Aneurysmal subarachnoid hemorrhage (aSAH)

One of the most frequently treated cerebrovascular pathologies in neurosurgery are intracranial aneurysms [IA], which are found incidentally or present in a ruptured state as aneurysmal subarachnoid hemorrhage [aSAH]. Patients with severe courses suffer from protracted clinical and adverse sequelae. Elevated intracranial pressure [ICP] occurs due to the severity of the initial arterial blood-clot burden, acute hydrocephalus or consecutive cerebral herniation. Further contributing factors are in-hospital or periprocedural rebleeding as well as post-hemorrhagic acute and/or chronic malresorptive or occlusive hydrocephalus. Ischemic complications can either be iatrogenic or be caused by delayed cerebral vasospasms [DCVS] or delayed cerebral ischemia [DCI]. Thus, the affected patients are in need of invasive (surgical clipping, endovascular coiling, decompressive craniectomy, temporary external ventricular drainage [EVD] or permanent cerebrospinal-fluid [CSF] diversion) and non-invasive (medical) treatment. Specific anatomical features as well as demographic and patient-related factors inherently influence clinical presentation, the clinical course and treatment decision making, all of which add up to the long-term neurological morbidity and mortality.


The ruptured IA can be anatomically located in the anterior (carotid) circulation, including the internal carotid artery, the anterior cerebral artery, the anterior communicating artery [ACoA] and the middle cerebral artery [MCA]. More than three quarters of the aSAH-causing aneurysms are located in the anterior (carotid) circulation with ACoA aneurysms being the most frequent. Less frequently, ruptured IA are located within the posterior (vertebrobasilar) circulation, which includes the posterior communicating artery [PCoA], the basilar artery, the posterior inferior cerebellar artery [PICA] or the vertebral artery amongst others. The largest proportion of ruptured IA are ≥7 mm and less than 25mm in maximal diameter. Aneurysms between 5 to <7mm are defined as small, and ≤5 mm as very-small ruptured aneurysms. Aneurysms with sizes ≥25 mm are defined as giant aneurysms. Formation and rupture of IA likely results from a combination of genetic predisposition, acquired degenerative changes, and local hemodynamic stresses. In up to two thirds of patients with aSAH, a single ruptured IA is found. Known risk factors for aneurysm formation include constitutional factors, such as female sex, age >60 years, and genetic or acquired diseases, such as polycystic kidney disease and diabetes mellitus. In approximately one third of cases, multiple IA are detected, with an index aneurysm that bled, and bystander aneurysms that are coincidentally present within the same patient. Predisposing factors for aneurysm multiplicity include female sex, higher body mass index, smoking, and black race. In contrast to single ruptured IA, hypertension and a family history of cerebrovascular disease have been associated with aneurysm multiplicity in aSAH patients.


Previous cohort studies on aSAH consistently reported a female predominance in aSAH cohorts of approximately two-thirds of cases. It is further known that higher patient age and lower pre-ictal functional status independently predict worse poor outcome following aSAH. Several established grading scales yield objective measure of the severity of aSAH on admission and serve to guide treatment decisions and for prognostication. They include in particular the World Federation of Neurosurgical Societies [WFNS] classification with the Glasgow Coma Score [GCS] as its main component to assess patient’s vigilance, along with the presence or absence of a focal neurological deficit. Radiological scores such as the Fisher grading scale or the Barrow Neurological Institute [BNI] Grading Scale, quantify the presence or absence of a thick cisternal, ventricular or intracerebral blood clot on computed tomography [CT] scan, are used to predict the risk of periprocedural complications, hydrocephalus and/or delayed cerebral vasospasms [DCVS] with or without delayed cerebral infarction [DCI].


In order to create a nationwide registry comprising a large number of unselected aSAH patients, the “Swiss Study on Subarachnoid Hemorrhage [SOS] registry” was established as a prospectively kept unified database. Health care regulations resulted in a unique referral system for neurovascular emergencies to a limited number of centers, where neurovascular specialists contribute relevant data on aSAH from the point of care with uniform data entry and follow-up, as presented in the initial positioning paper of our group entitled “Introducing a nationwide registry: the Swiss study on aneurysmal subarachnoid haemorrhage (Swiss SOS)”. Thus, the Swiss-SOS study group was able to expand over the past decade to involve all tertiary neurovascular referral facilities in Switzerland. The resulting cohort of overall n=1866 aSAH patients between 2009-2015 offered us the opportunities for epidemiologic research with increased accuracy and statistical power. Findings out of such a high-quality registry can be applied to all Western countries with typical aging demographics and a similar health care system, meaning universal access and coverage.

 



Incidence of aSAH in Switzerland

Reported worldwide incidence rates of aneurysmal subarachnoid hemorrhage [aSAH] range from 3 to 23 per 100’000 persons/y. Some of the higher incidence numbers have been questioned in the past years. As a result of the above-mentioned collaboration effort, the study “Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS)” has been published recently by our Swiss-SOS study group. The incidence of ruptured intracranial aneurysm [IA] presenting with aSAH in Switzerland defined as 3.7 per 100 000 persons/y. Of note, aSAH only accounts for about 5% of strokes but has a disproportionate high morbidity and dependency rate along with a high mortality in younger patients compared to ischemic strokes or spontaneous intracerebral hemorrhage.

