Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study.

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65-0.84), P = 0.0014] but specificity was 0.59 (0.47-0.70), i.e. <0.80 (P < 0.0001). Nevertheless, the area under the receiver operating characteristic (AUROC) curve of delayed depression duration was 0.76 (0.69-0.83, P < 0.0001) for delayed infarction and 0.88 (0.81-0.94, P < 0.0001) for delayed ischaemia (reversible delayed neurological deficit or infarction). In secondary analysis, a new 180-min cut-off indicated delayed infarction with a targeted 0.62 sensitivity and 0.83 specificity. In awake patients, the AUROC curve of delayed depression duration was 0.84 (0.70-0.97, P = 0.001) and the prespecified 60-min cut-off showed 0.71 sensitivity and 0.82 specificity for reversible neurological deficits. In multivariate analysis, delayed depression duration (ß = 0.474, P < 0.001), delayed median Glasgow Coma Score (ß = -0.201, P = 0.005) and peak transcranial Doppler (ß = 0.169, P = 0.016) explained 35% of variance in delayed infarction. Another key finding was that spreading depolarization-variables were included in every multiple regression model of early, delayed and total brain damage, patient outcome and death, strongly suggesting that they are an independent biomarker of progressive brain injury. While the 60-min cut-off of cumulative depression in a 24-h window indicated reversible delayed neurological deficit, only a 180-min cut-off indicated new infarction with >0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented.

Activation of Platelets and Occurrence of Cerebral Vasospasm and Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage in a Prospective Pilot-Trial.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) often leads to poor outcome. The aim of the study was to assess platelet function in patients after SAH. METHODS: In this prospective observational study in patients suffering from SAH, platelet count and aggregability were assessed by multiple electrode aggregometry (MEA) over 14 days. RESULTS: In 12 of 18 patients, cerebral vasospasms (CVS) were diagnosed; of those, five developed delayed cerebral ischemia (DCI). We observed a significant increase in the platelet count compared to baseline from day 8 onwards (p < 0.037) and, in patients with CVS and DCI, a significant difference in outcome classified by the mRS (p = 0.047). Repeated measures ANOVA determined no differences in platelet aggregability in patients with or without CVS/DCI. CONCLUSIONS: Besides an increase in platelet count, we detected no increase in platelet aggregability. Nevertheless, patients after SAH may have increased platelet aggregability, which is not reflected by MEA.

Complication rate of intraarterial treatment of severe cerebral vasospasm after subarachnoid hemorrhage with nimodipine and percutaneous transluminal balloon angioplasty: Worth the risk?

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (SAH). Arterial cerebral vasospasm (CVS) is discussed as the main pathomechanism for DCI. Due to positive effects of per os nimodipine, intraarterial nimodipine application is used in patients with DCI. Further, percutaneous transluminal balloon angioplasty (PTA) is applied in focal high-grade spasm of intracranial arteries. However, clinical benefits of those techniques are unconfirmed in randomized trials so far, and complications might occur. We analyzed the occurrence of new infarcts in patients with severe CVS treated intra-arterially to assess benefits and risks of those techniques in a large single-center collective. MATERIALS AND METHODS: All imaging and clinical data of 88 patients with CVS after SAH and 188 procedures of intraarterial nimodipine infusion and additional PTA in selected cases (18 patients, 20 PTA procedures) treated at our institution were reviewed. In the event of new infarcts after endovascular treatment of CVS, infarct patterns were analyzed to determine the most probable etiology. RESULTS: Fifty-three percent of patients developed new cerebral infarction after intraarterial nimodipine and additional PTA in selected cases. Hereunder 47% were caused by persisting CVS. In 6% of patients, 3% of procedures respectively, new infarcts occurred due to complications of the intraarterial treatment including thromboembolism and arterial dissection. Of those, 3% of patients, 2% of procedures respectively, were assigned to thrombembolic complications of digital substraction angiography for intraarterial nimodipine. 17% of all patients treated with PTA (3/18=17%) showed infarction as a complication of PTA (15% of all PTA procedures). In 1% of patients, etiology of new infarction remained unclear. CONCLUSION: Ischemic complications occur in about 6% of patients treated intraarterially for CVS, 3% of procedures respectively. Further, to date a benefit for patients treated with this therapy could not be proven. Therefore, intraarterial treatment of CVS should be performed only in carefully selected cases.

