Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Predicting outcome after aneurysmal subarachnoid hemorrhage by exploitation of signal complexity: a prospective two-center cohort study.

BACKGROUND: Signal complexity (i.e. entropy) describes the level of order within a system. Low physiological signal complexity predicts unfavorable outcome in a variety of diseases and is assumed to reflect increased rigidity of the cardio/cerebrovascular system leading to (or reflecting) autoregulation failure. Aneurysmal subarachnoid hemorrhage (aSAH) is followed by a cascade of complex systemic and cerebral sequelae. In aSAH, the value of entropy has not been established yet. METHODS: aSAH patients from 2 prospective cohorts (Zurich-derivation cohort, Aachen-validation cohort) were included. Multiscale Entropy (MSE) was estimated for arterial blood pressure, intracranial pressure, heart rate, and their derivatives, and compared to dichotomized (1-4 vs. 5-8) or ordinal outcome (GOSE-extended Glasgow Outcome Scale) at 12 months using uni- and multivariable (adjusted for age, World Federation of Neurological Surgeons grade, modified Fisher (mFisher) grade, delayed cerebral infarction), and ordinal methods (proportional odds logistic regression/sliding dichotomy). The multivariable logistic regression models were validated internally using bootstrapping and externally by assessing the calibration and discrimination. RESULTS: A total of 330 (derivation: 241, validation: 89) aSAH patients were analyzed. Decreasing MSE was associated with a higher likelihood of unfavorable outcome independent of covariates and analysis method. The multivariable adjusted logistic regression models were well calibrated and only showed a slight decrease in discrimination when assessed in the validation cohort. The ordinal analysis revealed its effect to be linear. MSE remained valid when adjusting the outcome definition against the initial severity. CONCLUSIONS: MSE metrics and thereby complexity of physiological signals are independent, internally and externally valid predictors of 12-month outcome. Incorporating high-frequency physiological data as part of clinical outcome prediction may enable precise, individualized outcome prediction. The results of this study warrant further investigation into the cause of the resulting complexity as well as its association to important and potentially preventable complications including vasospasm and delayed cerebral ischemia.

Intra-aneurysmal contrast agent stasis during intraoperative digital subtraction angiography may predict long-term occlusion after clipping.

PURPOSE: The routine use of intraoperative digital subtraction angiography (iDSA) increases detection of intracranial aneurysm (IA) remnants after microsurgical clipping. Spontaneous thrombosis of IA remnants after clipping is considered a rare phenomenon. We analyse iDSA characteristics to find predictors for IA remnant thrombosis. METHODS: IA with intraoperative detection of a remnant after clipping were identified and divided into remnants experiencing spontaneous thrombosis, and remnants with long-term patency and/or remnant growth. Angiographic features of iDSA were analysed and compared between the two groups. RESULTS: Of 37 IAs with intraoperative remnant on 3D-iDSA, five sustained a spontaneous remnant thrombosis and remained occluded in long-term follow-up. In all five cases, iDSA revealed delayed inflow and consequent stasis of the contrast agent until the late venous phase. On the other hand, in all cases with persistent long-term IA remnants (n = 32) iDSA demonstrated timely arterial contrast inflow and wash-out without stasis of intra-aneurysmal contrast agent. CONCLUSIONS: Contrast stasis in IA remnants during iDSA appears to predict long-term IA occlusion, indicating that clip correction manoeuvres or even attempted endovascular treatment of the remnant IA may be avoided in these patients.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

Optimal Cerebral Perfusion Pressure and Brain Tissue Oxygen in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO2) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO2 as an adjunctive monitor for adequate or optimal local perfusion. METHODS: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO2 <20 mmHg. RESULTS: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO2 and deltaCPP (P<0.001) with PbtO2 decrease with deltaCPP <0 mmHg and stable PbtO2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI. CONCLUSIONS: We found a nonlinear relationship between PbtO2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO2. Nevertheless, the nature of PbtO2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO2), which cannot be fulfilled by both measurements interchangeably.