 



Impact of aneurysm morphology

Aneurysm location impacts clinical, anatomical and radiological characteristics of aSAH
The diagnosis of aneurysmal subarachnoid hemorrhage [aSAH] is based on computed tomography [CT] and computed tomography angiography [CTA], where an initial radiologic characterization of the ruptured intracranial aneurysm [IA] is made. The publication “Interrater Agreement in the Radiologic Characterization of Ruptured Intracranial Aneurysms Based on Computed Tomography Angiography” determined the interrater agreement of an initial CTA with special emphasis on the rater's level of experience. There was a high level of agreement for location (κ = 0.76, 95% confidence interval [CI] 0.74–0.79), side (κ = 0.95, CI 0.91–0.99), maximum diameter (intraclass correlation coefficient [ICC] 0.81, CI 0.70–0.90), and dome (ICC 0.78, CI 0.66–0.88) of intracranial aneurysms. In contrast, a lower level of agreement was observed for aneurysms' neck diameter (ICC 0.39, CI 0.28–0.58), the presence of multiple aneurysms (κ = 0.35, CI 0.30–0.40), and aneurysm morphology (blister κ = 0.11, CI –0.05 to 0.07; fusiform κ = 0.54, CI 0.48–0.60; multilobular, κ = 0.39 CI 0.33–0.45). This interrater agreement within “Swiss Study on Subarachnoid Hemorrhage [Swiss SOS] registry” investigators confirmed the benefit of CTA as initial diagnostic imaging in ruptured intracranial aneurysms, but not for aneurysm morphology and presence of multiple aneurysms.


Several Swiss SOS studies identified, that a ruptured (index) aneurysm’s location has significant impact on the clinical and radiological presentation and is predictive to identify bystander or mirror aneurysms (aneurysm multiplicity) as well their likely anatomical location.


The study entitled “Factors associated with clinical and radiological status on admission in patients with aneurysmal subarachnoid hemorrhage” included n=1787 aSAH patients collected between 2009-2014. Many previous studies focused on outcome analysis, while this study investigated how the anatomical location of the ruptured IA influences clinical presentation of patients with aSAH. We found that the proportion of patients who presented with a “high Glasgow Coma Score [GCS]” and a “good World Federation of Neurosurgical Societies [WFNS] grade” was lower in patients with a ruptured IA located within the posterior cerebral circulation and in those patients whose aneurysm was larger than 7 mm in maximal diameter. Indeed, we identified the ruptured aneurysms’ location and its size as independent predictors for the patients’ clinical and radiological condition at admission. Ruptured IA of the vertebral or basilar artery, which are in the midline and infratentorial near the brainstem, were correlated with low GCS score and low WFNS grade, and with higher rates of intubation. In contrast, ruptured IA of the medial cerebral artery [MCA], which are located supratentorial and more lateral and superficial within in the sylvian fissure, were correlated with “good” WFNS grade and with higher Fisher grade. In accordance, MCA location was positively correlated with the presence of a focal neurological deficit and with the presence of a cranial nerve deficit.


Another study entitled “Predictors of Occurrence and Anatomic Distribution of Multiple Aneurysms in Patients with Aneurysmal Subarachnoid Hemorrhage” addressed the anatomical distribution of the ruptured index aneurysm and non-ruptured bystander aneurysms in aSAH patients with aneurysm multiplicity, being the first study of its kind in the modern literature. We found, that ruptured anterior communicating artery [ACoA] aneurysms were the most common aneurysms in the patients presenting with a single ruptured IA, and MCA aneurysms the most common ruptured index aneurysm in patients presenting with multiple IA. Interestingly, we were able to identify the index aneurysm as the single strongest independent predictor of aneurysm multiplicity in multivariate analysis. Particularly, ruptured basilar artery (Odds Ratio [OR] 2.11; 95% CI, 1.30-3.44) and MCA (OR 1.86; 95% CI, 1.35-2.55) aneurysms were considerably more likely in patients with multiple IA than in those with single ruptured IA when compared with ACoA aneurysms 3. In addition to the index aneurysm, aSAH patients with multiple IA had one bystander in 72%; two bystanders, in 18%; three bystanders in 7%; four bystanders in 2.4%; five bystanders in 1%; and six bystanders in 0.2% of cases, most frequently located at the MCA. Of note the aneurysms were not randomly distributed along the circle of Willis, but rather presented in defined clusters. In multivariate analysis, the location of the index aneurysm was the strongest independent predictor for the likely constellations. Certain locations were especially prone to mirror aneurysm formation. We detected, that patients with a ruptured PCoA aneurysm for example were approximately 14 times more likely to harbor a BA bystander aneurysm and approximately 18 times more likely to harbor a mirror PCoA aneurysm than patients with a ruptured ACoA aneurysm.


A consecutive second study entitled “Impact of Aneurysm Multiplicity on Treatment and Outcome After Aneurysmal Subarachnoid Hemorrhage” investigated outcomes of aSAH patients with single ruptured IA and multiple IA. Again, a clear correlation of the location of the index aneurysm with the probability of finding multiple IA was found, and that the site of the index aneurysm predicted the likely anatomical distribution of bystander aneurysm(s). Another independent predictor for aneurysm multiplicity was a higher radiological blood clot burden (OR 1.67; 95% CI, 1.12-2.47), defined as Fisher grade 3-4.