Outcome and prognostic factors after delayed second subarachnoid haemorrhage.

BACKGROUND: Data of patients suffering from delayed second subarachnoid haemorrhage (SAH) after aneurysm treatment are still missing. Patients become clearly older than before. Thus, the risk suffering from a second delayed SAH rises. The aim of this study was to analyse clinical outcome and prognostic factors in patients after delayed second SAH. METHOD: From 1999 to 2013, 18 of 1,493 patients (1.2%) suffered from a second SAH. Clinical and radiological characteristics were entered into a prospective conducted database. Outcome was assessed according to modified Rankin Scale 6 months after second SAH. P < 0.05 was considered statistically significant. RESULTS: Eighteen patients were admitted to our department with a second SAH. The second SAH occurred at a mean interval of 144 months after surgical treatment and 78 months after endovascular treatment (P < 0.05), with an overall mean interval of 125 months. The earliest event of second SAH was after 35 months. In 11 (61%) patients, a de novo aneurysm was detected; in one patient (6%), no cause of second SAH was detected. In six (33%) cases, re-rupture of the formerly secured aneurysm was found. Half of the rebleedings occurred from a basilar aneurysm, 33% from an aneurysm of anterior communicating artery and in one patient from a median cerebral artery aneurysm. At second SAH, 8 of 18 patients presented WFNS grade I-III at time of admission (44%). Overall, favourable outcome was achieved in seven patients (39%). Four patients died (22%), one of them before treatment. Favourable outcome seems to be associated with younger age. In our patients, 39% achieved a favourable outcome after second SAH. CONCLUSIONS: A delayed second SAH is a rare entity. After delayed second SAH, age seems to be a prognostic factor for patients' outcome and patients seem to have a worse prognosis. Nonetheless, up to 40% of patients can achieve a favourable outcome.

Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage?

BACKGROUND: Under physiological cerebral conditions, levosimendan, a calcium-channel sensitizer, has a dose-dependent antagonistic effect on prostaglandin F2alpha (PGF)-induced vasoconstriction. This circumstance could be used in antagonizing delayed cerebral vasospasm (dCVS), one of the main complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and ischemic neurological deficits. Data already exist that identified neuroprotective effects of levosimendan in a traumatic brain injury model and additionally, it has been proven that this compound prevents narrowing of the basilar artery (BA) luminal area after SAH in an in vitro rabbit model. Takotsubo cardiomyopathy, a severe ventricular dysfunction, is also a well-known complication after SAH, associated with pulmonary edema and prolonged intubation. METHODS: The polypeptide endothelin-1 (ET-1) plays a key role in the development of dCVS after SAH. Therefore, the aim of the present investigation was to detect functional interactions between the calcium-sensitizing and the ET-1-dependent vasoconstriction after experimental-induced SAH; interactions between levosimendan and a substrate-specific vasorelaxation in the BA were also examined. It was reviewed whether levosimendan has a beneficial influence on endothelin(A) and/or endothelin(B1) receptors (ET-(A) and ET-(B1) receptors) in cerebral vessels after SAH. We also examined whether this drug could have antagonistic effects on a PGF-induced vasoconstriction. RESULTS: Under treatment with levosimendan after SAH, the endothelin system seems to be affected. The ET-1-induced contraction is decreased, not significantly. In addition, we detected changes in the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway. Preincubation with levosimendan causes a modulatory effect on the ET-(B1) receptor-dependent vasorelaxation. It induces an upregulation of the NO-cGMP pathway with a significantly increased relaxation. Even after PGF-induced precontraction a dose-dependent relaxation was registered, which was significantly higher (Emax) and earlier (pD2) compared to the concentration-effect curve without levosimendan. CONCLUSIONS: After experimental-induced dCVS, levosimendan seems to restore the well-known impaired function of the vasorelaxant ET-(B1) receptor. Levosimendan also reversed the PGF-induced contraction dose-dependently. Both of these mechanisms could be used for antagonizing dCVS in patients suffering SAH. Levosimendan could even be used additionally in treating patients developing takotsubo cardiomyopathy.

