Evaluation of FRESH scores in predicting outcome and quality of life after aneurysmal subarachnoid haemorrhage in a European patient cohort.

BACKGROUND: Despite aneurysmal subarachnoid haemorrhage (aSAH) patients often experiencing physical and mental disabilities impacting their quality of life (QoL), routine assessment of long-term QoL data and predictive tools are limited. This study evaluates the newly developed "functional recovery expected after subarachnoid haemorrhage" (FRESH) scores with long-term outcomes and QoL in European aSAH patients. METHODS: FRESH, FRESH-cog, and FRESH-quol scores were retrospectively obtained from aSAH patients. Patients were contacted, and the modified Rankin Scale (mRS), extended short form-36 (SF-36), and telephone interview for cognitive status (TICS) were collected and performed. The prognostic and empirical outcomes were compared. RESULTS: Out of 374 patients, 171 patients (54.1%) completed the SF-36, and 154 patients completed the TICS. The SF-36 analysis showed that 32.7% had below-average physical component summary (PCS) scores, and 39.8% had below-average mental component summary (MCS) scores. There was no significant correlation between the FRESH score and PCS (p = 0.09736), MCS (p = 0.1796), TICS (p = 0.7484), or mRS 10-82 months (average 46 months) post bleeding (p = 0.024), respectively. There was also no significant correlation found for "FRESH-cog vs. TICS" (p = 0.0311), "FRESH-quol vs. PCS" (p = 0.0204), "FRESH-quol vs. MCS" (p = 0.1361) and "FRESH-quol vs. TICS" (p = 0.1608). CONCLUSIONS: This study found no correlation between FRESH scores and validated QoL tools in a European population of aSAH patients. The study highlights the complexity of reliable long-term QoL prognostication in aSAH patients and emphasises the need for further prospective research to also focus on QoL as an important outcome parameter.

Revisiting the WFNS Score: Native Computed Tomography Imaging Improves Identification of Patients With "False Poor Grade" Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: In patients suffering from aneurysmal subarachnoid hemorrhage (aSAH), the optimal time to determine the World Federation of Neurosurgical Societies (WFNS) score remains controversial because of possible confounding factors. Goals of this study were (1) to analyze the most sensitive timepoint to determine the WFNS score in patients with aSAH and (2) to evaluate the impact of initial native computed tomography (CT) imaging on reducing the mismatch of "false poor grade" patients. METHODS: We retrospectively analyzed daily WFNS scores from admission until day 7 in 535 aSAH patients and evaluated their predictive value for the modified Rankin Scale at discharge and 6 months postbleeding. Patients with an initial WFNS score of IV-V who showed improvement to a WFNS score of I-II within the first 7 days (even short-term) were defined as "false poor grade" patients. We tried to identify the "false poor grade" patients using parameters of the initial native CT imaging. RESULTS: Later determination of the WFNS score (day 1 vs 7; pseudo-R 2 = 0.13 vs 0.21) increasingly improved its predictive value for neurological outcome at discharge ( P < .001). We identified 39 "false poor grade" patients who had significantly better outcomes than "real poor grade" patients (N = 220) (modified Rankin Scale-discharge: 0-2, 56% vs 1%, P < .001; 3-5: 41% vs 56%, P = .12; 6: 3% vs 43%, P < .001). "False poor grade" patients differed significantly in initial CT parameters. A predictive model called "initial CT WFNS" ( ICT WFNS) was developed, incorporating SEBES, Hijdra score, and LeRoux score (sensitivity = 0.95, specificity = 0.84, accuracy = 0.859, F1 = 0.673). ICT WFNS scores of ≤4.6 classified patients as "false poor grade." CONCLUSION: The initial WFNS score may misclassify a subgroup of patients with aSAH as poor grade, which can be avoided by later determination of the WFNS score, at days 3-4 losing its usefulness. Alternatively, the initial WFNS score can be improved in its predictive value, especially in poor-grade patients, using criteria from the initial native CT imaging, such as the Hijdra, LeRoux, and Subarachnoid Hemorrhage Early Brain Edema score, combined in the ICT WFNS score with even higher predictive power.

