 to p = 0.007), and poorer long-term outcome (p = 0.007 to p = 0.019). ROC curve analysis indicated that higher cDPP3 levels on d5-8 are predictive for a poor clinical outcome (area under the curve = 0.677, p = 0.007). In multivariate analysis, there was an independent association between cDPP3 levels on d5-8 and development of DCI-related infarctions (p = 0.038). CONCLUSION: Our results provide first evidence that cDPP3 could serve as a promising biomarker for early diagnosis of DCI-related infarctions in poor grade aSAH patients.

Computed tomography perfusion imaging after aneurysmal subarachnoid hemorrhage can detect cerebral vasospasm and predict delayed cerebral ischemia after endovascular treatment.

BACKGROUND: Endovascular treatment (ET) can improve angiographic cerebral vasospasm (CV) after aneurysmal subarachnoid hemorrhage, but was unrelated to clinical outcomes in previous analyses. Appropriate detection of CV and precise indications for ET are required. This study investigated whether changes in computed tomography perfusion (CTP) parameter can determine indications for ET in CV and predict its effectiveness. METHODS: Participants comprised 140 patients who underwent neck clipping or coil embolization. CTP was performed a week after aneurysmal treatment or when clinical deterioration had occurred. Patients were divided into ET and non-ET groups by propensity score matching. In addition, the ET group was divided into subgroups with and without new cerebral infarction (CI). All CTP images in the three groups were retrospectively investigated qualitatively and quantitatively. CI was diagnosed from CT at 3 months postoperatively. RESULTS: Of the 121 patients examined, 15 patients (11%) needed ET. In qualitative analysis, all ET group patients displayed extension of time-to-peak (TTP) at the region of vasospastic change, regardless of the presence of CI. Quantitative analysis showed significant decreases in cerebral blood volume (P < 0.01), cerebral blood flow (CBF) (P < 0.001), and extension in TTP (P < 0.01) in the ET group compared with the non-ET group. A significant decrease in CBF (P < 0.001) and extension in mean transit time (P < 0.001) was seen in the ET with CI subgroup compared with the ET without CI subgroup. CONCLUSION: CTP in the vasospastic period may be an indication for ET and predict the effectiveness of ET for CV to improve clinical outcomes.

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD). METHODS: In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule. RESULTS: Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2. CONCLUSIONS: Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.

A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH. METHODS: In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH. RESULTS: Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm. CONCLUSIONS: The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov).

Plea for an international Aneurysm Data Bank: description and perspectives.

The disease resulting in the formation, growth, and rupture of intracranial aneurysms is complex. Research is accumulating evidence that the disease is driven by many different factors, some constant and others variable over time. Combinations of factors may induce specific biophysical reactions at different stages of the disease. A better understanding of the biophysical mechanisms responsible for the disease initiation and progression is essential to predict the natural history of the disease. More accurate predictions are mandatory to adequately balance risks between observation and intervention at the individual level as expected in the age of personalized medicine. Multidisciplinary exploration of the disease also opens an avenue to the discovery of possible preventive actions or medical treatments. Modern information technologies and data processing methods offer tools to address such complex challenges requiring 1) the collection of a high volume of information provided globally, 2) integration and harmonization of the information, and 3) management of data sharing with a broad spectrum of stakeholders.Over the last decade an infrastructure has been set up and is now made available to the academic community to support and promote exploration of intracranial disease, modeling, and clinical management simulation and monitoring.The background and purpose of the infrastructure is reviewed. The infrastructure data flow architecture is presented. The basic concepts of disease modeling that oriented the design of the core information model are explained. Disease phases, milestones, cases stratification group in each phase, key relevant factors, and outcomes are defined. Data processing and disease model visualization tools are presented. Most relevant contributions to the literature resulting from the exploitation of the infrastructure are reviewed, and future perspectives are discussed.

Role of pregnancy and female sex steroids on aneurysm formation, growth, and rupture: a systematic review of the literature.