The oxygen reactivity index indicates disturbed local perfusion regulation after aneurysmal subarachnoid hemorrhage: an observational cohort study.

BACKGROUND: Cerebral autoregulation (CA) can be impaired in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). The Pressure Reactivity Index (PRx, correlation of blood pressure and intracranial pressure) and Oxygen Reactivity Index (ORx, correlation of cerebral perfusion pressure and brain tissue oxygenation, PbtO2) are both believed to estimate CA. We hypothesized that CA could be poorer in hypoperfused territories during DCI and that ORx and PRx may not be equally effective in detecting such local variances. METHODS: ORx and PRx were compared daily in 76 patients with aSAH with or without DCI until the time of DCI diagnosis. The ICP/PbtO2-probes of DCI patients were retrospectively stratified by being in or outside areas of hypoperfusion via CT perfusion image, resulting in three groups: DCI + /probe + (DCI patients, probe located inside the hypoperfused area), DCI + /probe- (probe outside the hypoperfused area), DCI- (no DCI). RESULTS: PRx and ORx were not correlated (r = - 0.01, p = 0.56). Mean ORx but not PRx was highest when the probe was located in a hypoperfused area (ORx DCI + /probe + 0.28 ± 0.13 vs. DCI + /probe- 0.18 ± 0.15, p < 0.05; PRx DCI + /probe + 0.12 ± 0.17 vs. DCI + /probe- 0.06 ± 0.20, p = 0.35). PRx detected poorer autoregulation during the early phase with relatively higher ICP (days 1-3 after hemorrhage) but did not differentiate the three groups on the following days when ICP was lower on average. ORx was higher in the DCI + /probe + group than in the other two groups from day 3 onward. ORx and PRx did not differ between patients with DCI, whose probe was located elsewhere, and patients without DCI (ORx DCI + /probe- 0.18 ± 0.15 vs. DCI- 0.20 ± 0.14; p = 0.50; PRx DCI + /probe- 0.06 ± 0.20 vs. DCI- 0.08 ± 0.17, p = 0.35). CONCLUSIONS: PRx and ORx are not interchangeable measures of autoregulation, as they likely measure different homeostatic mechanisms. PRx represents the classical cerebrovascular reactivity and might be better suited to detect disturbed autoregulation during phases with moderately elevated ICP. Autoregulation may be poorer in territories affected by DCI. These local perfusion disturbances leading up to DCI may be more readily detected by ORx than PRx. Further research should investigate their robustness to detect DCI and to serve as a basis for autoregulation-targeted treatment after aSAH.

Safety and functional outcome analysis of ventriculoperitoneal shunt placement for hydrocephalus within the critical phase of possible delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Shunt-dependent hydrocephalus (HC) is a common sequela following aneurysmal subarachnoid hemorrhage (aSAH). However, there is still poor evidence regarding the optimal timing of ventriculoperitoneal shunt (VPS) placement, particularly in the context of early aSAH-associated complications such as delayed cerebral ischemia (DCI). The purpose of this study was to compare the impact of early (< 21 days after aSAH) versus late (≥ 21 days after aSAH) VPS placement on the functional clinical outcome. We retrospectively analyzed data from 82 patients with VPS placement after aSAH enrolled in our institutional database between 2011 and 2021. We compared two groups, early VPS placement (< 21 days after aSAH) versus late VPS placement (≥ 21 days after aSAH) in terms of demographics, SAH grading, radiological parameters, externalized cerebrospinal fluid diversions, DCI, VPS variables, and functional outcome. We identified 53 patients with early and 29 patients with late VPS implantation. Baseline variables, such as the modified Rankin Scale (mRS), the World Federation of Neurological Surgeons Scale, the Glasgow Coma Scale, and Fisher grade were not significantly different between the groups. Postoperatively, the mRS (p = 0.0037), the Glasgow Outcome Scale (p = 0.0037), and the extended Glasgow Outcome Scale (p = 0.0032) showed significantly better functional results in patients with early cerebrospinal fluid diversion. The rate of DCI did not differ significantly between the groups (p = 0.53). There was no difference in the rate of VPS placement associated complications (p = 0.44) or overall mortality (p = 0.39). Early shunt implantation, within 21 days after aSAH and therefore during the timeframe of possible DCI, might not be harmful in patients developing HC after aSAH.

Intraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment Protocol.

BACKGROUND: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IANonly) treatment protocol for refractory DCI in an observational study. METHODS: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IANonly). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5). RESULTS: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IANonly 0.26±0.20 µg/kg per minute, P<0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P<0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P=0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P=0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P=0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P<0.01). CONCLUSIONS: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Optimal Cerebral Perfusion Pressure During Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University hospital neurocritical care unit. PATIENTS: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia). INTERVENTIONS: Induced hypertension greater than 180 mm Hg systolic blood pressure. MEASUREMENTS AND MAIN RESULTS: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 ± 12.5 to 86.3 ± 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 ± 11.2 to -7.7 ± 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 ± 0.33 to 0.19 ± 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 ± 8.3 mm Hg, no delayed cerebral ischemia 90.4 ± 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 ± 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension+ [n = 15] or progression of delayed cerebral ischemia: induced hypertension- [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51]). CONCLUSIONS: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies.

Baseline characteristics and outcome for aneurysmal versus non-aneurysmal subarachnoid hemorrhage: a prospective cohort study.

This study aims to investigate the characteristics of patients with mild aneurysmal and non-aneurysmal perimesencephalic and non-perimesencephalic subarachnoid hemorrhage (aSAH, pmSAH, npmSAH) with emphasis on admission biomarkers, clinical course, and outcome. A prospective cohort of 115 patients with aSAH (Hunt and Hess 1-3) and of 35 patients without aneurysms (16 pmSAH and 19 npmSAH) admitted between January 2014 and January 2020 was included. Demographic data, blood samples on admission, complications (hydrocephalus, shunt dependency, delayed cerebral ischemia DCI, DCI-related infarction, and mortality), and outcome after 6 months were analyzed. Demographic data was comparable between all groups except for age (aSAH 55 [48-65] vs. npmSAH 60 [56-68] vs. pmSAH 52 [42-60], p = 0.032) and loss of consciousness (33% vs. 0% vs. 0%, p = 0.0004). Admission biomarkers showed poorer renal function and highest glucose levels for npmSAH patients. Complication rate in npmSAH was high and comparable to that of aSAH patients (hydrocephalus, shunt dependency, DCI, DCI-related infarction, mortality), but nearly absent in patients with pmSAH. Favorable outcome after 6 months was seen in 92.9% of pmSAH, 83.3% of npmSAH, and 62.7% of aSAH (p = 0.0264). In this prospective cohort of SAH patients, npmSAH was associated with a complicated clinical course, comparable to that of patients with aSAH. In contrast, such complications were nearly absent in pmSAH patients, suggesting fundamental differences in the pathophysiology of patients with different types of non-aneurysmal hemorrhage. Our findings underline the importance for a precise terminology according the hemorrhage etiology as a basis for more vigilant management of npmSAH patients. NCT02142166, 05/20/2014, retrospectively registered.

Arteriovenous malformations of the filum terminale: clinical characteristics, angioarchitecture, and management of a rare spinal vascular pathology.