Clinical Outcome Prediction of Early Brain Injury in Aneurysmal Subarachnoid Hemorrhage: the SHELTER-Score.

BACKGROUND: Despite intensive research on preventing and treating vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage (aSAH), mortality and morbidity rates remain high. Early brain injury (EBI) has emerged as possibly the major significant factor in aSAH pathophysiology, emphasizing the need to investigate EBI-associated clinical events for improved patient management and decision-making. This study aimed to identify early clinical and radiological events within 72 h after aSAH to develop a conclusive predictive EBI score for clinical practice. METHODS: This retrospective analysis included 561 consecutive patients with aSAH admitted to our neurovascular center between 01/2014 and 09/2022. Fourteen potential predictors occurring within the initial 72 h after hemorrhage were analyzed. The modified Rankin Scale (mRS) score at 6 months, discretized to three levels (0-2, favorable; 3-5, poor; 6, dead), was used as the outcome variable. Univariate ordinal regression ranked predictors by significance, and forward selection with McFadden's pseudo-R2 determined the optimal set of predictors for multivariate proportional odds logistic regression. Collinear parameters were excluded, and fivefold cross-validation was used to avoid overfitting. RESULTS: The analysis resulted in the Subarachnoid Hemorrhage Associated Early Brain Injury Outcome Prediction score (SHELTER-score), comprising seven clinical and radiological events: age (0-4 points), World Federation of Neurosurgical Societies (0-2.5 points), cardiopulmonary resuscitation (CPR) (2 points), mydriasis (1-2 points), midline shift (0.5-1 points), early deterioration (1 point), and early ischemic lesion (2 points). McFadden's pseudo-R2 = 0.339, area under the curve for death or disability 0.899 and 0.877 for death. A SHELTER-score below 5 indicated a favorable outcome (mRS 0-2), 5-6.5 predicted a poor outcome (mRS 3-5), and ≥ 7 correlated with death (mRS 6) at 6 months. CONCLUSIONS: The novel SHELTER-score, incorporating seven clinical and radiological features of EBI, demonstrated strong predictive performance in determining clinical outcomes. This scoring system serves as a valuable tool for neurointensivists to identify patients with poor outcomes and guide treatment decisions, reflecting the great impact of EBI on the overall outcome of patients with aSAH.

Novel Insights into Pathophysiology of Delayed Cerebral Ischemia: Effects of Current Rescue Therapy on Microvascular Perfusion Heterogeneity.

General microvascular perfusion and its heterogeneity are pathophysiological features of delayed cerebral ischemia (DCI) that are gaining increasing attention. Recently, CT perfusion (CTP) imaging has made it possible to evaluate them radiologically using mean transit time (MTT) and its heterogeneity (measured by cvMTT). This study evaluates the effect of multimodal rescue therapy (intra-arterial nimodipine administration and elevation of blood pressure) on MTT and cvMTT during DCI in aneurysmal subarachnoid haemorrhage (aSAH) patients. A total of seventy-nine aSAH patients who underwent multimodal rescue therapy between May 2012 and December 2019 were retrospectively included in this study. CTP-based perfusion impairment (MTT and cvMTT) on the day of DCI diagnosis was compared with follow-up CTP after initiation of combined multimodal therapy. The mean MTT was significantly reduced in the follow-up CTP compared to the first CTP (3.7 ± 0.7 s vs. 3.3 ± 0.6 s; p < 0.0001). However, no significant reduction of cvMTT was observed (0.16 ± 0.06 vs. 0.15 ± 0.06; p = 0.44). Mean arterial pressure was significantly increased between follow-up and first CTP (98 ± 17 mmHg vs. 104 ± 15 mmHg; p < 0.0001). The combined multimodal rescue therapy was effective in addressing the general microvascular perfusion impairment but did not affect the mechanisms underlying microvascular perfusion heterogeneity. This highlights the need for research into new therapeutic approaches that also target these pathophysiological mechanisms of DCI.

Initial Temporal Muscle Thickness and Area: Poor Predictors of Neurological Outcome in Aneurysmal Subarachnoid Hemorrhage in a Central European Patient Cohort.