OBJECTIVE: Women have been shown to have a higher risk of cerebral aneurysm formation, growth, and rupture than men. The authors present a review of the recently published neurosurgical literature that studies the role of pregnancy and female sex steroids, to provide a conceptual framework with which to understand the various risk factors associated with cerebral aneurysms in women at different stages in their lives. METHODS: The PubMed database was searched for "("intracranial" OR "cerebral") AND "aneurysm" AND ("pregnancy" OR "estrogen" OR "progesterone")" between January 1980 and February 2019. A total of 392 articles were initially identified, and after applying inclusion and exclusion criteria, 20 papers were selected for review and analysis. These papers were then divided into two categories: 1) epidemiological studies about the formation, growth, rupture, and management of cerebral aneurysms in pregnancy; and 2) investigations on female sex steroids and cerebral aneurysms (animal studies and epidemiological studies). RESULTS: The 20 articles presented in this study include 7 epidemiological articles on pregnancy and cerebral aneurysms, 3 articles reporting case series of cerebral aneurysms treated by endovascular therapies in pregnancy, 3 epidemiological articles reporting the relationship between female sex steroids and cerebral aneurysms through retrospective case-control studies, and 7 experimental studies using animal and/or cell models to understand the relationship between female sex steroids and cerebral aneurysms. The studies in this review report similar risk of aneurysm rupture in pregnant women compared to the general population. Most ruptured aneurysms in pregnancy occur during the 3rd trimester, and most pregnant women who present with cerebral aneurysm have caesarean section deliveries. Endovascular treatment of cerebral aneurysms in pregnancy is shown to provide a new and safe form of therapy for these cases. Epidemiological studies of postmenopausal women show that estrogen hormone therapy and later age at menopause are associated with a lower risk of cerebral aneurysm than in matched controls. Experimental studies in animal models corroborate this epidemiological finding; estrogen deficiency causes endothelial dysfunction and inflammation, which may predispose to the formation and rupture of cerebral aneurysms, while exogenous estrogen treatment in this population may lower this risk. CONCLUSIONS: The aim of this work is to equip the neurosurgical and obstetrical/gynecological readership with the tools to better understand, critique, and apply findings from research on sex differences in cerebral aneurysms.

Quantitative versus qualitative blood amount assessment as a predictor for shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Reliable tools are lacking to predict shunt-dependent hydrocephalus (SDHC) development after aneurysmal subarachnoid hemorrhage (aSAH). Quantitative volumetric measurement of hemorrhagic blood is a good predictor of SDHC but might be impractical in the clinical setting. Qualitative assessment performed using scales such as the modified Fisher scale (mFisher) and the original Graeb scale (oGraeb) is easier to conduct but provides limited predictive power. In between, the modified Graeb scale (mGraeb) keeps the simplicity of the qualitative scales yet adds assessment of acute hydrocephalus, which might improve SDHC-predicting capabilities. In this study the authors investigated the likely capabilities of the mGraeb and compared them with previously validated methods. This research also aimed to define a tailored mGraeb cutoff point for SDHC prediction. METHODS: The authors performed retrospective analysis of patients admitted to their institution with the diagnosis of aSAH between May 2013 and April 2016. Out of 168 patients, 78 were included for analysis after the application of predefined exclusion criteria. Univariate and multivariate analyses were conducted to evaluate the use of all 4 methods (quantitative volumetric assessment and the mFisher, oGraeb, and mGraeb scales) to predict the likelihood of SDHC development based on clinical data and blood amount assessment on initial CT scans. RESULTS: The mGraeb scale was demonstrated to be the most robust predictor of SDHC, with an area under the curve (AUC) of 0.848 (95% CI 0.763-0.933). According to the AUC results, the performance of the mGraeb scale was significantly better than that of the oGraeb scale (χ2 = 4.49; p = 0.034) and mFisher scale (χ2 = 7.21; p = 0.007). No statistical difference was found between the AUCs of the mGraeb and the quantitative volumetric measurement models (χ2 = 12.76; p = 0.23), but mGraeb proved to be the simplest model since it showed the lowest Akaike information criterion (66.4), the lowest Bayesian information criterion (71.2), and the highest R2Nagelkerke coefficient (39.7%). The initial mGraeb showed more than 85% specificity for predicting the development of SDHC in patients presenting with a score of 12 or more points. CONCLUSIONS: According to the authors' data, the mGraeb scale is the simplest model that correlates well with SDHC development. Due to limited scientific evidence of treatments aimed at SDHC prevention, we propose an mGraeb score higher than 12 to identify patients at risk with high specificity. This mGraeb cutoff point might also serve as a useful prognostic tool since patients with SDHC after aSAH have worse functional outcomes.