OBJECTIVE: The goal of this study was to describe clinical and neuroradiological features of arteriovenous malformations of the filum terminale (FT AVMs) and to present the authors' diagnostic and therapeutic management in this rare disease. METHODS: The presented cases were retrieved from a retrospectively collected database of all spinal vascular malformations treated between June 1992 and December 2021 at the Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen. Pretreatment and follow-up clinical and neuroradiological data were analyzed for this study. RESULTS: Data in 15 patients with FT AVM with a mean age of 60 years were included, with an overall incidence of FT AVM of 19% among all spinal AVMs in our cohort. Twelve of 15 (80%) patients were men. Nonspecific but typical clinical and MR findings of thoracolumbar congestive myelopathy were found in all patients. Spinal MR angiography, performed in 10 patients, identified in all cases the arterialized FT vein as well as a lumbar/lumbosacral location of an AV shunt. Digital subtraction angiography (DSA) showed an arterial supply solely via the FT artery in 12/15 (80%) patients and via an additional feeder from the lumbosacral region in the other 3/15 (20%) patients. All patients were treated surgically. During 1-year follow-up, 2 patients presented with recurrent FT AVM due to further arterial supply from the lumbosacral region, and were treated surgically. Neurological status was improved in all patients within the 1-year follow-up, with marginal further changes during long-term follow-up. CONCLUSIONS: Congestive myelopathy is the major pathological mechanism of symptoms in these patients, with no evidence for intradural bleeding. Missing the presence of possible multiple arterial supply of FT AVM during DSA may result in misdiagnosis and/or insufficient treatment. Due to the frequently prolonged course of FT artery, resection of the FT AVM may be a favorable treatment modality in comparison with endovascular treatment. Follow-up examinations are obligatory within the first 3 years after treatment, and further MR angiography and DSA examinations are indicated if congestive myelopathy persists.

Decompressive hemicraniectomy after aneurysmal subarachnoid hemorrhage-justifiable in light of long-term outcome?

PURPOSE: Decompressive hemicraniectomy (DHC) is a potentially lifesaving procedure in refractory intracranial hypertension, which can prevent death from brainstem herniation but may cause survival in a disabled state. The spectrum of indications is expanding, and we present long-term results in a series of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). METHODS: We performed a retrospective analysis of previously registered data including all patients treated for SAH between 2010 and 2018 in a single institution. Patients treated with decompressive hemicraniectomy due to refractory intracranial hypertension were identified. Clinical outcome was assessed by means of the Glasgow outcome scale after 12 months. RESULTS: Of all 341 SAH cases, a total of 82 (24.0%) developed intracranial hypertension. Of those, 63 (18.5%) patients progressed into refractory ICP elevation and were treated with DHC. Younger age (OR 0.959, 95% CI 0.933 to 0.984; p = 0.002), anterior aneurysm location (OR 0.253, 95% CI 0.080 to 0.799; 0.019; p = 0.019), larger aneurysm size (OR 1.106, 95% CI 1.025 to 1.194; p = 0.010), and higher Hunt and Hess grading (OR 1.944, 95% CI 1.431 to 2.641; p < 0.001) were independently associated with the need for DHC. After 1 year, 10 (15.9%) patients after DHC were categorized as favorable outcome. Only younger age was independently associated with favorable outcome (OR 0.968 95% CI 0.951 to 0.986; p = 0.001). CONCLUSIONS: Decompressive hemicraniectomy, though lifesaving, has only a limited probability of survival in a clinically favorable condition. We identified young age to be the sole independent predictor of favorable outcome after DHC in SAH.

Revisiting the Timeline of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Toward a Temporal Risk Profile.

