Single-cell atlas of the human brain vasculature across development, adulthood and disease.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Shaping the brain vasculature in development and disease in the single-cell era.

The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis - the formation of new blood vessels - is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the 'neurovascular link' defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.

Embolization techniques of spontaneous direct carotid-cavernous fistulae: a single-center experience.

PURPOSE: Spontaneous direct carotid-cavernous fistula (CCF) are usually caused by a ruptured carotid cavernous aneurysm. We studied treatment of spontaneous direct CCFs in a single-center cohort of a high-volume tertiary referral center, reporting anatomical details, technical approaches of treatment, and outcomes. METHODS: Adult patients with a spontaneous direct CCF treated between 2010-2022 with follow-up MRI and/or DSA imaging available were retrospectively analyzed. We studied age, sex, clinical presentation, angiographic findings, treatment techniques, outcomes, and complications. RESULTS: Out of 80 patients with CCFs, twelve patients were treated for a non-traumatic direct CCF (15%) in 13 sessions. Median age was 65 years. Two patients had an underlying connective tissue disorder. In 10 cases, the direct CCF was caused by a ruptured cavernous carotid aneurysm. The direct CCFs were treated by endovascular transarterial embolization (10 cases), transvenous embolization (1 case), or surgery (1 case). Selective closure of the shunt was possible in 10 patients. Two patients were treated with parent vessel occlusion (PVO; one endovascular; one surgical, with bypass). Complications occurred in 2 / 12 patients (17%), with permanent morbidity in two patients (17%): trigeminal neuralgia after PVO and new infarct after surgical PVO and bypass. Selective closure of CCF resulted in no morbidity. There was no mortality in our series. CONCLUSION: Spontaneous direct CCFs are caused by rupture of a cavernous carotid aneurysm in most cases. Selective closure of the shunt, usually feasible transarterially with coils, achieves good results. Reconstructive endovascular techniques are preferred to minimize treatment related neurological complications.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Complication of Middle Cerebral Artery Aneurysm Surgery: An M2 Tear at the Neck, Managed with a Salvage M2-to-M2 In Situ Bypass.

An unexpected rupture at the aneurysm neck, with or without adjacent arterial injury or compromise of distal branches during microsurgical clipping, can be a challenging surgical problem to resolve. In this presented case of a neurologically intact 65-year-old woman, elective clipping of an unruptured right middle cerebral artery bifurcation aneurysm was complicated by an unexpected M2 tear at the neck, involving the origin of the frontal M2. Attempts to seal the tear directly, using various techniques, failed; therefore, it was ultimately managed with sacrifice of the vessel and a salvage side-to-side M2-to-M2 in situ bypass. Six months after surgery, the patient demonstrated moderate disability but was able to ambulate with a cane.

Repeat Flow Diversion for Cerebral Aneurysms Failing Prior Flow Diversion: Safety and Feasibility From Multicenter Experience.

BACKGROUND: Aneurysmal persistence after flow diversion (FD) occurs in 5% to 25% of aneurysms, which may necessitate retreatment. There are limited data on safety/efficacy of repeat FD-a frequently utilized strategy in such cases. METHODS: A series of consecutive patients undergoing FD retreatment from 15 centers were reviewed (2011-2019), with inclusion criteria of repeat FD for the same aneurysm at least 6 months after initial treatment, with minimum of 6 months post-retreatment imaging. The primary outcome was aneurysmal occlusion, and secondary outcome was safety. A multivariable logistic regression model was constructed to identify predictors of incomplete occlusion (90%-99% and <90% occlusion) versus complete occlusion (100%) after retreatment. RESULTS: Ninety-five patients (median age, 57 years; 81% women) harboring 95 aneurysms underwent 198 treatment procedures. Majority of aneurysms were unruptured (87.4%), saccular (74.7%), and located in the internal carotid artery (79%; median size, 9 mm). Median elapsed time between the first and second treatment was 12.2 months. Last available follow-up was at median 12.8 months after retreatment, and median 30.6 months after the initial treatment, showing complete occlusion in 46.2% and near-complete occlusion (90%-99%) in 20.4% of aneurysms. There was no difference in ischemic complications following initial treatment and retreatment (4.2% versus 4.2%; P>0.99). On multivariable regression, fusiform morphology had higher nonocclusion odds after retreatment (odds ratio [OR], 7.2 [95% CI, 1.97-20.8]). Family history of aneurysms was associated with lower odds of nonocclusion (OR, 0.18 [95% CI, 0.04-0.78]). Likewise, positive smoking history was associated with lower odds of nonocclusion (OR, 0.29 [95% CI, 0.1-0.86]). History of hypertension trended toward incomplete occlusion (OR, 3.10 [95% CI, 0.98-6.3]), similar to incorporated branch into aneurysms (OR, 2.78 [95% CI, 0.98-6.8]). CONCLUSIONS: Repeat FD for persistent aneurysms carries a reasonable success/safety profile. Satisfactory occlusion (100% and 90%-99% occlusion) was encountered in two-thirds of patients, with similar complications between the initial and subsequent retreatments. Fusiform morphology was the strongest predictor of retreatment failure.

