The role of previous medical history and secondary complications for the outcome of aneurysmal subarachnoid hemorrhage in elderly patients.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) presents a devastating diagnosis for elderly individuals, resulting in high morbidity and mortality rates. The aim of the study was to analyze the impact of medical history and complications during SAH on the outcome of elderly patients. METHODS: Consecutive SAH cases aged ≥ 65 years old treated in our hospital between 01/2003 and 06/2016 were included (n = 218). Data on comorbidities, previous medication, initial severity, secondary complications, and the outcome were collected. Study endpoints were occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months after SAH. RESULTS: Cerebral infarcts were documented in 111 (51.2 % ) individuals. Multivariate analysis showed that angiographic vasospasm caused an increase (adjusted odds ratio [aOR] = 3.11, p = 0.022) in the risk of infarction, whereas aspirin treatment decreased (aOR = 0.25, p = 0.001) the risk of infarction. In turn, increasing age (aOR = 1.11, p = 0.002), intracranial hypertension (>20 mmHg, aOR = 3.32, p = 0.006) and acute kidney failure (aOR = 6.65, p = 0.035) during SAH were independently related to the risk of in-hospital mortality (n = 50; 22.9 % ). Finally, patients' age (aOR = 1.09, p = 0.022), high initial SAH burden (WFNS ≥ 4: aOR = 7.5, p < 0.0001; intraventricular hemorrhage: aOR = 4.38, p = 0.007), aneurysm clipping (aOR = 4.07, p = 0.018), and intracranial hypertension during SAH (aOR = 4.08, p = 0.006) were independent predictors of unfavorable outcome (n = 106/192; 55.5 % ). Previous medical history showed no negative impact on the severity, course and outcome of SAH. CONCLUSION: About half of elderly SAH patients face poor outcomes after aneurysm securing. The initial severity of and complications during SAH are the major contributors to poor treatment results. Our findings might help to optimize the treatment strategies.

The value of ventricular measurements in the prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Chronic hydrocephalus requiring shunt placement is a common complication of aneurysmal subarachnoid hemorrhage (SAH). Different risk factors and prediction scores for post-SAH shunt dependency have been evaluated so far. We analyzed the value of ventricle measurements for prediction of the need for shunt placement in SAH patients. METHODS: Eligible SAH cases treated between 01/2003 and 06/2016 were included. Initial computed tomography scans were reviewed to measure ventricle indices (bifrontal, bicaudate, Evans', ventricular, Huckman's, and third ventricle ratio). Previously introduced CHESS and SDASH scores for shunt dependency were calculated. Receiver operating characteristic analyses were performed for diagnostic accuracy of the ventricle indices and to identify the clinically relevant cut-offs. RESULTS: Shunt placement followed in 221 (36.5%) of 606 patients. In univariate analyses, all ventricular indices were associated with shunting (all: p<0.0001). The area under the curve (AUC) ranged between 0.622 and 0.662. In multivariate analyses, only Huckman's index was associated with shunt dependency (cut-off at ≥6.0cm, p<0.0001) independent of the CHESS score as baseline prediction model. A combined score (0-10 points) containing the CHESS score components (0-8 points) and Huckman's index (+2 points) showed better diagnostic accuracy (AUC=0.751) than the CHESS (AUC=0.713) and SDASH (AUC=0.693) scores and the highest overall model quality (0.71 vs. 0.65 and 0.67), respectively. CONCLUSIONS: Ventricle measurements are feasible for early prediction of shunt placement after SAH. The combined prediction model containing the CHESS score and Huckman's index showed remarkable diagnostic accuracy regarding identification of SAH individuals requiring shunt placement. External validation of the presented combined CHESS-Huckman score is mandatory.