 

Aneurysm size impacts clinical, anatomical and radiological characteristics of aSAH
Our first study “Factors associated with clinical and radiological status on admission in patients with aneurysmal subarachnoid hemorrhage” investigated how the initial diameter of the ruptured IA influences clinical presentation of patients with aSAH. Interestingly, aneurysm size of ≥7 mm was correlated with a low GCS score and WFNS grade (e.g., more comatous state at admission) when compared to ≤5 mm. Additionally, aneurysm size of ≥7 mm had a higher likelihood for the presence of a cranial nerve deficit.

In our second study entitled “Predictors of Occurrence and Anatomic Distribution of Multiple Aneurysms in Patients with Aneurysmal Subarachnoid Hemorrhage” the mean diameter of the index aneurysm was larger in patients with multiple IA (7.7 mm vs 6.9 mm) when compared to patients with a single ruptured IA, and larger size of the index aneurysm (OR per 1 mm, 1.03; 95%CI, 1.01-1.06) was positively correlated with the presence of aneurysm multiplicity.

 

Clinical, radiological and anatomical factors impact aSAH treatment patterns and outcome
The study entitled “Decision-making and neurosurgeons' agreement in the management of aneurysmal subarachnoid haemorrhage based on computed tomography angiography” was performed to further determine the neurosurgeon’s agreement in aSAH management with special emphasis on the rater’s level of experience. A secondary aim was to analyse potential aneurysm variables associated with the therapeutic recommendation. Thus, twelve neurosurgeons independently evaluated aneurysm characteristics and gave recommendations regarding the emergency management and aneurysm occlusion therapy. The study found and overall moderate agreement in treatment decision [κ = 0.43; 95% CI, 0.387–0.474] with moderate agreement for surgical (κ = 0.43; 95% CI, 0.386–0.479) and endovascular treatment recommendation (κ = 0.45; 95% CI, 0.398–0.49). Agreement on detailed treatment recommendations including clip, coil, bypass, stent, flow diverter and ventriculostomy was low to moderate. Inter-rater agreement did not significantly differ between residents and consultants. Middle cerebral artery [MCA] aneurysm location was a positive predictor of surgical treatment (odds ratio [OR], 49.57; 95% CI, 10.416–235.865; p < 0.001), while patients aged >65 years (OR, 0.12; 95% CI, 0.03–0.0434; p = 0.001), fusiform aneurysm type (OR, 0.18; 95% CI, 0.044–0.747; p = 0.018) and intracerebral haematoma (ICA) aneurysm location (OR, 0.24; 95% CI, 0.088–0.643; p = 0.005) were associated with a recommendation for endovascular treatment. The study concluded, that agreement on aSAH management varies considerably across neurosurgeons, while therapeutic decision-making is challenging on an individual patient level.


Consecutive studies from our Swiss-SOS study group analyzed treatment and outcome for specific aneurysms locations of the anterior (carotid) and posterior (vertebrobasilar) circulation. The study “Patterns of care for ruptured aneurysms of the middle cerebral artery: analysis of a Swiss national database (Swiss SOS)” found, that ruptured IA of the MCA presented with a higher rate of concomitant intracerebral hemorrhage (41.9% vs 16.7%) in computed tomography, when compared to Non-MCA aneurysms. Surgical treatment was the dominant treatment modality in MCA patients and at a significantly higher rate (81.7% vs 36.7%) when compared Non-MCA aneurysms. MCA location was found to be a strong independent predictor of surgical treatment (aOR 8.49; 95%CI, 5.89-12.25) due to supratentorial, and more lateral and superficial location within in the sylvian fissure. Patient with MCA aneurysms were less likely to die during the acute hospitalization (aOR 0.52, 95%CI, 0.30-0.91), however, their rate of a favorable outcome was lower at discharge when compared to other aneurysm locations (55.7% vs 63.7%).


The study “Ruptured posterior circulation aneurysms: epidemiology, patterns of care, and outcomes from the Swiss SOS national registry” provided epidemiological characterization of n=264 (14.6%) subjects presenting with ruptured posterior circulation aneurysms within our Swiss-SOS cohort and assessed the treatment patterns and neurological outcomes. Patients were divided in 3 groups (upper, lower, and middle third) according to anatomical aneurysm location. Opposite to the above-described surgical treatment paradigm for MCA aneurysms, endovascular occlusion was the mainstay of treatment for posterior (vertebra-basilar) aneurysms, 72% in the upper third, 68% in the middle third, and 58.8% in the lower third (which includes posterior inferior cerebellar artery [PICA] aneurysms). Posterior circulation aneurysms displayed a favorable outcome in two-thirds of patients at discharge and at long term. These results were found to be similar to high volume neurovascular centers worldwide, reflecting the importance of centralized care at specialized neurovascular centers. This study amongst the other proofed, that findings from our registry can be applied to all Western countries with typical demographics and a similar health care system.