The Impact of Tracheostomy Timing on Clinical Outcome and Adverse Events in Poor-Grade Subarachnoid Hemorrhage.

OBJECTIVE: The value of optimal timing of tracheostomy in patients with subarachnoid hemorrhage is controversially debated. This study investigates whether early or late tracheostomy is associated with beneficial outcome or reduced rates of adverse events. DESIGN: Retrospective observational multicentric on patients prospectively inserted into a database. SETTING: Neurologic ICUs of one academic hospital and two secondary hospitals in Germany. PATIENTS: Data of all patients admitted to the Goethe University Hospital between 2006 and 2011 with poor-grade subarachnoid hemorrhage were prospectively entered into a database. All patients who underwent tracheostomy were included for analysis. Follow-up was maintained in primary and secondary ICUs. INTERVENTIONS: Patients underwent tracheostomy upon expected long-term ventilation. Early tracheostomy was defined as performed on days 1-7 and late tracheostomy on days 8-20 after admission. MEASUREMENT AND MAIN RESULTS: We compared 148 consecutive patients admitted with poor-grade (World Federation of Neurosurgical Societies, 3-5) subarachnoid hemorrhage. Early tracheostomy was performed in 39 patients and late tracheostomy in 109 patients. In early versus late tracheostomy groups, no significant differences were observed with regard to ICU mortality (7.7% vs 7.3%; p=0.93) and median modified Rankin Scale after 6 months (3 vs 3; p=0.94). Of the early group, pneumonia developed in 19 patients, whereas in the late group, pneumonia developed in 75 patients (48.7% vs 68.8%; p=0.03; odds ratio, 2.32; 95% CI, 1.1-4.9). Six patients of the early group (15.4%) and 36 patients of the late group (33%) suffered from respiratory adverse event (p=0.04; odds ratio, 2.71; 95% CI, 1.04-7.06). Mechanical ventilation was shorter (17.4 vs 22.3 d; p<0.05) and decannulation occurred earlier (42 vs 54 d; p=0.039) in the early tracheostomy group. CONCLUSIONS: Tracheostomy within 7 days of critical care admission is a feasible and safe procedure for patients with poor-grade subarachnoid hemorrhage. Early tracheostomy was not associated with an improvement in mortality or neurologic outcome but associated with fewer respiratory adverse events.

Clinical outcome and prognostic factors of patients with angiogram-negative and non-perimesencephalic subarachnoid hemorrhage: benign prognosis like perimesencephalic SAH or same risk as aneurysmal SAH?

Subarachnoid hemorrhage (SAH) is usually caused by a ruptured intracranial aneurysm. However, in some patients, no source of hemorrhage might be detected despite repeated digital subtraction angiography (DSA). Our objective was to analyze factors influencing the clinical outcome in patients suffering from non-aneurysmal and non-perimesencephalic (NPM) SAH. Between 1999 and 2011, 68 of 1,188 patients with SAH (5.7%) suffered from non-aneurysmal and NPM-SAH. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months (mRS 0-2 favorable vs. 3-6 unfavorable). In patients with angiogram-negative and NPM-SAH, favorable outcome was achieved in 56 patients (82.4%). In the multivariate analysis, age <65 years and non-Fisher 3 bleeding pattern were significantly associated with favorable outcome. Angiogram-negative and NPM-SAH had good prognoses. Patients with non-Fisher-type 3 bleeding had excellent outcomes similar to patients with perimesencephalic SAH, but patients with Fisher-type 3 bleeding were at risk for poor outcome like aneurysmal SAH patients due to cerebral vasospasm and delayed cerebral ischemia. Age and bleeding type were detected as prognostic factors in the multivariate analysis.

Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients.