Vessel wall MRI characteristics of endovascularly treated aneurysms: association with angiographic vasospasm.

OBJECTIVE: The aim of this paper was to evaluate the association between intracranial vessel wall MRI enhancement characteristics and the development of angiographic vasospasm in endovascularly treated aneurysm patients. METHODS: Consecutive cases of both ruptured and unruptured intracranial aneurysms that were treated endovascularly, followed by intracranial vessel wall MRI in the immediate postoperative period, were included. Two raters blinded to clinical data and follow-up imaging independently evaluated for the presence, pattern, and intensity of wall enhancement. Development of angiographic vasospasm was independently evaluated. Delayed cerebral ischemia; cerebral infarct; procedural details; and presence and grade of subarachnoid, parenchymal, and intraventricular hemorrhage were evaluated. Statistical associations were determined on a per-vessel segment and per-patient basis. RESULTS: Twenty-nine patients with 30 treated aneurysms (8 unruptured and 22 ruptured) were included in this study. Interobserver agreement was substantial for the presence of enhancement (κ = 0.67) and nearly perfect for distribution (κ = 0.87) and intensity (κ = 0.84) of wall enhancement. Patients with ruptured aneurysms had a significantly greater number of enhancing segments than those with unruptured aneurysms (29.9% vs 7.2%; OR 5.5, 95% CI 2.2-13.7). For ruptured cases, wall enhancement was significantly associated with subsequent angiographic vasospasm while controlling for grade of hemorrhage (adjusted OR 3.9, 95% CI 1.7-9.4). Vessel segments affected by balloon, stent, or flow-diverter use demonstrated greater enhancement than those not affected (OR 22.7, 95% CI 5.3-97.2 for ruptured; and OR 12.9, 95% CI 3.3-49.8 for unruptured). CONCLUSIONS: Vessel wall enhancement after endovascular treatment of ruptured aneurysms is associated with subsequent angiographic vasospasm.

Clinical prediction of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

OBJECTIVEThe aim of this study was to derive a clinically applicable decision rule using clinical, radiological, and laboratory data to predict the development of delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients.METHODSPatients presenting over a consecutive 9-year period with subarachnoid hemorrhage (SAH) and at least 1 angiographically evident aneurysm were included. Variables significantly associated with DCI in univariate analysis underwent multivariable logistic regression. Using the beta coefficients, points were assigned to each predictor to establish a scoring system with estimated risks. DCI was defined as neurological deterioration attributable to arterial narrowing detected by transcranial Doppler ultrasonography, CT angiography, MR angiography, or catheter angiography, after exclusion of competing diagnoses.RESULTSOf 463 patients, 58% experienced angiographic vasospasm with an overall DCI incidence of 21%. Age, modified Fisher grade, and ruptured aneurysm location were significantly associated with DCI. This combination of predictors had a greater area under the receiver operating characteristic curve than the modified Fisher grade alone (0.73 [95% CI 0.67-0.78] vs 0.66 [95% CI 0.60-0.71]). Patients 70 years or older with modified Fisher grade 0 or 1 SAH and a posterior circulation aneurysm had the lowest risk of DCI at 1.2% (0 points). The highest estimated risk was 38% (17 points) in patients 40-59 years old with modified Fisher grade 4 SAH following rupture of an anterior circulation aneurysm.CONCLUSIONSAmong patients presenting with aSAH, this score-based clinical prediction tool exhibits increased accuracy over the modified Fisher grade alone and may serve as a useful tool to individualize DCI risk.