The study “Ruptured PICA aneurysms: presentation and treatment outcomes compared to other posterior circulation aneurysms” finally took a closer look into n=74 (28%) ruptured PICA-aneurysms within our Swiss-SOS cohort, which are relatively uncommon and located in the lower third of the posterior (vertebra-basilar) circulation. While clinical and radiological characteristics at admission were comparable between PICA and non-PICA aneurysms, surgical treatment was accomplished at a higher rate (28% vs. 4.8%), respectively. However, no statistically significant difference was found between the two groups in terms of complications after treatment and neurological outcome at 1-year follow-up, with no significant difference in the mortality rate between both groups.

 



Impact of patient age and sex

Patient age impacts clinical and radiological characteristics of aSAH
While previous studies focused on outcome analysis, the purpose of the study “Factors associated with clinical and radiological status on admission in patients with aneurysmal subarachnoid hemorrhage” was to investigate what factors determine the patients’ clinical and radiological status at the time point of initial admission. We detected, that the proportion of patients who presented with a high Glasgow Coma Score [GCS] / low World Federation of Neurosurgical Societies [WFNS] grade (e.g., good grade at clinical presentation) decreased with increasing patient age. Inversely, increasing patient age by steps of 10 years was positively correlated with low GCS score (e.g., poorer grade at clinical presentation). A patient’s risk for presenting with a low GCS on admission consecutively increased by 10.5% per each 10 years of additional age. Increasing patient age by 10 years was also correlated with low WFNS grade, with high Fisher grade, with presence of a large blood clot, and with the presence of a focal neurological deficit (e.g., poorer grade at clinical presentation). Interestingly, the impact of lower pre-ictal functional status largely paralleled the impact of increasing patient age. However, the study remained underpowered to estimate the effect.

 

Patient sex impacts clinical and anatomical characteristics of aSAH
In our first study entitled “Factors associated with clinical and radiological status on admission in patients with aneurysmal subarachnoid hemorrhage”, the female to male ratio was 1.52, as generally described in the literature. Our studies on aneurysm multiplicity detected female predominance in all locations except the anterior communicating artery [ACoA] and vertebral artery where the male-to-female ratio was approximately even. This finding accounted for patients with a single-ruptured intracranial aneurysm [IA] as well as patients with multiple IA. Male sex was considerably less likely in patients with middle cerebral artery [MCA] aneurysms (OR 0.34; 95% CI, 0.26-0.45), internal carotid artery, aneurysms (OR 0.28; 95% CI, 0.20-0.38), and posterior communicating artery [PCoA] aneurysms (OR 0.17; 95% CI, 0.10-0.27) compared with patients with aneurysms arising from the ACoA. In addition, the percentage of women was detected to be higher in patients with multiple IA compared to patients single ruptured IA (72.2% vs 63.7%). Male sex was correlated with a lower probability of aneurysm multiplicity (OR 0.76; 95% CI, 0.59-0.98).

 



Impact of aneurysm treatment

Patients with aneurysmal subarachnoid hemorrhage [aSAH] can suffer from a protracted clinical course and adverse sequelae. Elevated intracranial pressure [ICP] occurs due to the severity of the initial arterial blood-clot burden, acute hydrocephalus or consecutive cerebral herniation. Further contributing factors are in-hospital or periprocedural rebleeding as well as post-hemorrhagic acute and/or chronic malresorptive or occlusive hydrocephalus. Ischemic complications can either be iatrogenic or be caused by delayed cerebral vasospasms [DCVS] or delayed cerebral ischemia [DCI]. Thus, the affected patients are in need of invasive (surgical clipping, endovascular coiling, decompressive craniectomy, temporary external ventricular drainage [EVD] or permanent cerebrospinal-fluid [CSF] diversion) and non-invasive (medical) treatment. Specific anatomical features as well as demographic and patient-related factors inherently influence clinical presentation, the clinical course and treatment decision making, all of which add up to the long-term neurological morbidity and mortality.

 

Complications of aneurysm treatment impact morbidity and mortality of aSAH
The study “Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage Analysis of a Nationwide Database (Swiss SOS)” from our “Swiss Study on Subarachnoid Hemorrhage [Swiss SOS]” group detected a 20% rate of in-hospital mortality within the nationwide cohort of aSAH patients. In 11% of the cases, active treatment was discontinued after hospital admission, meaning that no aneurysm was occlusion attempted. After exclusion of these patients, in-hospital mortality was 14% amongst the actively treated patients. It is common sense, that a ruptured intracranial aneurysm [IA] has to be treated with surgical clipping or endovascular interventions to avoid a devastating aneurysm re-rupture in aSAH patients. It is therefore not surprising, that in-hospital rebleeding prior aneurysm treatment (adjusted odds ratio [aOR], 7.69; 95% CI, 3.00-19.71) was found to be a strong independent predictor of in-hospital mortality along with DCI (aOR, 3.66; 95%CI, 1.94-6.89) and intraventricular hemorrhage (aOR, 2.65; 95%CI, 1.38-5.09) in the said study.