BACKGROUND: Subarachnoid hemorrhage (SAH) is mainly caused by ruptured cerebral aneurysms but in up to 15% of patients with SAH no bleeding source could be identified. Our objective was to analyze patient characteristics, clinical outcome and prognostic factors in patients suffering from non-aneurysmal SAH. METHODS: From 1999 to 2009, data of 125 patients with non-aneurysmal SAH were prospectively entered into a database. All patients underwent repetitive cerebral angiography. Outcome was assessed according to the modified Rankin Scale (mRS) (mRS 0-2 favorable vs. 3-6 unfavorable). Also, patients were divided in two groups according to the distribution of blood in the CT scan (perimesencephalic and non-perimesencephalic SAH). RESULTS: 106 of the 125 patients were in good WFNS grade (I-III) at admission (85%). Overall, favorable outcome was achieved in 104 of 125 patients (83%). Favorable outcome was associated with younger age (P < 0.001), good admission status (P < 0.0001), and absence of hydrocephalus (P = 0.001).73 of the 125 patients suffered from perimesencephalic SAH, most patients (90%) were in good grade at admission, and 64 achieved favorable outcome.52 of the 125 patients suffered from non-perimesencephalic SAH and 40 were in good grade at admission. Also 40 patients achieved favorable outcome. CONCLUSIONS: Patients suffering from non-aneurysmal SAH have better prognosis compared to aneurysm related SAH and poor admission status was the only independent predictor of unfavorable outcome in the multivariate analysis. Patients with a non-perimesencephalic SAH have an increased risk of a worse neurological outcome. These patients should be monitored attentively.

Frequency, risk of hemorrhage and treatment considerations for cerebral arteriovenous malformations with associated aneurysms.

BACKGROUND: Data on arteriovenous malformations (AVMs) of the brain with AVM-associated aneurysms (AAA) are scarce. This study addresses the incidence, rate of hemorrhage, treatment strategies and stability during follow-up in a neurovascular center. METHODS: We retrospectively reviewed patients harboring an AVM with at least one AAA treated at our neurovascular center between 2002 and 2013. RESULTS: Of 216 patients, 59 (27.3%) had at least one AAA (n = 92 aneurysms total). Compared to patients without AAA, hemorrhagic presentation occurred more frequently (61.0% versus 43.9%, p = 0.025), and the rate of infratentorial AVMs was higher (37.3% versus 16.6%, p = 0.001). The aneurysm was the origin of the bleeding in most cases, most often categorized as a feeding artery aneurysm. Overall, the first and recurrent hemorrhage were associated with a high mortality and morbidity (15.3% and 39%, respectively). Aneurysms were treated by coiling (n = 21), surgery (n = 18), or embolizaton with liquid embolization agents (n = 11). All aneurysms treated by embolization and surgery remained occluded during follow-up (mean follow-up 39.0 ± 45.0 months). However, in incomplete AVM obliteration, significant recurrence of the treated aneurysm was noted after endovascular coiling (37.5%), which may be related to the persistence of pathological blood flow. CONCLUSION: In our series, AAA was a significant risk factor for hemorrhage and was associated with a poor outcome. It seems worthwhile to consider whether the aneurysm itself is a risk factor or only an epiphenomenon of severely altered hemodynamics induced by these special AVMs and therefore only the most common site of rupture. As the complication rate was low for aneurysm occlusion, we recommend treating these aneurysms whenever possible. Furthermore, obliteration of the AVM should be strived for as this subtype may be associated with an increased risk of hemorrhage.

Natural history of small unruptured anterior circulation aneurysms: a prospective cohort study.

BACKGROUND AND PURPOSE: The natural history of small unruptured intracranial aneurysms of the anterior circulation in the European population is unclear. Therefore, the management of unruptured intracranial aneurysms <7 mm in the anterior circulation is controversial. METHODS: Between June 1999 and June 2012, 384 unruptured intracranial aneurysms of the anterior circulation <7 mm in diameter underwent conservative treatment and regular annual follow-up in our institution. Patient- and aneurysm-specific information, as well as information on aneurysm enlargement and rupture, was entered into a prospectively conducted database. RESULTS: The mean follow-up duration was 48.5±37 months. Three aneurysms enlarged during the follow-up period and were treated by surgical clipping. Three aneurysms were ruptured during the follow-up period. The overall annual incidence of subarachnoid hemorrhage was 0.2% during the follow-up. In the multivariate Cox proportional hazard regression analysis, hypertension (P<0.001; hazard ratio, 2.6; 95% confidence interval, 2.1-3.3) and <50 years of age (P=0.04; hazard ratio, 1.3; 95% confidence interval, 1.01-1.7) were significant independent predictors of aneurysm rupture. CONCLUSIONS: The present data indicate that the annual incidence of subarachnoid hemorrhage associated with small anterior circulation unruptured intracranial aneurysms is low in this single-institution prospective cohort study. The natural course varies according to arterial hypertension and patient age.