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling.

RATIONALE: We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. OBJECTIVE: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. METHODS AND RESULTS: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. CONCLUSIONS: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.

Molecular and genetic mechanisms in brain arteriovenous malformations: new insights and future perspectives.

Brain arteriovenous malformations (bAVMs) are rare vascular lesions made of shunts between cerebral arteries and veins without the interposition of a capillary bed. The majority of bAVMs are asymptomatic, but some may be revealed by seizures and potentially life-threatening brain hemorrhage. The management of unruptured bAVMs remains a matter of debate. Significant progress in the understanding of their pathogenesis has been made during the last decade, particularly using genome sequencing and biomolecular analysis. Herein, we comprehensively review the recent molecular and genetic advances in the study of bAVMs that not only allow a better understanding of the genesis and growth of bAVMs, but also open new insights in medical treatment perspectives.

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation.

BACKGROUND: Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. METHODS: Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. RESULTS: COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels' lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. CONCLUSION: COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.

High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations.

Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.10.1093/brain/awy307_video1awy307media15978667388001.

Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells.

Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and maintenance, the energy requirements of these cells and the mechanisms that regulate their energy production are unknown. Here, we show that the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2, IGF2BP2) regulates oxidative phosphorylation (OXPHOS) in primary glioblastoma (GBM) sphere cultures (gliomaspheres), an established in vitro model for CSC expansion. We demonstrate that IMP2 binds several mRNAs that encode mitochondrial respiratory chain complex subunits and that it interacts with complex I (NADH:ubiquinone oxidoreductase) proteins. Depletion of IMP2 in gliomaspheres decreases their oxygen consumption rate and both complex I and complex IV activity that results in impaired clonogenicity in vitro and tumorigenicity in vivo. Importantly, inhibition of OXPHOS but not of glycolysis abolishes GBM cell clonogenicity. Our observations suggest that gliomaspheres depend on OXPHOS for their energy production and survival and that IMP2 expression provides a key mechanism to ensure OXPHOS maintenance by delivering respiratory chain subunit-encoding mRNAs to mitochondria and contributing to complex I and complex IV assembly.

Endonasal and Transoral Approaches to the Craniovertebral Junction: A Quantitative Anatomical Study.

BACKGROUND: The endoscopic endonasal approach has recently been added to the surgical armamentarium to access the anterior craniovertebral junction (CVJ). Comparative analyses with the transoral approach are scarce. The aim of this study was to provide a quantitative anatomical analysis of both approaches. METHODS: In four specimens the endoscopic endonasal approach (before and after sphenoidectomy) and the transoral approach (without and with a soft palate split) were performed. ApproachViewer-part of GTx-UHN (Guided Therapeutics software, developed at University Health Network, Toronto, ON, Canada)-was used to quantify and visualize the working volume, as well as the exposed area, of each surgical approach. Different modalities (crossing and non-crossing) were used to quantify the exposure of the deep surface, providing an indirect quantitative value of the 'surgical freedom'. The lowest point exposed by the endonasal approaches was compared with that predicted by preoperative radiological lines. Non-parametric Welch analysis of variance (ANOVA) was used for statistical analyses. RESULTS: The working volume was significantly larger and the distance to the target was shorter with the transoral approaches than with the endonasal approaches. Clival exposure was better with the endonasal approaches than with the non-crossing transoral approach without a soft palate split; areas below C1 were better exposed with the transoral routes. The nasoaxial line best predicted surgical exposure with the endonasal approaches. CONCLUSION: Endoscopic endonasal and transoral approaches to the anterior CVJ provide optimal exposure of different areas that overlap at the level of C1 when no anatomical anomalies are present. A split of the soft palate is not necessary during the transoral approach if it is combined with an endoscopic endonasal approach.