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Acute hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (SAH). Several ventricular indices have been introduced to enable measurements of ventricular morphology. Previously, researchers have showed their diagnostic value for various neurological disorders. In this study, we evaluated the association between ventricular indices and the clinical course, occurrence of complications and outcome of SAH. METHODS: A total of 745 SAH patients with available early admission computed tomography scans were included in the analyses. Six ventricular indices (bifrontal, bicaudate, ventricular and third ventricle ratios and Evans' and Huckman's indices) were measured. Primary endpoints included the occurrence of cerebral infarctions, in-hospital mortality and a poor outcome at 6 months. Secondary endpoints included different adverse events in the course of SAH. Clinically relevant cut-offs for the indices were determined using receiver operating curves. Univariate analyses were performed. Multivariate analyses were conducted on significant findings in a stepwise backward regression model. RESULTS: The higher the values of the ventricular indices were and the older the patient was, the higher the WFNS and Fisher's scores were, and the lower the SEBES score was at admission. Patients with larger ventricles showed a shorter duration of intracranial pressure increase > 20 mmHg and required decompressive craniectomy less frequently. Ventricular indices were independently associated with the parameters of inflammatory response after SAH (C-reactive protein in serum and interleukin-6 in cerebrospinal fluid and fever). Finally, there were independent correlations between larger ventricles and all the primary endpoints. CONCLUSIONS: The lower risk of intracranial pressure increase and absence of an association with vasospasm or systemic infections during SAH, and the poorer outcome in individuals with larger ventricles might be related to a more pronounced neuroinflammatory response after aneurysmal bleeding. These observations might be helpful in the development of specific medical and surgical treatment strategies for SAH patients depending on the initial ventricle measurements.

Regular medication as a risk factor for intracranial aneurysms: A comparative case-control study.

Background: Previous medical history strongly contributes to the genesis of intracranial aneurysms (IA). A possible impact of regular medication on the occurrence of abdominal aortic aneurysms has been reported. Aim: To evaluate the value of regular medication on the risk of development and rupture of IA. Methods: Data on medication use and related comorbidities were obtained from the institutional IA registry. A 1:1 age- and sex-matched patient sample was collected from the population-based Heinz Nixdorf Recall Study with individuals from the same area. Results: In the analysis comparing IA cohort (n = 1960) with the matched normal population (n = 1960), the use of statins (adjusted odds ratio, 1.34 [95% confidence interval 1.02-1.78]), antidiabetics (1.46 [1.08-1.99]), and calcium channel blockers (1.49 [1.11-2.00]) was independently associated with higher risk of IA, whereas uricostatics (0.23 [0.14-0.38]), aspirin (0.23 [0.13-0.43]), beta-blockers (0.51 [0.40-0.66]), and angiotensin-converting enzyme inhibitors (0.38 [0.27-0.53]) were related to lower risk of IA. In the multivariable analysis within the IA cohort (n = 2446), SAH patients showed higher drug exposure with thiazide diuretics (2.11 [1.59-2.80]), but lower prevalence of remaining antihypertensive medication-beta-blockers (0.38 [0.30-0.48]), calcium channel blockers (0.63 [0.48-0.83]), angiotensin-converting enzyme inhibitors (0.56 [0.44-0.72]), and angiotensin-1 receptor blockers (0.33 [0.24-0.45]). Patients with ruptured IA were less likely to be treated with statins (0.62 [0.47-0.81]), thyroid hormones (0.62 [0.48-0.79]), and aspirin (0.55 [0.41-0.75]). Conclusions: Regular medication might impact the risks related to the development and rupture of IA. Further clinical trials are required to clarify the effect of regular medication on IA genesis.

Circadian rhythm and aneurysmal subarachnoid hemorrhage: Is there an alarm clock for the rupture timing?

BACKGROUND AND PURPOSE: Data on the temporal distribution of the bleeding time of intracranial aneurysms are limited to a few small studies. With this study, the aim was to analyze time patterns of the occurrence of aneurysmal subarachnoid hemorrhage (SAH), particularly focusing on the impact of patients' socio-demographic and clinical characteristics on the ictus timing. METHODS: The study is based on an institutional SAH cohort with 782 consecutive cases treated between January 2003 and June 2016. Data were collected on the ictus time, patients' socio-demographic and clinical characteristics, as well as the initial severity and outcome. Univariate and multivariate analyses were performed on the bleeding timeline. RESULTS: There were two peaks in the circadian rhythm of SAH, one in the morning (7-9 a.m.) and the other in the evening (7-9 p.m.). The strongest alterations in the bleeding time patterns were observed for weekdays, patients' age, sex and ethnicity. Individuals with chronic alcohol and painkiller consumption showed a higher bleeding peak between 1 and 3 p.m. Finally, the bleeding time showed no impact on the severity, clinically relevant complications and the outcome of SAH patients. CONCLUSIONS: This study is one of the very few detailed analyses of the impact of specific socio-demographic, ethnic, behavioral and clinical characteristics on the rupture timing of aneurysms. Our results point to the possible relevance of the circadian rhythm for the rupture event, and therefore might be useful in the elaboration of preventive measures against aneurysm rupture.