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts.

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular bloodcomponent to depolarizationcomponent (P = 0.010); and 0.44 for the path from depolarizationcomponent to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarizationcomponent as mediator (path coefficients from bloodcomponent to depolarizationcomponent = 0.23, P = 0.03; path coefficients from depolarizationcomponent to delayed infarctcomponent = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (path coefficients from intraventricular haemorrhage to vasospasmcomponent = 0.24, P = 0.03; path coefficients from vasospasmcomponent to delayed infarctcomponent = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.

Course of Preexisting Migraine Following Spontaneous Subarachnoid Hemorrhage.

Background: Our objective was to observe the course of preexisting migraine following subarachnoid hemorrhage (SAH) in patients with and without craniotomy. Methods: We designed an exploratory analysis and hypothesis-generating study of prospectively collected data starting by recruiting patients suffering from SAH with the Hunt and Hess scale score of ≤ 4. Out of 994 cases, we identified 46 patients with preexisting active migraine defined by at least four attacks in the year before SAH. According to the treatment, we subdivided the patients into two groups: the first group included patients with surgical aneurysm clipping with transection of the middle meningeal artery (MMA) and accompanying trigeminal nerve branches and the second group included patients with endovascular aneurysm coiling or without any interventional treatment. During the follow-up, we recorded the course of migraine frequency, duration, intensity, and character. Results: For both groups (craniotomy n = 31, without craniotomy n = 15), a significant improvement regarding the preexisting migraine during a mean follow-up of 46 months (min. 12 months, max. 114 months) was seen regarding complete remission or at least >50% reduction in migraine attacks (p < 0.001 and p = 0.01). On comparing the groups, this effect was significantly more pronounced in patients with craniotomy (for no recurrence of migraine: p = 0.049). After craniotomy, 77.4% of the patients had no further attacks of migraine headache and 19.4% showed a reduction of >50% while only 2.2% did not report any relevant change. In the non-surgical group, 46.7% had no further migraine attacks, 20% had a reduction of >50%, while no change was noted in 33.3%. Conclusions: Our study provides evidence that the dura mater might be related to migraine headaches and that transection of the MMA and accompanying trigeminal dural nerve branches might disrupt the pathway leading to a reduction of migraine attacks. However, coiling alone ameliorated migraine complaints.

Unsecured intracranial aneurysms and induced hypertension in cerebral vasospasm: is induced hypertension safe?

BACKGROUND: Induced hypertension is an established therapy to treat cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH) to prevent delayed ischemic deficits. Currently, there is minimal evidence available assessing the risk of induced hypertension in the presence of unsecured aneurysms. The aim of this study was to investigate the impact of induced hypertension on the rupturing of unsecured aneurysms in treating CVS. METHODS: We conducted a retrospective analysis between 1999 and 2009. Patients with unsecured aneurysms treated with induced hypertension were identified and stratified as having (1) additional unruptured unsecured aneurysms or (2) ruptured unsecured aneurysms. Hemodynamic parameters were analyzed and any bleeding recorded. RESULTS: Forty-five patients were included. Of those, 41 had 71 additional unruptured unsecured aneurysms and four patients had four ruptured unsecured aneurysms. The mean size of unsecured aneurysms was: 4.0 ± 1.9 mm (additional unruptured) and 5.3 ± 2.2 mm (ruptured), respectively. No aneurysm ruptured during therapy. Combining our data with previously published studies, there appears to be no increase of risk for aneurysm rupture by induced hypertension when compared to the natural history (0.5% for group 1, 2.9% for group 2). CONCLUSION: These data corroborate that induced hypertension may be a safe treatment option to prevent cerebral infarction in CVS, even in the presence of unsecured aneurysms. Our findings suggest that induced hypertension does not increase rupture of unsecured aneurysms. Given the high risk for cerebral infarction in severe CVS, we conclude that induced hypertension should not be omitted due to the presence of unsecured aneurysms.