BACKGROUND: Delayed cerebral ischemia (DCI) is one of the main determinants of clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). The classical description of risk for DCI over time is currently based on the outdated concept of angiographic vasospasm. The goal of this study was to assess the temporal risk profile of DCI, defined by extended clinical and radiological criteria, as well as the impact the time point of DCI onset has on clinical outcome. METHODS: All patients with aneurysmal SAH referred to a single tertiary care center between 2010 and 2018 were considered for inclusion. This study was designed as a retrospective cohort analysis and data were extracted from existing patient files. In conscious patients, DCI was diagnosed clinically, and in unconscious patients, diagnosis was based on perfusion computed tomography imaging and multimodal neuromonitoring. Extended Glasgow Outcome Scale scores were assessed after 12 months and compared between patients with early (< day 7) and late (≥ day 7) DCI onset. RESULTS: The median delay from day of the hemorrhage (day 0) until detection of the first DCI event was 7.0 days, with an interquartile range of 5 days. The probability of DCI development over time demonstrated a bimodal distribution with a peak risk on day 5 (0.084; confidence interval 0.05.5-0.122) and a second peak on day 9 (0.077; confidence interval 0.045-0.120). A total of 27 patients (15.6%) suffered dominant hemispheric or severe bilateral DCI-related infarctions, resulting in the withdrawal of technical life support. Of those, the majority (20 patients, 22.2%) presented with early DCI onset (vs. late onset: 7 patients, 8.4%; p = 0.013). CONCLUSIONS: The risk profile of DCI over time mirrors the description of angiographic vasospasm; however, it comes with an added timely delay of 1 to 2 days. Early occurrence of DCI (before day 7) is associated with a higher infarct load and DCI-related mortality. Although the exact causal relationship remains to be determined, the time point of DCI onset may serve as an independent prognostic criterion in decision-making.

Incremental Versus Immediate Induction of Hypertension in the Treatment of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a common complication of aneurysmal subarachnoid hemorrhage and contributes to unfavorable outcome. In patients with deterioration despite prophylactic nimodipine treatment, induced hypertension (iHTN) can be considered, although the safety and efficacy of induction are still a matter of debate. In this study, two iHTN treatment algorithms were compared with different approaches toward setting pressure targets. METHODS: In a cohort of 325 consecutive patients with subarachnoid hemorrhage, 139 patients were treated by induced hypertension as a first tier treatment. On diagnosing DCI, blood pressure was raised via norepinephrine infusion in 20-mm Hg increments in 37 patients (iHTNincr), whereas 102 patients were treated by immediate elevation to systolic pressure above 180 mm Hg (iHTNimm). Treatment choice was based on personal preference of the treating physician but with a gradual shift away from incremental elevation. Both groups were evaluated for DCI-caused infarction, the need of additional endovascular rescue treatment, the occurrence of pressor-treatment-related complications, and clinical outcome assessed by the extended Glasgow outcome scale after 12 months. RESULTS: The rate of refractory DCI requiring additional rescue therapy was comparable in both groups (48.9% in iHTNincr, 40.0% in iHTNimm; p = 0.332). The type of induced hypertension was not independently associated with the occurrence of DCI-related infarction in a logistic regression model (odds ratio 1.004; 95% confidence interval 0.329-3.443; p = 0.942). Similar rates of pressor-treatment-related complications were observed in both treatment groups. Favorable outcome was reached in 44 (43.1%) patients in the immediate vs. 10 (27.0%) patients in the incremental treatment group (p = 0.076). However, only Hunt and Hess grading was identified as an independent predictor variable of clinical outcome (odds ratio 0.422; 95% confidence interval 0.216-0.824; p = 0.012). CONCLUSIONS: Immediate induction of hypertension with higher pressure targets did not result in a lower rate of DCI-related infarctions but was not associated with a higher complication rate compared with an incremental approach. Future tailored blood pressure management based on patient- and time-point-specific needs will hopefully better balance the neurological advantages versus the systemic complications of induced hypertension.

Vector Angle Analysis of Multimodal Neuromonitoring Data for Continuous Prediction of Delayed Cerebral Ischemia.