Comparing radiographic scores for prediction of complications and outcome of aneurysmal subarachnoid hemorrhage: Which performs best?

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high morbidity and mortality proceeding from the initial severity and following complications of aSAH. Various scores have been developed to predict these risks. We aimed to analyze the clinical value of different radiographic scores for prognostication of aSAH outcome. METHODS: Initial computed tomography scans (≤48 h after ictus) of 745 aSAH cases treated between January 2003 and June 2016 were reviewed with regard to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and Claassen, Barrow Neurological Institute (BNI), Hijdra, original Graeb and Fisher scale scores. The primary endpoints were development of delayed cerebral ischemia (DCI), in-hospital mortality and unfavorable outcome (modified Rankin Scale score >3) at 6 months after subarachnoid hemorrhage. Secondary endpoints included the different complications that can occur during aSAH. Clinically relevant cutoffs were defined using receiver-operating characteristic curves. The radiographic scores with the highest values for area under the curve (AUC) were included in the final multivariate analysis. RESULTS: The Hijdra sum score had the most accurate predictive value and independent associations with all primary endpoints: DCI (AUC 0.678, adjusted odds ratio [aOR] 2.83; p < 0.0001); in-hospital mortality (AUC 0.704, aOR 2.83; p < 0.0001) and unfavorable outcome (AUC 0.726, aOR 2.91; p < 0.0001). Multivariate analyses confirmed the independent predictive value of the radiographic scales for risk of decompressive craniectomy (SEBES and Fisher score), cerebral vasospasm (SEBES, BNI score and Fisher score) and shunt dependency (Hijdra ventricle score and Fisher score) after aSAH. CONCLUSIONS: Initial radiographic severity of aSAH was independently associated with occurrence of different complications during aSAH and the final outcome. The Hijdra sum score showed the highest diagnostic accuracy and robust predictive value for early detection of risk of DCI, in-hospital mortality and unfavorable outcome after aSAH.

Small intracranial aneurysms of the anterior circulation: A negligible risk?

BACKGROUND AND PURPOSE: According to the International Study of Unruptured Intracranial Aneurysms, small (<7 mm) unruptured intracranial aneurysms (IAs) of the anterior circulation (aC) carry a neglectable 5-year rupture risk. In contrast, some studies report frequencies of >20% of all ruptured IAs being small IAs of the aC. This contradiction was addressed in this study by analyzing the rates and risk factors for rupture of small IAs within the aC. METHODS: Of the institutional observational cohort, 1676 small IAs of the aC were included. Different demographic, clinical, laboratory, and radiographic characteristics were collected. A rupture risk score was established using all independent prognostic factors. The score performance was checked using receiver operating characteristic curve analysis. RESULTS: Of all registered small IAs of the aC, 20.1% were ruptured. The developed small IAs of the aC (SIAAC) score (range = -4 to +13 points) contained five major risk factors: IA location and size, arterial hypertension, alcohol abuse, and chronic renal failure. In addition, three putative protective factors were also included in the score: hypothyroidism, dyslipidemia, and peripheral arterial disease. Increasing rates of ruptured IA with increasing SIAAC scores were observed, from 0% (≤-1 points) through >50% (≥8 points) and up to 100% in patients scoring ≥12 points. The SIAAC score achieved excellent discrimination (area under the curveSIAAC  = 0.803) and performed better than the PHASES (Population,Hypertension, Age, Size of the aneurysm, Earlier SAH from another aneurysm, Site of aneurysm) score. CONCLUSIONS: Small IAs of the aC carry a considerable rupture risk. After external validation, the proposed rupture risk score might provide a basis for better decision-making regarding the treatment of small unruptured IAs of the aC.

