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.

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.

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).

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.

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.

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.

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).

MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH.

BACKGROUND: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH. METHODS: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA. RESULTS: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI. CONCLUSION: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.

Early diffusion-weighted MRI lesions after treatment of unruptured intracranial aneurysms: a prospective study.

OBJECTIVE Diffusion-weighted MRI was used to assess periprocedural lesion load after repair of unruptured intracranial aneurysms (UIA) by microsurgical clipping (MC) and endovascular coiling (EC). METHODS Patients with UIA were assigned to undergo MC or EC according to interdisciplinary consensus and underwent diffusion-weighted imaging (DWI) 1 day before and 1 day after aneurysm treatment. Newly detected lesions by DWI after treatment were the primary end point of this prospective study. Lesions detected by DWI were categorized as follows: A) 1-3 DWI spots < 10 mm, B) > 3 DWI spots < 10 mm, C) single DWI lesion > 10 mm, or D) DWI lesion related to surgical access. RESULTS Between 2010 and 2014, 99 cases were included. Sixty-two UIA were treated by MC and 37 by EC. There were no significant differences between groups in age, sex, aneurysm size, occurrence of multiple aneurysms in 1 patient, or presence of lesions detected by DWI before treatment. Aneurysms treated by EC were significantly more often located in the posterior circulation (p < 0.001). Diffusion-weighted MRI detected new lesions in 27 (43.5%) and 20 (54.1%) patients after MC and EC, respectively (not significant). The pattern of lesions detected by DWI varied significantly between groups (p < 0.001). Microembolic lesions (A and B) found on DWI were detected more frequently after EC (A, 14 cases; B, 5 cases) than after MC (A, 5 cases), whereas C and D were rare after EC (C, 1 case) and occurred more often after MC (C, 12 cases and D, 10 cases). No procedure-related unfavorable outcomes were detected. CONCLUSIONS According to the specific techniques, lesion patterns differ between MC and EC, whereas the frequency of new lesions found on DWI is similar after occlusion of UIA. In general, the lesion load was low in both groups, and lesions were clinically silent. Clinical trial registration no.: NCT01490463 ( clinicaltrials.gov ).

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group.

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

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.

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.

Aneurysm Location as a Prognostic Outcome Factor After Subarachnoid Hemorrhage From Internal Carotid Artery Aneurysms and Potential Impact for Further Experimental Subarachnoid Hemorrhage Models.

OBJECTIVE: Prognostic factors of favorable and unfavorable clinical outcome after aneurysmal subarachnoid hemorrhage (SAH) are still not completely known. We retrospectively analyzed the aneurysm location as a factor for patients' outcome after aneurysmal SAH. METHODS: We retrospectively selected patients from our prospectively collected database with aneurysm at the carotid bifurcation artery (n = 23) and posterior communicating artery (n = 170). Outcome was assessed using the modified Rankin Scale (mRS) (favorable [mRS score, 0-2] vs. unfavorable [mRS score, 3-6]) 6 months after SAH. RESULTS: A good clinical admission status (World Federation of Neurological Surgery grade I-III) has a significant influence on mRS score after SAH. In univariate analysis, advanced age, Fisher grade 3, early hydrocephalus, severity of cerebral vasospasm (CVS), longer stay on the intensive care unit, and posterior communicating artery aneurysms were associated with an unfavorable outcome. Multivariate analysis showed 4 prognostic factors for a favorable outcome: good admission status (odds ratio [OR], 10.8); aneurysms of carotid bifurcation artery (OR, 4.3); absence of mild or severe CVS (OR, 3.4); and patients age less than 55 years (OR, 2.1). CONCLUSIONS: Despite the usual prognostic factors (good admission status, younger age, absence of CVS) for a favorable outcome after SAH, the aneurysm location (carotid bifurcation artery) itself seems to be a prognostic factor. Also, aneurysms of the carotid bifurcation artery showed less occurrence of an early hydrocephalus, which is an indicator for the presence of an early brain injury. According to these results, we question if experimental animal models (especially the endovascular model using the perforation of the carotid bifurcation artery) have to be re-evaluated.

Non-aneurysmal non-perimesencephalic subarachnoid hemorrhage: effect of rehabilitation at short-term and in a prospective study of long-term follow-up.