Early blood-brain barrier dysfunction predicts neurological outcome following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Disease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome. METHODS: Data were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blinded and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24-48 h, 6-8 days, 12-15 days and 6-12 months) after the initial hemorrhage. Volume of brain with apparent pathology and/or BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the World Federation of Neurosurgical Societies and Rosen-Macdonald scores. Outcome at ≥6 months was assessed using the extended Glasgow outcome scale and disease course (progressive or non-progressive based on imaging-detected loss of normal brain tissue in consecutive scans). Logistic regression was used to define biomarkers that best predict outcomes. Receiver operating characteristic analysis was performed to assess accuracy of outcome prediction models. FINDINGS: In the present cohort, 63% of patients had progressive and 37% non-progressive disease course. Progressive course was associated with worse outcome at ≥6 months (sensitivity of 98% and specificity of 97%). Brain volume with BBBD was significantly larger in patients with progressive course already 24-48 h after admission (2.23 (1.23-3.17) folds, median with 95%CI), and persisted at all time points. The highest probability of a BBB-disrupted voxel to become pathological was found at a distance of ≤1 cm from the brain with apparent pathology (0·284 (0·122-0·594), p < 0·001, median with 95%CI). A multivariate logistic regression model revealed power for BBBD in combination with RMS at 24-48 h in predicting outcome (ROC area under the curve = 0·829, p < 0·001). INTERPRETATION: We suggest that early identification of BBBD may serve as a key predictive biomarker for neurological outcome in aSAH. FUND: Dr. Dreier was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (DFG DR 323/5-1 and DFG DR 323/10-1), the Bundesministerium für Bildung und Forschung (BMBF) Center for Stroke Research Berlin 01 EO 0801 and FP7 no 602150 CENTER-TBI. Dr. Friedman was supported by grants from Israel Science Foundation and Canada Institute for Health Research (CIHR). Dr. Friedman was supported by grants from European Union's Seventh Framework Program (FP7/2007-2013; grant #602102).

Disruption of the blood-brain barrier by intra-arterial administration of papaverine: a technical note.

INTRODUCTION: Various endovascular techniques can be used to treat cerebral vasospasm after aneurysmal subarachnoid haemorrhage (SAH) including intra-arterial administration of vasodilator drugs such as papaverine or nicardipine and balloon dilatation of the affected vessel segment. Papaverine is known to have side effects, and we report a possible new one. MATERIALS AND METHODS: After the treatment of cerebral vasospasm in a SAH patient by intra-arterial administration of papaverine into the left posterior cerebral artery, severe mesencephalic extravasation of blood and contrast media was detected. RESULTS: After reviewing the literature, the authors conclude that interruption of the blood-brain barrier by papaverine most likely combined with a secondary hyperperfusion phenomena, and perhaps a direct toxic effect on brain tissue was the mechanism of this major complication. CONCLUSION: In treating vasospasm in areas with a high density of perforating arteries, especially in the posterior circulation, papaverine should be used cautiously because a safe regimen has yet to be established. In this situation, alternative agents such as calcium channel blockers could be considered, but evidence-based data are still missing.

Transsphenoidal Removal of Recurrent Osteoid Osteoma of Clivus.

BACKGROUND: An osteoid osteoma (OO) is a benign bone neoplasm that typically occurs in the long bone diaphysis. We found only 8 cases of OOs of the skull base in the literature, and none of them were located in the clivus. CASE DESCRIPTION: A 44-year-old female patient with a history of 2 previous transsphenoidal surgeries with partial removal of an OO of the clivus at another hospital, 11 and 4 years ago, presented to our department with recurrent progressive left-sided headache and facial pain over the past 6 months, which were aggravated at night. A new computed tomography (CT) scan of the head revealed a low-density, well-demarcated area surrounded by a high-density sclerotic bone in the clivus. A total transsphenoidal microscopic removal of the lesion was performed with the use of intraoperative neuronavigation. The patient recovered from surgery without any new deficits, and the headache was relieved during her inpatient hospital stay. A CT scan of the head that was performed 1 day after surgery revealed the complete removal of the lesion. The patient was discharged on day 5 after surgery. A follow-up examination conducted 3 months after surgery showed that the patient still had no headache or any other symptoms. A follow-up CT scan revealed no remnant or recurrent tumor. CONCLUSION: The transsphenoidal approach with the use of neuronavigation appears to be a good choice to achieve total removal of an OO of the upper part of the clivus in case of persistent pain and lack of sufficient effect by nonsteroidal antiinflammatory drugs.