Preoperative cervical traction with Gardner-Wells tongs: who profits most?

BACKGROUND: Preoperative traction with the Gardner-Wells tongs (PTGWT) is a valuable option for cervical spine injuries with malalignment. The aim of this study was to analyze the factors related to the treatment success of PTGWT. METHODS: All consecutive cases with PTGWT due to cervical spine injury with malalignment treated between 01/2010 and 09/2020 were included. Patients' records were reviewed for demographic and clinical characteristics. Treatment success was evaluated upon the angle correction in the sagittal plane using the computed tomography scans before and after the treatment. RESULTS: Of 20 patients in the final analysis (median age: 77.5 years; 12 females [60%]), 14 individuals were treated for the type-II odontoid fracture, and six cases presented with subluxation fractures between C3 and C7. After PTGWT and subsequent intraoperative reposition, there was an improvement of the median deviation angle from initial 32° to 5.5°. PTGWT resulted in a significant improvement of the median deviation angle for the odontoid (17°, P<0.0001), but not for the subluxation (4°, P=0.10) fractures. The time interval between trauma and PTGWT was associated with the treatment success of subluxation (P=0.051) but not of odontoid (P=0.87) fractures. Older individuals aged ≥51 years showed better reposition results with PTGWT (17° vs. 7.5°, P=0.02). There were no PTGWT-related complications in the cohort. CONCLUSIONS: PTGWT is an effective and safe treatment for cervical spine injuries with malalignment. The patients with odontoid fractures might particularly profit from the PTGWT. Treatment delay seems more relevant for PTGWT success in subluxation than in odontoid fractures.

Systematic review and meta-analysis of outcome-relevant anemia in patients with subarachnoid hemorrhage.

Anemia is a common, treatable condition in patients with aneurysmal subarachnoid hemorrhage (SAH) and has been associated with poor outcome. As there are still no guidelines for anemia management after aneurysm rupture, we aimed to identify outcome-relevant severity of anemia in SAH. We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library for publications before Oct 23rd, 2022, reporting on anemia in SAH patients. The presence and severity of anemia were assessed according to the reported hemoglobin values and/or institutional thresholds for red blood cells transfusion (RBCT). Out of 1863 original records, 40 full-text articles with a total of 14,701 patients treated between 1996 and 2020 were included in the final analysis (mean 445.48 patients per study). A substantial portion of patients developed anemia during SAH (mean pooled prevalence 40.76%, range 28.3-82.6%). RBCT was administered in a third of the cases (mean 32.07%, range 7.8-88.6%), with institutional threshold varying from 7.00 to 10.00 g/dL (mean 8.5 g/dL). Anemia at the onset of SAH showed no impact on SAH outcome. In contrast, even slight anemia (nadir hemoglobin < 11.0-11.5 g/dL) occurring during SAH was associated with the risk of cerebral infarction and poor outcome at discharge and follow-up. The strongest association with SAH outcome was observed for nadir hemoglobin values ranging between 9.0 and 10.0 g/dL. The effect of anemia on SAH mortality was marginal. The development of anemia during SAH is associated with the risk of cerebral infarction and poor outcome at discharge and follow-up. Outcome-relevant severity of post-SAH anemia begins at hemoglobin levels clearly above the thresholds commonly set for RBCT. Our findings underline the need for further studies to define the optimal management of anemia in SAH patients.

Impact of Anemia Severity on the Outcome of an Aneurysmal Subarachnoid Hemorrhage.