A particularly rare complication associated with surgical clipping is intraprocedural aneurysm rupture. The Swiss-SOS study “Computed tomography angiography spot sign predicts intraprocedural aneurysm rupture in subarachnoid hemorrhage” was performed in order to find predictors for intraoperative aneurysm rupture amongst n=118 aSAH patients with an intracerebral hemorrhage at presentation and aneurysms treatment. Within this small cohort, an intraprocedural aneurysm rupture occurred in 29 patients (16%), of which 6 out of 18 patients (33%) presented with a positive and 23 out of 163 patients (14%) with a negative spot sign on the initial computed tomography angiography [CTA] imaging. Impressively, patients with a positive spot-sign were three times as likely to show an intraoperative aneurysm rupture (OR 3.04; 95%CI, 1.04-8.92) and worse modified Rankin Scale [mRS] score at discharge when compared to patients with a negative spot sign (mRS 5 vs. 4), while mortality rates remained similar at discharge and 1-year.


A more frequently observed complication of microsurgical clipping or endovascular interventions is the peri-interventional occlusion of cerebral arteries resulting in post-interventional infarctions that mostly are detected on the first computed tomography imaging after treatment. The study “Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage Analysis of a Nationwide Database (Swiss SOS)” identified such cerebral infarctions after aneurysm treatment to be predictors for in-hospital mortality (aOR 2.57; 95%CI, 1.43-4.62). Cerebral infarctions after aneurysm treatment were as well a primary radiological endpoint of our study “Impact of Aneurysm Multiplicity on Treatment and Outcome After Aneurysmal Subarachnoid Hemorrhage”, where we examined in detail, how aneurysm multiplicity impacts treatment and outcome following aSAH. The incidence of an ischemic stroke, detected by computed tomography, was found to be higher in patients with multiple IA compared to patients with a single ruptured IA, both after aneurysm treatment (19.3% vs 15.1%) and at discharge (24% vs 21.4%). Aneurysm multiplicity was found to be an independent predictor for occurrence of a new focal neurological deficit between admission and discharge (OR 1.40; 95%CI, 1.08-1.81), the primary clinical endpoint of our study. Yet, the MIA and SIA groups did not differ in terms of either functional outcome or overall survival.


Overall, current prognostic tools in aSAH are constrained by being primarily based on patient and disease characteristics on admission. The study “Development of a Complication- and Treatment-Aware Prediction Model for Favorable Functional Outcome in Aneurysmal Subarachnoid Hemorrhage Based on Machine Learning” therefore aimed to develop and validate a complication- and treatment-aware outcome prediction tool in aSAH. This cohort study included Swiss SOS data from 2009 to 2015. Supervised machine learning algorithms were trained to predict a binary outcome at discharge (mRS ≤ 3: favorable; mRS 4-6: unfavorable). Clinical and radiological variables on admission (“Early” Model) as well as additional variables regarding secondary complications and disease management (“Late” Model) were used. Performance of both models was assessed by classification performance metrics on an out-of-sample test dataset. The study observed a favorable functional outcome at discharge in 1156 (62.0%) of 1866 patients. Both models scored a high accuracy of 75% to 76% on the test set. The “Late” outcome model outperformed the “Early” model with an area under the receiver operator characteristics curve (AUC) of 0.85 vs 0.79, corresponding to a specificity of 0.81 vs 0.70 and a sensitivity of 0.71 vs. 0.79, respectively.


This study was able to demonstrate, that both machine learning models show a good discrimination and calibration confirmed on application to an internal test dataset of patients with a wide range of disease severity treated in different institutions within the Swiss SOS registry. The data indicates that the inclusion of variables reflecting the clinical course of the patient may lead to outcome predictions with superior predictive power compared to a model based on admission data only.

 



Delayed cerebral vasospasms (DCVS) and cerebral ischemia (DCI)

Patients with aneurysmal subarachnoid hemorrhage [aSAH] can suffer from a protracted clinical course and adverse sequelae. Elevated intracranial pressure [ICP] occurs due to the severity of the initial arterial blood-clot burden, acute hydrocephalus or consecutive cerebral herniation. Further contributing factors are in-hospital or periprocedural rebleeding as well as post-hemorrhagic acute and/or chronic malresorptive or occlusive hydrocephalus. Ischemic complications can either be iatrogenic or be caused by delayed cerebral vasospasms [DCVS] or delayed cerebral ischemia [DCI]. Thus, the affected patients are in need of invasive (surgical clipping, endovascular coiling, decompressive craniectomy, temporary external ventricular drainage [EVD] or permanent cerebrospinal-fluid [CSF] diversion) and non-invasive (medical) treatment. Specific anatomical features as well as demographic and patient-related factors inherently influence clinical presentation, the clinical course and treatment decision making, all of which add up to the long-term neurological morbidity and mortality.

Several established grading scales yield objective measure of the severity of aSAH on admission and serve to guide treatment decisions and for prognostication. They include in particular the World Federation of Neurosurgical Societies [WFNS] classification with the Glasgow Coma Score [GCS] as its main component to assess patient’s vigilance, along with the presence or absence of a focal neurological deficit. Radiological scores such as the Fisher grading scale or the Barrow Neurological Institute [BNI] Grading Scale, quantify the presence or absence of a thick cisternal, ventricular or intracerebral blood clot on computed tomography [CT] scan, are used to predict the risk of periprocedural complications, hydrocephalus and/or DCVS with or without DCI.