Rapid ventricular pacing for clip reconstruction of complex unruptured intracranial aneurysms: results of an interdisciplinary prospective trial.

OBJECTIVE To date, treatment of complex unruptured intracranial aneurysms (UIAs) remains challenging. Therefore, advanced techniques are required to achieve an optimal result in treating these patients safely. In this study, the safety and efficacy of rapid ventricular pacing (RVP) to facilitate microsurgical clip reconstruction was investigated prospectively in a joined neurosurgery, anesthesiology, and cardiology study. METHODS Patients with complex UIAs were prospectively enrolled. Both the safety and efficacy of RVP were evaluated by recording cardiovascular events and outcomes of patients as well as the amount of aneurysm occlusion after the surgical clip reconstruction procedure. A questionnaire was used to evaluate aneurysm preparation and clip application under RVP. RESULTS Twenty patients (mean age 51.6 years, range 28-66 years) were included in this study. Electrode positioning was easy in 19 (95%) of 20 patients, and removal of electrodes was easily accomplished in all patients (100%). No complications associated with the placement of the pacing electrodes occurred, such as cardiac perforation or cardiac tamponade. RVP was applied in 16 patients. The mean aneurysm size was 11.1 ± 5.5 mm (range 6-30 mm). RVP proved to be a very helpful tool in aneurysm preparation and clip application in 15 (94%) of 16 patients. RVP was used for a mean duration of 60 ± 25 seconds, a mean heart rate of 173 ± 23 bpm (range 150-210 bpm), and a reduction of mean arterial pressure to 35-55 mm Hg. RVP leads to softening of the aneurysm sac facilitating its mobilization, clip application, and closure of the clip blades. In 2 patients, cardiac events were documented that resolved without permanent sequelae in both. In every patient with successful RVP (n = 14) a total or near-total aneurysm occlusion was documented. In the 1 patient in whom the second RVP failed due to pacemaker electrode dislocation, additional temporary clipping was required to secure the aneurysm, but was not as sufficient as RVP. This led to an incomplete clipping of the aneurysm and finally a remnant on postoperative digital subtraction angiography. A pacemaker lead dislocation occurred in 3 (19%) of 16 patients, but intraoperative repositioning requires less than 20 seconds. Outcome was favorable in all patients according to the modified Rankin Scale. CONCLUSIONS To the best of the authors' knowledge this is the first prospective interdisciplinary study of RVP use in patients with UIAs. RVP is an elegant technique that facilitates clip reconstruction in complex UIAs. The safety of the procedure is good. However, because this procedure requires extensive preoperative cardiological workup of the patient and an experienced neurosurgery and neuroanesthesiology team with much cerebrovascular expertise, actually it remains reserved for selected elective cases and highly specialized centers. Clinical trial registration no.: NCT02766972 (clinicaltrials.gov).

Posterior fossa AVMs: Increased risk of bleeding and worse outcome compared to supratentorial AVMs.