Objective: Previous reports indicate a negative impact of anemia on the outcome of an aneurysmal subarachnoid hemorrhage (SAH). We aimed to identify the outcome-relevant severity of post-SAH anemia. Methods: SAH cases treated at our institution between 01/2005 and 06/2016 were included (n = 640). The onset, duration, and severity (nadir hemoglobin (nHB) level) of anemia during the initial hospital stay were recorded. Study endpoints were new cerebral infarctions, a poor outcome six months post-SAH (modified Rankin scale > 3), and in-hospital mortality. To assess independent associations with the study endpoints, different multivariable regression models were performed, adjusted for relevant patient and baseline SAH characteristics as well as anemia-associated clinical events during the SAH. Results: The rates of anemia were 83.3%, 67.7%, 40.0%, 15.9%, and 4.5% for an nHB < 11 g/dL, < 10 g/dL, < 9 g/dL, < 8 g/dL, and < 7 g/dL, respectively. The higher the anemia severity, the later was the onset (post-SAH days 2, 4, 5.4, 7.6 and 8, p < 0.0001) and the shorter the duration (8 days, 6 days, 4 days, 3 days, and 2 days, p < 0.0001) of anemia. In the final multivariable analysis, only an nHB < 9 g/dL was independently associated with all study endpoints: adjusted odds ratio 1.7/3.22/2.44 for cerebral infarctions/in-hospital mortality/poor outcome. The timing (post-SAH day 3.9 vs. 6, p = 0.001) and duration (3 vs. 5 days, p = 0.041) of anemia with an nHB < 9 g/dL showed inverse associations with the risk of in-hospital mortality, but not with other study endpoints. Conclusions: Anemia is very common in SAH patients affecting four of five individuals during their hospital stay. An nHB decline to < 9 g/dL was strongly associated with all study endpoints, independent of baseline characteristics and SAH-related clinical events. Our data encourage further prospective evaluations of the value of different transfusion strategies in the functional outcomes of SAH patients.

Ischemia-induced inflammation in arteriovenous malformations.

OBJECTIVE: The pathophysiology of development, growth, and rupture of arteriovenous malformations (AVMs) is only partially understood. However, inflammation is known to play an essential role in many vascular diseases. This feasibility study was conducted to investigate the expression of enzymes (cyclooxygenase 2 [COX-2] and NLRP3 [NOD-, LRR-, and pyrin domain-containing protein 3]) in the AVM nidus that are essential in their inflammatory pathways and to explore how these influence the pathophysiology of AVMs. METHODS: The study group comprised 21 patients with partially thrombosed AVMs. The cohort included 8 ruptured and 13 unruptured AVMs, which had all been treated microsurgically. The formaldehyde-fixed and paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 and NLRP3 (COX-2 clone: CX-294; NLRP3: ab214185). The authors correlated MRI and clinical data with immunohistochemistry, using the Trainable Weka Segmentation algorithm for analysis. RESULTS: The median AVM volume was 2240 mm3. The proportion of NLRP3-positive cells was significantly higher (26.23%-83.95%), compared to COX-2 positive cells (0.25%-14.94%, p < 0.0001). Ruptured AVMs had no higher expression of NLRP3 (p = 0.39) or COX-2 (p = 0.44), compared to nonruptured AVMs. Moreover, no patient characteristics could be reported that showed significant correlations to the enzyme expression. CONCLUSIONS: NLRP3 consistently showed an approximately 10-fold higher expression level than COX-2, making the inflammatory process in AVMs appear to be mainly associated with ischemic (NLRP3)-driven rather than with mechanical (COX-2)-driven inflammatory pathways. No direct associations between NLRP3 and COX-2 expression and radiological, standard histopathological, or patient characteristics were found in this cohort.

Characterization of Temozolomide Resistance Using a Novel Acquired Resistance Model in Glioblastoma Cell Lines.