BACKGROUND: Dysfunctional cerebral autoregulation often precedes delayed cerebral ischemia (DCI). Currently, there are no data-driven techniques that leverage this information to predict DCI in real time. Our hypothesis is that information using continuous updated analyses of multimodal neuromonitoring and cerebral autoregulation can be deployed to predict DCI. METHODS: Time series values of intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure (CPP), optimal CPP (CPPOpt), ΔCPP (CPP - CPPOpt), mean arterial pressure, and pressure reactivity index were combined and summarized as vectors. A validated temporal signal angle measurement was modified into a classification algorithm that incorporates hourly data. The time-varying temporal signal angle measurement (TTSAM) algorithm classifies DCI at varying time points by vectorizing and computing the angle between the test and reference time signals. The patient is classified as DCI+ if the error between the time-varying test vector and DCI+ reference vector is smaller than that between the time-varying test vector and DCI- reference vector. Finally, prediction at time point t is calculated as the majority voting over all the available signals. The leave-one-patient-out cross-validation technique was used to train and report the performance of the algorithms. The TTSAM and classifier performance was determined by balanced accuracy, F1 score, true positive, true negative, false positive, and false negative over time. RESULTS: One hundred thirty-one patients with aneurysmal subarachnoid hemorrhage who underwent multimodal neuromonitoring were identified from two centers (Columbia University: 52 [39.7%], Aachen University: 79 [60.3%]) and included in the analysis. Sixty-four (48.5%) patients had DCI, and DCI was diagnosed 7.2 ± 3.3 days after hemorrhage. The TTSAM algorithm achieved a balanced accuracy of 67.3% and an F1 score of 0.68 at 165 h (6.9 days) from bleed day with a true positive of 0.83, false positive of 0.16, true negative of 0.51, and false negative of 0.49. CONCLUSIONS: A TTSAM algorithm using multimodal neuromonitoring and cerebral autoregulation calculations shows promise to classify DCI in real time.

Invasive Multimodal Neuromonitoring in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review.

Background and Purpose: Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care. Methods: Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (ptiO2), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment. Results: Forty-seven studies reporting INM in the context of DCI were included (ptiO2: N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring. Conclusions: Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

Dynamic Detection of Delayed Cerebral Ischemia: A Study in 3 Centers.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage negatively impacts long-term recovery but is often detected too late to prevent damage. We aim to develop hourly risk scores using routinely collected clinical data to detect DCI. METHODS: A DCI classification model was trained using vital sign measurements (heart rate, blood pressure, respiratory rate, and oxygen saturation) and demographics routinely collected for clinical care. Twenty-two time-varying physiological measures were computed including mean, SD, and cross-correlation of heart rate time series with each of the other vitals. Classification was achieved using an ensemble approach with L2-regularized logistic regression, random forest, and support vector machines models. Classifier performance was determined by area under the receiver operating characteristic curves and confusion matrices. Hourly DCI risk scores were generated as the posterior probability at time t using the Ensemble classifier on cohorts recruited at 2 external institutions (n=38 and 40). RESULTS: Three hundred ten patients were included in the training model (median, 54 years old [interquartile range, 45-65]; 80.2% women, 28.4% Hunt and Hess scale 4-5, 38.7% Modified Fisher Scale 3-4); 101 (33%) developed DCI with a median onset day 6 (interquartile range, 5-8). Classification accuracy before DCI onset was 0.83 (interquartile range, 0.76-0.83) area under the receiver operating characteristic curve. Risk scores applied to external institution datasets correctly predicted 64% and 91% of DCI events as early as 12 hours before clinical detection, with 2.7 and 1.6 true alerts for every false alert. CONCLUSIONS: An hourly risk score for DCI derived from routine vital signs may have the potential to alert clinicians to DCI, which could reduce neurological injury.

Treatment of Delayed Cerebral Ischemia in Good-Grade Subarachnoid Hemorrhage: Any Role for Invasive Neuromonitoring?