 

Delayed cerebral vasospasms and cerebral ischemia impact morbidity and mortality of aSAH
Prognostically relevant adverse sequelae of acute aSAH are ischemic strokes caused by spontaneous DCVS and DCI and post-hemorrhagic hydrocephalus. These potential complications are very common and have a crucial impact on morbidity and mortality of the affected patients.

 

Spontaneous narrowing of the cerebral arteries following aSAH present as DCVS usually occuring on days 3 to 14 after the ictus. DCVS are defined as local vasospasm visible on computed tomographic angiography or digital subtraction angiography accompanied by neurological worsening for at least 2 hours. Previous data reliably confirmed that the amount of subarachnoid blood in aSAH correlates with the incidence DCVS and of DCI and thus increased morbidity and mortality. DCI are defined as brain infarction visible on computed tomography or magnetic resonance imaging in the first 6 weeks after SAH. The most commonly used grading scales to predict vasospasm or DCI in aSAH are the Fisher or the modified Fisher scales, which account for the blood extension in the subarachnoid space as well as for presence of intraventricular or cerebral hemorrhage. A study performed by our Swiss-SOS study group entitled “The Barrow Neurological Institute Grading Scale as a Predictor for Delayed Cerebral Ischemia and Outcome After Aneurysmal Subarachnoid Hemorrhage: Data From a Nationwide Patient Registry (Swiss SOS)”. This validation study focused on the prediction of DCVS based on the maximal blood-clot thickness in any arachnoidal cistern or fissure detected on the initial computed tomography imaging in aSAH patients. Previously, the BNI grading scale has been confirmed in single-centre cohorts, and the prospectively collected nationwide aSAH registry hence provided the unique opportunity to validate the BNI grading scale in a large, unselected, and multicultural cohort. Overall, 409 out of 1321 patients (31%) developed DCI with a high DCI rate in the Fisher grade 3 cohort (34%). Our study confirmed that DCI rates went up progressively from 26% (BNI 2) to 38% (BNI 5) and the corresponding odds ratio [OR] for DCI increased from 1.9 (95% CI, 1.0-3.5) to 3.4 (95% CI, 2.1-5.3), respectively. BNI grade 5 patients had high rates of unfavorable outcome with 75% at discharge and 58% at 1 year follow-up. The likelihood for unfavorable outcome was confirmed to be high in BNI grade 5 patients with OR 5.9 (95% CI, 3.9-8.9) at discharge and OR 6.6 (95% CI, 4.1-10.5) at 1 year follow-up, a finding that was sufficiently confirmed with the Fisher grade in several previous studies. With increasing rates of successful ruptured aneurysm treatment and reduced in-hospital rebleeding rates, DCI are considered to be one of the most relevant factors impacting neurological outcome and mortality in aSAH patients.

 



Hydrocephalus treatment and complications

Patients with aneurysmal subarachnoid hemorrhage [aSAH] can suffer from a protracted clinical course and adverse sequelae. Elevated intracranial pressure [ICP] occurs due to the severity of the initial arterial blood-clot burden, acute hydrocephalus or consecutive cerebral herniation. Further contributing factors are in-hospital or periprocedural rebleeding as well as post-hemorrhagic acute and/or chronic malresorptive or occlusive hydrocephalus. Ischemic complications can either be iatrogenic or be caused by delayed cerebral vasospasms [DCVS] or delayed cerebral ischemia [DCI]. Thus, the affected patients are in need of invasive (surgical clipping, endovascular coiling, decompressive craniectomy, temporary external ventricular drainage [EVD] or permanent cerebrospinal-fluid [CSF] diversion) and non-invasive (medical) treatment. Specific anatomical features as well as demographic and patient-related factors inherently influence clinical presentation, the clinical course and treatment decision making, all of which add up to the long-term neurological morbidity and mortality.

 

Acute and chronic posthemorrhagic hydrocephalus impacts outcome of aSAH
Acute hydrocephalus arises in approximately one third of patients with aSAH and is treated with temporary cerebrospinal fluid [CSF]-diversion using an external ventricular drain [EVD] in 6 to 30% of cases. Depending on the presence and extent of subarachnoid and intraventricular blood, prolonged EVD duration is necessary. The circulating blood frequently causes a chronic mal-resorptive hydrocephalus and the necessity for permanent CSF diversion, most frequently via a ventriculo-peritoneal shunting procedure. Acknowledged mechanisms are the exacerbation of inflammatory processes, thrombogenicity, and disturbances of CSF-dynamics. According to the literature, between 8% and 63% of aSAH patients eventually undergo such a permanent CSF diversion (shunting) procedure. Hemorrhage-associated factors associated with permanent CSF diversion are a high blood clot burden, acute hydrocephalus, re-hemorrhage and posterior location of the ruptured aneurysm. Constitutional factors leading to permanent CSF diversion are age ≥ 60 years. Nowadays, nosocomial infections, especially catheter-related infectious complications causing nosocomial meningitis or ventriculitis are considered as an important risk-factors for permanent CSF diversion in aSAH patients.