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era.

OBJECTIVE: Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture. METHODS: A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis. RESULTS: A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response. CONCLUSIONS: Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

Microsurgery for ARUBA Trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)-Eligible Unruptured Brain Arteriovenous Malformations.

BACKGROUND AND PURPOSE: The management of unruptured brain arteriovenous malformations (ubAVMs) remains controversial despite ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation), a controlled trial that suggested superiority of conservative management over intervention. However, microsurgery occurred in only 14.9% of ARUBA intervention cases, raising concerns about the study's generalizability. Our purpose was to evaluate whether, in a larger ARUBA-eligible ubAVM population, microsurgery produces acceptable outcomes. METHODS: Demographic data, AVM characteristics, and treatment outcomes were evaluated in 155 ARUBA-eligible bAVMs treated with microsurgery between 1994 and 2014. Outcomes were rates of early disabling deficits and permanent disabling deficits with modified Rankin Scale score ≥3 or any permanent neurological deficits with modified Rankin Scale score ≥1. Covariates associated with outcomes were determined by regression analysis. RESULTS: Of 977 AVM patients, 155 ARUBA-eligible patients had microsurgical resection (71.6% surgery only and 25.2% with preoperative embolization). Mean follow-up was 36.1 months. Complete obliteration was achieved in 94.2% after initial surgery and 98.1% on final angiography. Early disabling deficits and permanent disabling deficits occurred in 12.3% and 4.5%, respectively, whereas any permanent neurological deficit (modified Rankin Scale score ≥1) occurred in 16.1%. Among ubAVM of Spetzler-Martin grades 1 and 2, complete obliteration occurred in 99.2%, with early disabling deficits and permanent disabling deficits occurring in 9.3% and 3.4%, respectively. Major bleeding was the only significant predictor of early disabling deficits on multivariate analysis (P<0.001). CONCLUSIONS: Microsurgery in this cohort produced less disabling deficits than ARUBA with similar morbidity and AVM obliteration as other cohort series. This disparity between our results and ARUBA suggests that future controlled trials should focus on the safety and efficacy of microsurgery with or without adjunctive embolization in carefully selected ubAVM patients.

Clipping of ruptured intracranial aneurysms in a hybrid room environment-a case-control study.

BACKGROUND: Hybrid room treatment (HRT) provides the surgeon immediate intraoperative angiography control of aneurysm occlusion and vessel patency. Since it is relatively resource demanding, in clinical routine HRT is reserved for elective cases. However, since its introduction in our department in 2008, several random cases of ruptured intracranial aneurysms (IAs) have been treated in the HR. This study aims to compare the clinical and radiological outcomes of these cases with cases treated conventionally using a matched pair analysis. METHODS: Twenty (20%) consecutive patients with ruptured IA treated by microsurgical clipping in the HR between 2009 and 2015 were retrospectively matched with "conventionally" (C) treated patients (overall n = 101). Clinical and radiological outcome variables were assessed and compared. RESULTS: Despite a trend in favor of the HR group, no significant difference between both matched groups (HR vs. C) could be demonstrated regarding the functional outcome (upper/lower good recovery 16/20 vs. 17/20, p > 0.05), frequency of clipping-related vascular insults on CT scans (0/20 vs. 3/20, p > 0.05), aneurysm remnant rate on postoperative angiography (1/20 vs. 4/20, p > 0.05) and retreatment rate (0/20 vs. 1/20, p > 0.05). When cumulating all outcome events by a scoring system, however, the HR cohort showed a significantly lower occurrence of events (p < 0.05). In three cases co-treatment by an endovascular approach was performed in the HR cohort. CONCLUSION: In this relatively small cohort, a matched pair analysis revealed a discrete but not significant tendency toward a lower frequency of aneurysm remnants and clipping-related vascular insults in the HR cohort. However, HR cohort patients benefited from direct endovascular co-treatment in selected cases.