BACKGROUND: A recently published prospective study identified an impaired outcome of patients with non-perimesencephalic (NPM) subarachnoid hemorrhage (SAH). Our objective was to analyze the long-term outcome of patients with subsequent rehabilitation after NPM SAH. METHODS: A comparison of patients with NPM SAH receiving subsequent in-patient rehabilitation was done at discharge (using the modified Rankin scale (mRS)), short-term outcome after 6 months (mRS), and prospectively using a questionnaire (short-form health survey with 36 questions (SF-36)), which was sent to 66 patients. RESULTS: Thirty-seven patients answered the SF-36, on average 6.3 years after ictus (range 1.5-14 years). After NPM SAH, the mRS is impaired. Patients with subsequent rehabilitation had a significant better improvement until short-term follow-up. Until long-term outcome, the psychological items were non-significantly reduced, whereas all physical items (physical functioning, role limitations because of physical health problems, bodily pain, and general health perceptions) were significantly decreased compared to the standard population. In patients with subsequent rehabilitation, all items were only non-significantly reduced. About 16% of the patients developed secondary neurological and/or psychiatric diseases. CONCLUSIONS: The quality of life (QoL) is decreased after NPM SAH. In the long-term follow-up, a significant reduction in physical items was identified. Due to subsequent in-patient rehabilitation after NPM SAH, the impairment can be improved significantly until short-term follow-up. Whereas patients with NPM SAH had a significantly decreased QoL at long-term follow-up, for patients with rehabilitation, the QoL was only slightly (non-significantly) reduced. Therefore, patients should receive subsequent rehabilitation after NPM SAH to improve the functional short-term outcome (mRS) and long-term QoL. www.clinicaltrials.gov (Identifier No. NCT02334657).

Cerebral vasospasm and delayed cerebral infarctions in 225 patients with non-aneurysmal subarachnoid hemorrhage: the underestimated risk of Fisher 3 blood distribution.

OBJECTIVE: Recent data have shown increasing numbers of non-aneurysmal subarachnoid hemorrhage (NASAH). However, data are limited and often only small series have been published. Our objective was to analyze the rate of cerebral vasospasm (CVS), delayed cerebral infarction (DCI), and their influence on the clinical outcome, especially in patients with diffuse Fisher 3 bleeding pattern NASAH (Fi3). METHODS: Between 1999 and 2014, 225 patients had NASAH. CVS, DCI, and outcome (according to the modified Rankin Scale at 6 months) were analyzed retrospectively. Patients were stratified according to the bleeding type. After univariate analysis a multivariate analysis was performed and NASAH Fi3 was also compared with aneurysmal SAH Fi3. RESULTS: Patient characteristics and the outcome of perimesencephalic (PM) and non-PM (NPM) SAH were similar. Excluding Fi3, PM and NPM without Fi3 had similar patient characteristics, clinical course, and outcome. In particular, the Fi3 subgroup had a significantly increased risk of CVS, DCI, unfavorable outcome, hydrocephalus, and death. Early hydrocephalus was associated with Fi3 and intraventricular hemorrhage. The multivariate regression model showed the variables elderly patients, Fi3, and early hydrocephalus as independent and significant predictors for an unfavorable outcome. A further comparison of NASAH Fi3 with aneurysmal SAH Fi3 showed similar characteristics, CVS rate, and mortality. CONCLUSIONS: Patients with NASAH without a Fi3 bleeding pattern had a similar excellent outcome to patients with PM-SAH. Patients with Fi3 had a high risk for early hydrocephalus, CVS, DCI, and an unfavorable outcome, similar to patients with aneurysmal SAH. After multivariate analysis, early hydrocephalus, elderly patients, and Fi3 were identified as negative prognostic factors. Therefore, patients with Fi3 are at risk and need careful clinical observation.

Outcome of Patients with Long-Lasting Cerebral Vasospasm After Subarachnoid Hemorrhage: Is Prolonged Treatment for Cerebral Vasospasm Worthwhile? A Matched-Pair Analysis.

OBJECTIVE: Cerebral vasospasm (CVS) occurs regularly between days 3 and 12 after subarachnoid hemorrhage (SAH). Yet, some patients suffering from SAH have long-lasting cerebral vasospasm (LL-CVS, i.e., longer than 14 days). The outcome of these patients with a very long treatment is unknown. METHODS: Patients with SAH were entered into a prospectively collected database. In unconscious patients, CVS was treated until a reversal of CVS was confirmed by imaging. Outcome was assessed with the modified Rankin Scale (mRS; favorable [mRS 0-2] and unfavorable [mRS 3-6]) 6 months after SAH. Data were compared by matched pair analysis. RESULTS: Of 1126 patients, 106 had LL-CVS (9.4%). The mean of treatment was until day 20 (range, 15-42). Of these patients, more than 30% needed treatment longer than 21 days after SAH; 29% had a small intracerebral hematoma (ICH; <50 mL). Hydrocephalus that required external ventricular drainage was present in 81%. Outcomes were favorable in 60%, and 8% died. In the multivariate logistic regression analysis, risk factors for an unfavorable outcome were elderly patients, poor admission status, and the presence of small ICH. Compared with the matched control group, who had "regular-lasting" CVS, patients with LL-CVS had a significant better outcome (60% vs. 49%) and a significant lower mortality rate (8% vs. 27%). CONCLUSION: Patients with LL-CVS had a significant better outcome than patients with "regular-lasting" CVS. Risk factors for worse outcome of patients with LL-CVS were a worse admission status, elderly age, and the presence of small ICH. We recommend using an objective method to validate the reversal of CVS in unconscious patients.