The temporalis muscle area (TMA) has been proclaimed as a surrogate parameter for estimating skeletal muscle mass. Pilot studies in Asian populations suggested temporal muscle thickness (TMT) and TMA as prognostic factors for neurological outcomes in aneurysmal subarachnoid hemorrhage (aSAH) patients. This study aimed to validate these findings in a larger European patient cohort. We retrospectively analyzed age, sex, aneurysm location, treatment, World Federation of Neurosurgical Societies (WFNS) grade, Fisher score, and modified Rankin Score (mRS) at six months in patients with aSAH. TMT and TMA measurements were obtained from initial native CT scans. Logistic regression with the dichotomized six-month mRS as the outcome incorporating TMT, weighted average of TMT, or TMA as predictors was performed. Of the included 478 patients, 66% were female, the mean age was 56, and 48% of patients had an mRS of three to six after six months. The mean TMT at the level of the Sylvian fissure was 5.9 (±1.7) mm in males and 4.8 (±1.8) mm in females. The mean TMA was 234.5 (±107.9) mm2 in females and 380 (±134.1) mm2 in males. WFNS grade (p < 0.001), Fisher score (p < 0.001), and age (p < 0.05) correlated significantly with the mRS after six months. No correlation was found between mRS after six months and the TMT at the Sylvian fissure (p = 0.3), the weighted average of TMT (p = 0.1), or the TMA (p = 0.1). In this central European patient cohort of 478 individuals, no significant associations were found between TMT/TMA and neurological outcomes following aSAH. Further prospective studies in diverse patient populations are necessary to determine the prognostic value of TMA and TMT in aSAH patients.

Evaluation of MTT Heterogeneity of Perfusion CT Imaging in the Early Brain Injury Phase: An Insight into aSAH Pathopysiology.

The concept of early brain injury (EBI) is based on the assumption of a global reduction in brain perfusion following aneurysmal subarachnoid hemorrhage (aSAH). However, the heterogeneity of computed tomography perfusion (CTP) imaging in EBI has not yet been investigated. In contrast, increased mean transit time (MTT) heterogeneity, a possible marker of microvascular perfusion heterogeneity, in the delayed cerebral ischemia (DCI) phase has recently been associated with a poor neurological outcome after aSAH. Therefore, in this study, we investigated whether the heterogeneity of early CTP imaging in the EBI phase is an independent predictor of the neurological outcome after aSAH. We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation (cvMTT) in early CTP scans (within 24 h after ictus) of 124 aSAH patients. Both linear and logistic regression were used to model the mRS outcome, which were treated as numerical and dichotomized values, respectively. Linear regression was used to investigate the linear dependency between the variables. No significant difference in cvMTT between the patients with and those without EVD could be observed (p = 0.69). We found no correlation between cvMTT in early CTP imaging and initial modified Fisher (p = 0.07) and WFNS grades (p = 0.23). The cvMTT in early perfusion imaging did not correlate significantly with the 6-month mRS for the entire study population (p = 0.15) or for any of the subgroups (without EVD: p = 0.21; with EVD: p = 0.3). In conclusion, microvascular perfusion heterogeneity, assessed by the heterogeneity of MTT in early CTP imaging, does not appear to be an independent predictor of the neurological outcome 6 months after aSAH.

Blood Pressure Affects the Early CT Perfusion Imaging in Patients with aSAH Reflecting Early Disturbed Autoregulation.