 

Complications of acute and chronic hydrocephalus treatment impacts outcome of aSAH
The concomitant occurrence of acute and chronic hydrocephalus and the risk of DCVS in aSAH patients generates controversies in neuro-intensive care treatment. The necessity of additional interventions for the aSAH sequelae leaves the clinicians with unanswered questions in terms of optimal management and pose additional risks for the patients. This clinical dilemma was subject of a recently published retrospective single-cohort study from our group entitled “Early permanent cerebrospinal fluid diversion in aneurysmal subarachnoid hemorrhage: does a lower rate of nosocomial meningitis outweigh the risk of delayed cerebral vasospasm related morbidity?”. There is a legitimate concern that surgical procedures requiring patient transfer, general anesthesia and intensified sedation with potential intraoperative hemodynamic disturbances might increase the risk of cerebral hypoperfusion and thus of DCVS and DCI. Therefore, neurosurgical practice generally prefers to perform permanent CSF diversion procedures after the DCVS phase. Furthermore, it is assumed that a higher frequency of permanent CSF diversion device obstruction caused by the circulating blood occurs in early stages of the disease.

 

On the other hand, prolonged EVD leads to a progressive bacterial colonization of the ventricular catheter with cutaneous microbes. Catheter-related infectious complications causing nosocomial meningitis or ventriculitis (EVD-associated infections [EVDAI]) have an incidence of 11.4 per 1000 catheter-days in the first two weeks. Induced immunodepression in the subset of aSAH patients has been determined to predispose for bacterial infections. Nowadays, EVDAI is considered to be one of the most important nosocomial infections that negatively influence the neurological outcome of aSAH, eventually leading to chronic hydrocephalus. It was found that aSAH with EVDAI carried the highest risk (61%), with only 50% of patients not having CSF diversion at 1 year. It was found that aSAH patients who sustained EVDAI were 5 times more likely to undergo permanent CSF diversion than those who did not. Confirmation of EVDAI follow an interdisciplinary approach in accordance with the modified criteria for nosocomial infections of the Centers for Disease Control and Prevention [CDC]: Usually, the presence of an agar-plate positive culture of the CSF or catheter tip accompanied by further pathological CSF findings or at least one new sign or symptom of CNS infection in the absence of any other known cause needs to be present. EVDAI can also be diagnosed in some cases with negative cultures in which there are pathological CSF findings and/or clinical manifestations of infection and antimicrobial therapy is given. Patients with confirmed EVDAI are usually treated with susceptibility adapted antimicrobial therapy following evidence-based recommendations.

 



Mortality, neurological and neuropsychological outcome

Several established grading scales yield objective measure of the severity of aSAH on admission and serve to guide treatment decisions and for prognostication. They include in particular the World Federation of Neurosurgical Societies [WFNS] classification with the Glasgow Coma Score [GCS] as its main component to assess patient’s vigilance, along with the presence or absence of a focal neurological deficit. Radiological scores such as the Fisher grading scale or the Barrow Neurological Institute [BNI] Grading Scale, quantify the presence or absence of a thick cisternal, ventricular or intracerebral blood clot on computed tomography [CT] scan, are used to predict the risk of periprocedural complications, hydrocephalus and/or delayed cerebral vasospasms [DCVS] with or without delayed cerebral infarction [DCI].

 

Mortality after aSAH
The study “Predictors of In-Hospital Death After Aneurysmal Subarachnoid Hemorrhage Analysis of a Nationwide Database (Swiss SOS)” from our “Swiss Study on Subarachnoid Hemorrhage [Swiss SOS]” group detected a 20% rate of in-hospital mortality within the nationwide cohort of aSAH patients. In 11% of the cases, active treatment was discontinued after hospital admission, meaning that no intracranial aneurysm [IA] occlusion was attempted. After exclusion of these patients, in-hospital mortality was 14% amongst the actively treated patients. It is common sense, that a ruptured IA has to be treated with surgical clipping or endovascular interventions to avoid a devastating aneurysm re-rupture in aSAH patients. It is therefore not surprising, that in-hospital rebleeding prior aneurysm treatment (adjusted odds ratio [aOR], 7.69; 95% CI, 3.00-19.71) was found to be a strong independent predictor of in-hospital mortality along with DCI (aOR, 3.66; 95%CI, 1.94-6.89) and intraventricular hemorrhage (aOR, 2.65; 95%CI, 1.38-5.09) in the said study.


The prediction of risk of mortality or functional outcome at three months after aSAH according to score on the Glasgow outcome scale was part of the “Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study”, where the “Swiss Study on Subarachnoid Hemorrhage [Swiss SOS]” group collaborated. The aim of the study was to develop and validate a set of practical prediction tools that reliably estimate the outcome of aneurysmal subarachnoid hemorrhage [aSAH] based on a cohort of 10 936 patients with logistic regression analysis to combine predictors and treatment modality. Clinical prediction models were developed with individual patient data from 10 936 patients and validated with data from 3355 patients after development of the model. In the validation cohort, a core model including patient age, premorbid hypertension, and neurological grade on admission to predict risk of functional outcome had good discrimination, with an area under the receiver operator characteristics curve (AUC) of 0.80 (95% confidence interval 0.78 to 0.82). When the core model was extended to a “neuroimaging model,” with inclusion of clot volume, aneurysm size, and location, the AUC improved to 0.81 (0.79 to 0.84). A full model that extended the neuroimaging model by including treatment modality had AUC of 0.81 (0.79 to 0.83). Discrimination was lower for a similar set of models to predict risk of mortality (AUC for full model 0.76, 0.69 to 0.82). All models showed satisfactory calibration in the validation cohort. The authors concluded, that prediction models reliably estimate the outcome of patients who were managed in various settings for ruptured IA that caused subarachnoid hemorrhage. The thus study suggests that the web based SAHIT prognostic calculator (http://sahitscore.com) and the related app could be adjunctive tools to support management of patients.