BACKGROUND: Good-grade aneurysmal subarachnoid hemorrhage (Hunt and Hess 1-2) is generally associated with a favorable prognosis. Nonetheless, patients may still experience secondary deterioration due to delayed cerebral ischemia (DCI), contributing to poor outcome. In those patients, neurological assessment is challenging and invasive neuromonitoring (INM) may help guide DCI treatment. METHODS: An observational analysis of 135 good-grade SAH patients referred to a single tertiary care center between 2010 and 2018 was performed. In total, 54 good-grade SAH patients with secondary deterioration evading further neurological assessment, were prospectively enrolled for this analysis. The cohort was separated into two groups: before and after introduction of INM in 2014 (pre-INMSecD: n = 28; post-INMSecD: n = 26). INM included either parenchymal oxygen saturation measurement (ptiO2), cerebral microdialysis or both. Episodes of DCI (ptiO2 < 10 mmHg or lactate/pyruvate > 40) were treated via induced hypertension or in refractory cases by endovascular means. The primary outcome was defined as the extended Glasgow outcome scale after 12 months. In addition, we recorded the amount of imaging studies performed and the occurrence of silent and overall DCI-related infarction. RESULTS: Secondary deterioration, impeding neurological assessment, occurred in 54 (40.0%) of all good-grade SAH patients. In those patients, a comparable rate of favorable outcome at 12 months was observed before and after the introduction of INM (pre-INMSecD 14 (50.0%) vs. post-INMSecD 16, (61.6%); p = 0.253). A significant increase in good recovery (pre-INMSecD 6 (50.0%) vs. post-INMSecD 14, (61.6%); p = 0.014) was observed alongside a reduction in the incidence of silent infarctions (pre-INMSecD 8 (28.6%) vs. post-INMSecD 2 (7.7%); p = 0.048) and of overall DCI-related infarction (pre-INMSecD 12 (42.8%) vs. post-INMSecD 4 (23.1%); p = 0.027). The number of CT investigations performed during the DCI time frame decreased from 9.8 ± 5.2 scans in the pre-INMSecD group to 6.1 ± 4.0 (p = 0.003) in the post-INMSecD group. CONCLUSIONS: A considerable number of patients with good-grade SAH experiences secondary deterioration rendering them neurologically not assessable. In our cohort, the introduction of INM to guide DCI treatment in patients with secondary deterioration increased the rate of good recovery after 12 months. Additionally, a significant reduction of CT scans and infarction load was recorded, which may have an underestimated impact on quality of life and more subtle neuropsychological deficits common after SAH.

Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity.

Elevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCB:albumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3 + ß3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/A = 0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/A = 1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function. Acutely administered UCB (U/A = 0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Cav2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Cav2.3 channels. Together, these findings show that UCB affects cloned and native Cav2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.

Surgical nuances and placement of subgaleal drains for supratentorial procedures-a prospective analysis of efficacy and outcome in 150 craniotomies.

BACKGROUND: For supratentorial craniotomy, surgical access, and closure technique, including placement of subgaleal drains, may vary considerably. The influence of surgical nuances on postoperative complications such as cerebrospinal fluid leakage or impaired wound healing overall remains largely unclear. With this study, we are reporting our experiences and the impact of our clinical routines on outcome in a prospectively collected data set. METHOD: We prospectively observed 150 consecutive patients undergoing supratentorial craniotomy and recorded technical variables (type/length of incision, size of craniotomy, technique of dural and skin closure, type of dressing, and placement of subgaleal drains). Outcome variables (subgaleal hematoma/CSF collection, periorbital edema, impairment of wound healing, infection, and need for operative revision) were recorded at time of discharge and at late follow-up. RESULTS: Early subgaleal fluid collection was observed in 36.7% (2.8% at the late follow-up), and impaired wound healing was recorded in 3.3% of all cases, with an overall need for operative revision of 6.7%. Neither usage of dural sealants, lack of watertight dural closure, and presence of subgaleal drains, nor type of skin closure or dressing influenced outcome. Curved incisions, larger craniotomy, and tumor size, however, were associated with an increase in early CSF or hematoma collection (p < 0.0001, p = 0.001, p < 0.01 resp.), and larger craniotomy size was associated with longer persistence of subgaleal fluid collections (p < 0.05). CONCLUSIONS: Based on our setting, individual surgical nuances such as the type of dural closure and the use of subgaleal drains resulted in a comparable complication rate and outcome. Subgaleal fluid collections were frequently observed after supratentorial procedures, irrespective of the closing technique employed, and resolve spontaneously in the majority of cases without significant sequelae. Our results are limited due to the observational nature in our single-center study and need to be validated by supportive prospective randomized design.