BACKGROUND: Early computed tomography perfusion (CTP) is frequently used to predict delayed cerebral ischemia following aneurysmatic subarachnoid hemorrhage (aSAH). However, the influence of blood pressure on CTP is currently controversial (HIMALAIA trial), which differs from our clinical observations. Therefore, we aimed to investigate the influence of blood pressure on early CTP imaging in patients with aSAH. METHODS: We retrospectively analyzed the mean transit time (MTT) of early CTP imaging within 24 h after bleeding prior to aneurysm occlusion with respect to blood pressure shortly before or after the examination in 134 patients. We correlated the cerebral blood flow with the cerebral perfusion pressure in the case of patients with intracranial pressure measurement. We performed a subgroup analysis of good-grade (World Federation of Neurosurgical Societies [WFNS] I-III), poor-grade (WFNS IV-V), and solely WFNS grade V aSAH patients. RESULTS: Mean arterial pressure (MAP) significantly correlated inversely with the mean MTT in early CTP imaging (R = - 0.18, 95% confidence interval [CI] - 0.34 to - 0.01, p = 0.042). Lower mean blood pressure was significantly associated with a higher mean MTT. Subgroup analysis revealed an increasing inverse correlation when comparing WFNS I-III (R = - 0.08, 95% CI - 0.31 to 0.16, p = 0.53) patients with WFNS IV-V (R = - 0.2, 95% CI - 0.42 to 0.05, p = 0.12) patients, without reaching statistical significance. However, if only patients with WFNS V are considered, a significant and even stronger correlation between MAP and MTT (R = - 0.4, 95% CI - 0.65 to 0.07, p = 0.02) is observed. In patients with intracranial pressure monitoring, a stronger dependency of cerebral blood flow on cerebral perfusion pressure is observed for poor-grade patients compared with good-grade patients. CONCLUSIONS: The inverse correlation between MAP and MTT in early CTP imaging, increasing with the severity of aSAH, suggests an increasing disturbance of cerebral autoregulation with the severity of early brain injury. Our results emphasize the importance of maintaining physiological blood pressure values in the early phase of aSAH and preventing hypotension, especially in patients with poor-grade aSAH.

Treatment of Unique Bilateral Distal Fusiform Superior Cerebellar Artery Aneurysms with Mini-Flow Diverter Device Implantation: Case Report.

Currently, surgical revascularization procedures using intracranial-intracranial (IC-IC) or extracranial-intracranial (EC-IC) bypass and distal clipping or trapping are the valid and rescue treatment modality for extremely rare unilateral distal fusiform superior cerebellar artery (SCA) aneurysms. Yet, in case of bilateral fusiform SCA aneurysms, surgical therapy reaches its limit. Mini-flow diverter devices (FDDs) have only recently become available for treating fusiform aneurysms of such small vessels. We report the unique case of bilateral distal fusiform SCA aneurysms in a 43-year-old man with subarachnoid hemorrhage (Fisher grade IV and World Federation of Neurosurgical Societies [WFNS] grade II) treated with endovascular implantation of bilateral mini-FDDs with excellent outcome and no radiographic signs of infarction. Yet, occlusion of one of the FDDs was found in the follow-up, which again shows the eminent danger of occlusion in case of an implantation of FDDs in such small-caliber vessels, which leaves the discussion about the optimal therapy method open.

Meta-review on Perforation Model of Subarachnoid Hemorrhage in Mice: Filament Material as a Possible Moderator of Mortality.

Robust preclinical models are inevitable for researchers to unravel pathomechanisms of subarachnoidal hemorrhage (SAH). For the mouse perforation model of SAH, the goal of this meta-review was the determination of variances in mortality, SAH severity grade, and vasospasm, and their experimental moderators, as many researchers are facing with incomparable results. We searched on the databases PubMed, Embase, and Web of Science for articles describing in vivo experiments using the SAH perforation mouse model and measuring mortality, SAH grade, and/or vasospasm. After screening, 42 articles (total of 1964 mice) were included into systematic review and meta-analysis. Certain model characteristics were insufficiently reported, e.g., perforation location (not reported in six articles), filament (material (n = 15) and tip texture (n = 25)), mouse age (n = 14), and weight (n = 10). Used injective anesthetics and location of perforation showed large variation. In a random-effects meta-analysis, the overall animal mortality following SAH was 21.3% [95% CI: 17.5%, 25.7%] and increased with longer observational periods. Filament material significantly correlated with animal mortality (p = 0.024) after exclusion of hyperacute studies (time after SAH induction < 24 h). Reported mean SAH grade was 10.7 [9.6, 11.7] on the scale of Sugawara (J Neurosci Methods 167:327-34, 2008). Furthermore, mean diameter of large cerebral arteries after SAH was reduced by 27.6% compared to sham-operated non-SAH mice. Uniforming standards of experimental procedures and their reporting are indispensable to increase overall comparability.

The rupture of an anterior communicating artery aneurysm does not associate with an asymmetry in the A1 or A2 arteries: a retrospective study of radiological features.