 

Neurological outcome after aSAH
Although initially established as a score to predict poor outcome in aSAH patients, favorable outcomes are seen in up to 50% of patients with WFNS grade V aSAH. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. In 2022, the international prospective multicentre study in poor-grade aSAH patients entitled “Herniation World Federation of Neurosurgical Societies Scale Improves Prediction of Outcome in Patients With Poor-Grade Aneurysmal Subarachnoid Hemorrhage” was published. The WFNS scale has previously been modified by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort (Swiss SOS registry). For this, the WFNS classification was compared with a modified version - the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes after neurological resuscitation (modified Rankin Scale score 4–6). Of the 250 patients included, 237 reached the primary end point. The specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P<0.001) whereas the sensitivity decreased from 0.88 to 0.37 (P<0.001), and the positive predictive value from 61.9 to 88.3 (weighted generalized score statistic, P<0.001). For mortality, the specificity increased from 0.19 to 0.93 (McNemar, P<0.001), and the positive predictive value from 52.5 to 86.7 (weighted generalized score statistic, P<0.001). Thus, the identification of objective positive signs of brain stem dysfunction significantly improved the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification – namely the presence of brain stem signs for grade V – is suggested to be added to the WFNS classification for better prognostication of poor grade aSAH patients.


In another study entitled “Home-Time as a Surrogate Marker for Functional Outcome After Aneurysmal Subarachnoid Hemorrhage”, the time spent at the patient’s home (home-time) was validated as an outcome measure after aSAH. Commonly used tools to determine functional outcome after aneurysmal subarachnoid hemorrhage (aSAH) have limitations, and home-time has previously been proposed as a robust outcome measure after ischemic stroke. The Swiss Study on Subarachnoid Hemorrhage [Swiss SOS]” group therefore analyzed home-time data from 1076 of 1866 patients (57.7%), and multiple imputation was used to fill-in missing data from the remaining 790 patients. We found that increasing home-time was associated with improved modified Rankin Scale [mRS] scores at time of hospital discharge (P<0.0001) and at 1-year follow-up (P<0.0001). Within each of the 8 participating hospitals, the relationship between home-time and mRS was maintained. The paper therefore concludes, that home-time for the first 90 days after aSAH offers a robust and easily ascertainable outcome measure, discriminating particularly well across better recovery levels at time of hospital discharge and at 1-year follow-up. This measure complies with the modern trend of patient-centered healthcare and research, representing an outcome that is particularly relevant to the patient.

 

Neuropsychological after aSAH
The publication “Current practice in neuropsychological outcome reporting after aneurysmal subarachnoid haemorrhage” of the Swiss SOS group underlined the paradox of a high incidence of neuropsychological deficits (NPD) in aSAH patients, with only little patients being systematically tested for NPD in clinical research. Neurosurgeons and neuropsychologists from KSA, USB, ISB, HUG, KSSG and USZ met in Aarau and agreed on establishing a Swiss standard for neuropsychological testing after aSAH (later on, EOC and CHUV would agree to participate), and published a positioning paper on this matter (“Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations”). Results of this standardized neuropsychological patient follow-up would then be implemented into the Swiss SOS project. The definitive test-battery (examining all relevant cognitive domains, preferably using tests available in German (“Neuropsychologische Testung nach aneurysmatischer Subarachnoidalblutung”), French (“Evaluation neuropsychologique dans l’hémorragie sousarachnoïdienne anévrismale”), Italian, English with normative data available for the Swiss cultural area) still had to be elaborated by an elected task force of neuropsychologists and neurosurgeons. It was decided, that the neuropsychological follow-up visit would likewise measure the quality of life and ability to work, as well as the incidence and severity of depression, fatigue and anxiety.


To date, the exact relationship between DCI following aSAH and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. The study “Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage—Protocol of a Swiss Nationwide Observational Study (MoCA–DCI Study)” described the ongoing stury that assesses the relationship between DCI and neuropsychological outcome after aSAH; 1. by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 months with a baseline examination before the DCI-period; 2. to determine the reliability of the MoCA, when applied in an ICU setting. The prospective, multicenter, and observational study performed at all Swiss neurovascular centers participating in the Swiss SOS aims to recruite n = 240 consecutive aSAH patients for part 1 and n = 50 patients with acute brain injury for part 2. Expected outcomes are the effect size of the relationship between DCI and neuropsychological outcome (MoCA) for part 1 and the reliability measures for the MoCA (part 2). The institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.

 

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