Infratentorial AVMs are often considered as potentially hazardous as they are thought to present more often with hemorrhage, may harbor AVM-associated aneurysms more frequently and to be associated with poor outcome. The aim of our study is to compare features of supratentorial and infratentorial AVMs. We retrospectively analyzed 316 consecutive patients with cerebral AVM presenting to our neurovascular center between 2005 and 2015. Location and angioarchitecture of the AVM including AVM-associated aneurysms, bleeding events, and outcome during follow up were analyzed. Outcome was assessed using the modified Rankin Scale (mRS) and stratified into favorable (mRS 0-2) and unfavorable (mRS 3-6). 41.6% of the patients with a supratentorial AVM (stAVM) and 69.2% of the patients with an infratentorial AVM (itAVM) were presented with a hemorrhage initially (p < .001). Patients with itAVMs were older at presentation (mean 48.1 vs. 37.9 years, p < .001). ItAVMs furthermore were smaller (95.1% <3 cm nidus-diameter, p < .001) and had lower Spetzler-Martin-Grades (p = .04). Associated aneurysms were more frequent in itAVMs (38.5% vs. 20.7%, p < .004) and were associated with an increased risk of hemorrhage at presentation (30.9% vs. 18.7%, p = .013). Outcome was poor in 10.8% of the patients with stAVM and in 28.3% of patients with itAVM (p < .001). The risk of a new hemorrhage-associated deficit was significantly higher in itAVMs (p < .001). Most posterior fossa AVMs are associated with an increased hemorrhage rate. Thus they are a predictor for poor outcome and should be treated even if unruptured to maintain good neurological function.

Increased risk of delayed cerebral ischemia in subarachnoid hemorrhage patients with additional intracerebral hematoma.

OBJECTIVE Delayed cerebral ischemia (DCI) has a major impact on the outcome of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to assess the influence of an additional intracerebral hematoma (ICH) on the occurrence of DCI. METHODS The authors conducted a single-center retrospective analysis of cases of SAH involving patients treated between 2006 and 2011. Patients who died or were transferred to another institution within 10 days after SAH without the occurrence of DCI were excluded from the analysis. RESULTS Additional ICH was present in 123 (24.4%) of 504 included patients (66.7% female). ICH was classified as frontal in 72 patients, temporal in 24, and perisylvian in 27. DCI occurred in 183 patients (36.3%). A total of 59 (32.2%) of these 183 patients presented with additional ICH, compared with 64 (19.9%) of the 321 without DCI (p = 0.002). In addition, DCI was detected significantly more frequently in patients with higher World Federation of Neurosurgical Societies (WFNS) grades. The authors compared the original and modified Fisher Scales with respect to the occurrence of DCI. The modified Fisher Scale (mFS) was superior to the original Fisher Scale (oFS) in predicting DCI. Furthermore, they suggest a new classification based on the mFS, which demonstrates the impact of additional ICH on the occurrence of DCI. After the different scales were corrected for age, sex, WFNS score, and aneurysm site, the oFS no longer was predictive for the occurrence of DCI, while the new scale demonstrated a superior capacity for prediction as compared with the mFS. CONCLUSIONS Additional ICH was associated with an increased risk of DCI in this study. Furthermore, adding the presence or absence of ICH to the mFS improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI.

Outcome, Prognostic Factors, and Follow-Up Results After Subarachnoid Hemorrhage from Pericallosal Artery Aneurysms.

OBJECTIVE: Pericallosal artery aneurysms (PAAs) are usually rare (2%-5%), and treatment is challenging for both surgical and endovascular modalities. We performed this analysis to determine the outcome and prognostic factors after subarachnoidal hemorrhage (SAH) caused by ruptured PAAs. METHODS: A total of 32 patients with ruptured PAA were admitted to our hospital between 1999 and 2014, added to our prospective database, and analyzed retrospectively. Outcome was measured based on the modified Rankin Scale (mRS) at 6 months after ictus (favorable mRS score, 0-2 vs. unfavorable mRS score, 3-6). RESULTS: Only 16 (50%) patients had a good clinical status at admission (World Federation of Neurological Surgeons Grading System [WFNS] grades I-III), whereas 12 patients (37.5%) were comatose (WFNS grade V). In 18 patients (56%), intracerebral hemorrhage was confirmed, in 18 patients (56%) cerebrospinal fluid drainage was required immediately after admission, and in 5 cases (16%) decompressive craniectomy was performed. There were 17 patients (53.1%) who achieved a favorable outcome (mRS score 0-2) at follow-up. Unfavorable outcome was associated with smoking, cerebral infarction, and worse admission status after multiple logistic regression analysis. CONCLUSIONS: Poor admission status, cerebral infarction, and smoking seem to be crucial factors for unfavorable outcome after SAH from PAA.