Temozolomide (TMZ) is the first line of standard therapy in glioblastoma (GBM). However, relapse occurs due to TMZ resistance. We attempted to establish an acquired TMZ resistance model that recapitulates the TMZ resistance phenotype and the relevant gene signature. Two GBM cell lines received two cycles of TMZ (150 µM) treatment for 72 h each. Regrown cells (RG2) were defined as TMZ resistant cells. MTT assay revealed significantly less susceptibility and sustained growth of RG2 compared with parental cells after TMZ challenge. TMZ-induced DNA damage significantly decreased in 53BP1-foci reporter transduced-RG2 cells compared with parental cells, associated with downregulation of MSH2 and MSH6. Flow cytometry revealed reduced G2/M arrest, increased EdU incorporation and suppressed apoptosis in RG2 cells after TMZ treatment. Colony formation and neurosphere assay demonstrated enhanced clonogenicity and neurosphere formation capacity in RG2 cells, accompanied by upregulation of stem markers. Collectively, we established an acute TMZ resistance model that recapitulated key features of TMZ resistance involving impaired mismatch repair, redistribution of cell cycle phases, increased DNA replication, reduced apoptosis and enhanced self-renewal. Therefore, this model may serve as a promising research tool for studying mechanisms of TMZ resistance and for defining therapeutic approaches to GBM in the future.

Pathophysiology of Intracranial Aneurysms: COX-2 Expression, Iron Deposition in Aneurysm Wall, and Correlation With Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: The pathophysiology of development, growth, and rupture of intracranial aneurysms (IAs) is only partly understood. Cyclooxygenase 2 (COX-2) converts arachidonic acid to prostaglandin H2, which, in turn, is isomerized to prostaglandin E2. In the human body, COX-2 plays an essential role in inflammatory pathways. This explorative study aimed to investigate COX-2 expression in the wall of IAs and its correlation to image features in clinical (1.0T, 1.5T, and 3.0T) magnetic resonance imaging (MRI) and ultra-high-field 7T MRI. METHODS: The study group comprised 40 patients with partly thrombosed saccular IAs. The cohort included 17 ruptured- and 24 unruptured IAs, which had all been treated microsurgically. Formaldehyde-fixed paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 (Dako, Santa Clara, CA; Clone: CX-294). We correlated Perls Prussian blue staining, MRI, and clinical data with immunohistochemistry, analyzed using the Trainable Weka Segmentation algorithm. RESULTS: Aneurysm dome size ranged between 2 and 67 mm. The proportion of COX-2 positive cells ranged between 3.54% to 85.09%. An upregulated COX-2 expression correlated with increasing IA dome size (P=0.047). Furthermore, there was a tendency of higher COX-2 expression in most ruptured IAs (P=0.064). At all field strengths, MRI shows wall hypointensities due to iron deposition correlating with COX-2 expression (P=0.022). CONCLUSIONS: Iron deposition and COX-2 expression in IAs walls correlate with signal hypointensity in MRI, which might, therefore, serve as a biomarker for IA instability. Furthermore, as COX-2 was also expressed in small unruptured IAs, it could be a potential target for specific medical treatment.

In the wall lies the truth: a systematic review of diagnostic markers in intracranial aneurysms.

OBJECTIVE: Despite recent advances in molecular biology and genetics, the development of intracranial aneurysms (IA) is still poorly understood. Elucidation of the processes occurring in the IA wall is essential for a better understanding of IA pathophysiology. We sought to analyze the current evidence from histological, molecular and genetic studies of IA. METHODS: We systematically searched PubMed, Scopus, Web of Science and Cochrane Library for articles published before Mar 1, 2019 reporting on different diagnostic markers in human IA specimens. Expression of the markers in IA wall (vs. healthy arterial wall) and association with the rupture status were analyzed. The quality of the included studies and the level of the evidence for the markers were incorporated into the final data assessment. RESULTS: We included 123 studies reporting on analyses of 3476 IA (median 19 IA/study) published between 1966 and 2018. Based on microscopic, biochemical, genetic and biomechanical analyses, data on 358 diagnostic targets in the IA wall were collected. We developed a scale to distribute the diagnostic markers according to their specificity for IA or healthy arterial wall, as well as for ruptured or unruptured IA. We identified different functional pathways, which might reflect the intrinsic and extrinsic processes underlying IA pathophysiology. CONCLUSIONS: Multiple histological and molecular markers and the related functional pathways contributing to the development of IA might present promising targets for future therapeutic interventions. Because of small numbers of IA samples in each study, 89% of the analyzed diagnostic markers presented with the lowest level of evidence. This underlines the need for the initiation of a multi-centric prospective histological IA register for pooled data analysis.