BACKGROUND AND OBJECTIVES: Although the formation and rupture risk of an anterior communicating artery (ACoA) aneurysm has been the subject of many studies, no previous study has primarily searched for the relationship of the parent and daughter vessels and the impact of their size/diameter ratio on the potential rupture risk of an AcoA aneurysm. The objective of this study is to explore this link and to further analyse the surrounding vasculature of the anterior communicating artery aneurysm. MATERIALS AND METHODS: We conducted a retrospective analysis of 434 patients: 284 patients with an ACoA aneurysm (121 unruptured and 162 ruptured) and 150 control patients without an ΑCoA aneurysm. Radiological angiography investigations were used to assess the diameter ratios of the parent vessels in addition to ACoA aneurysm morphology parameters. RESULTS: When comparing the ruptured to the unruptured cases, we observed no significant difference in the parent or daughter vessel diameter ratios. Younger patient age (OR 0.96, p = 0.00) and a higher aneurysm size ratio (OR 1.10, p = 0.02) were of prognostic importance concerning the rupture risk of the aneurysm. The A1 diameter ratio and the A2 diameter were not statistically significant (OR 1.00, p = 0.99, and OR 3.38, p = 0.25 respectively). CONCLUSIONS: In our study, we focused on asymmetry in the parent and daughter vessels as well as traditional ACoA aneurysm morphological characteristics. We were able to label younger patient age and a greater size ratio as independent prognostic factors for ACoA aneurysm rupture. We were unable to label parent and daughter vessel asymmetry as prognostic factors. To validate our findings, parent and daughter vessel asymmetry should be subjected to future prospective studies.

Asymmetry of P1 and vertebral arteries is not related to basilar tip aneurysm development or rupture.

OBJECTIVE: Lately, morphological parameters of the surrounding vasculature aside from aneurysm size, specific for the aneurysm location, e.g., posterior cerebral artery angle for basilar artery tip aneurysms, could be identified to correlate with the risk of rupture. We examined further image-based morphological parameters of the aneurysm surrounding vasculature that could correlate with the growth or the risk of rupture of basilar artery tip aneurysms. METHODS: Data from 83 patients with basilar tip aneurysms (27 not ruptured; 56 ruptured) and 100 control patients were assessed (50 without aneurysms and 50 with aneurysms of the anterior circle of Willis). Anatomical parameters of the aneurysms were assessed and analyzed, as well as of the surrounding vasculature, namely the asymmetry of P1 and the vertebral arteries. RESULTS: Patients with basilar tip aneurysm showed no significant increase in P1 or vertebral artery asymmetry compared with the control patients or patients with aneurysms of the anterior circulation, neither was there a significant difference in asymmetry between cases with ruptured and unruptured aneurysms. Furthermore, we observed no significant correlations between P1 asymmetry and the aneurysm size or number of lobuli in the aneurysms. CONCLUSION: We observed no significant difference in aneurysm size, rupture, or lobulation associated with P1 or vertebral artery (surrounding vasculature) asymmetry. Therefore, the asymmetry of the surrounding vessels does not seem to be a promising morphological parameter for the evaluation of probability of rupture and growth in basilar tip aneurysms in future studies.

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells.

IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.

Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells.

Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.

Analyses of Synthetic N-Acyl Dopamine Derivatives Revealing Different Structural Requirements for Their Anti-inflammatory and Transient-Receptor-Potential-Channel-of-the-Vanilloid-Receptor-Subfamily-Subtype-1 (TRPV1)-Activating Properties.

We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for the activation of transient-receptor-potential channels of the vanilloid-receptor subtype 1 (TRPV1) and inhibition of inflammation. The potency of NOD in activating TRPV1 was significantly higher compared with those of variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted ( N-octanoyl tyramine), or the ester functionality consisted of a bulky fatty acid ( N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its potency, which was further increased when the carbonyl and amide groups (ΔNODR) were interchanged. With the exception of ΔNOD, the presence of an intact catechol structure was obligatory for the inhibition of VCAM-1 and the induction of HO-1 expression. Because TRPV1 activation and the inhibition of inflammation by N-acyl dopamines require different structural entities, our findings provide a framework for the rational design of TRPV1 agonists with improved anti-inflammatory properties.