The Sutureless Excimer Laser Anastomosis Clip Pilot Study: a feasibility and safety study.

BACKGROUND: The excimer laser-assisted non-occlusive anastomosis (ELANA) bypass technique may have the advantage of its non-occlusive design in the treatment of last-resort cases where endovascular treatment or direct clipping is considered to be unsafe. However, the technique remains technically challenging. Therefore, a sutureless ELANA Clip device (SEcl) was developed to simplify the technique avoiding tedious anastomosis stitching in depth. The present study investigates the clinical feasibility and safety of the SEcl technique. METHODS: Three patients with complex and large aneurysms in the anterior circulation were selected after multidisciplinary consensus that the aneurysms were too complex for endovascular or direct clipping treatment options. Bypass surgery was considered as a last-resort treatment option, and after preoperative evaluation and informed consent, SEcl bypass surgery was performed. Applicability, technical aspects and patient outcomes are assessed. RESULTS: All aneurysms were excluded from the circulation. The creation of the intracranial anastomosis was easier and faster. No device-related serious adverse events were encountered, and all outcomes were favorable (one patient stable Modified Rankin Scale, two patients improved). CONCLUSION: The SEcl anastomosis technique is feasible and, considering the severity of the disease, relatively safe. It can be considered a treatment option in very difficult-to treat last-resort aneurysm cases. From this study, further developments in minimizing clip size and application in cardiac surgery are initiated.

RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations.

Background and Purpose- Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM. Methods- We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P<0.05). We selected 10 genes for validation using droplet digital polymerase chain reaction. We performed functional pathway analysis accounting for potential gene-length bias, to establish enhancement of biological pathways involved in BAVMs. We further assessed which Gene Ontology terms were enriched. Results- We found 736 upregulated genes in BAVMs including genes implicated in the cytoskeletal machinery and cell-migration and genes encoding for inflammatory cytokines and secretory products of neutrophils and macrophages. Furthermore, we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-ß signaling. We confirmed the differential expression of top 10 ranked genes. Functional pathway analysis showed enrichment of the protein digestion and absorption pathway (false discovery rate-adjusted P=1.70×10-2). We identified 47 enriched Gene Ontology terms (false discovery rate-adjusted P<0.05) implicated in cytoskeleton network, cell-migration, endoplasmic reticulum, transmembrane transport, and extracellular matrix composition. Conclusions- Our genome-wide RNA-sequencing study points to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of BAVMs. Our study may lend support to potential receptivity of BAVMs to medical therapeutics, including those promoting vessel maturation, and anti-inflammatory and immune-modifying drugs.

Effects of dobutamine and phenylephrine on cerebral perfusion in patients undergoing cerebral bypass surgery: a randomised crossover trial.

BACKGROUND: Patients undergoing cerebral bypass surgery are prone to cerebral hypoperfusion. Currently, arterial blood pressure is often increased with vasopressors to prevent cerebral ischaemia. However, this might cause vasoconstriction of the graft and cerebral vasculature and decrease perfusion. We hypothesised that cardiac output, rather than arterial blood pressure, is essential for adequate perfusion and aimed to determine whether dobutamine administration resulted in greater graft perfusion than phenylephrine administration. METHODS: This randomised crossover study included 10 adult patients undergoing cerebral bypass surgery. Intraoperatively, patients randomly and sequentially received dobutamine to increase cardiac index or phenylephrine to increase mean arterial pressure (MAP). An increase of >10% in cardiac index or >10% in MAP was targeted, respectively. Before both interventions, a reference phase was implemented. The primary outcome was the absolute difference in graft flow between the reference and intervention phase. We compared the absolute flow difference between each intervention and constructed a random-effect linear regression model to explore treatment and carry-over effects. RESULTS: Graft flow increased with a median of 4.1 (inter-quartile range [IQR], 1.7-12.0] ml min-1) after dobutamine administration and 3.6 [IQR, 1.3-7.8] ml min-1 after phenylephrine administration (difference -0.6 ml min-1; 95% confidence interval [CI], -14.5 to 5.3; P=0.441). There was no treatment effect (0.9 ml min-1; 95% CI, 0.0-20.1; P=0.944) and no carry-over effect. CONCLUSIONS: Both dobutamine and phenylephrine increased graft flow during cerebral bypass surgery, without a preference for one method over the other. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register, NL7077 (https://www.trialregister.nl/trial/7077).

Functional and educational outcomes after treatment for intracranial arteriovenous malformations in children.

BACKGROUND: Arteriovenous malformations (AVMs) in the pediatric population are rare, yet they form the most frequent cause of hemorrhagic stroke in children. Compared to adults, children have been suggested to have beneficial neurological outcomes. However, few studies have focused on other variables than neurological outcomes. This study aims to assess the long-term functional and educational outcomes of children after multimodality approach of treatment for intracranial AVMs. METHODS: All children treated in our center between 1998 and 2016 for intracranial AVMs were reviewed. Patient characteristics, as well as AVM specifics, were collected. Functional outcomes were compared using the modified Rankin scale (mRs). Educational levels, using the International Standard Classification of Education (ISCED), were compared to the age-matched general population of the Netherlands. RESULTS: In total, 25 children were included at mean age of 10 years (range 2-16 years). Nineteen patients (76%) presented with intracranial bleeding. Mean follow-up was 11.5 ± 5.3 years (range 4.1-24.4). Four (16%) of patients were treated with embolization, three (12%) with microsurgery, and 18 patients (72%) received a combination of different treatment modalities. Altogether, 21 (84%) were embolized, 14 (56%) were treated with microsurgery, and eight (32%) received stereotactic radiosurgery. One child had a worse mRs at discharge compared to admission; all others improved (n = 11) or were stable (n = 13). At follow-up, all patients scored a stable or improved mRs compared to discharge, with 23 children (92%) scoring mRs 0 or 1. These 23 children followed regular education during follow-up without specialized or adapted schooling. No significant differences in educational level with the age-matched general population were found. CONCLUSION: This retrospective review shows positive long-term results of both functional and educational outcomes after multidisciplinary treatment of pediatric brain AVMs.

RNA Sequencing Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture.

BACKGROUND AND PURPOSE: Analyzing genes involved in development and rupture of intracranial aneurysms can enhance knowledge about the pathogenesis of aneurysms, and identify new treatment strategies. We compared gene expression between ruptured and unruptured aneurysms and control intracranial arteries. METHODS: We determined expression levels with RNA sequencing. Applying a multivariate negative binomial model, we identified genes that were differentially expressed between 44 aneurysms and 16 control arteries, and between 22 ruptured and 21 unruptured aneurysms. The differential expression of 8 relevant and highly significant genes was validated using digital polymerase chain reaction. Pathway analysis was used to identify enriched pathways. We also analyzed genes with an extreme pattern of differential expression: only expressed in 1 condition without any expression in the other. RESULTS: We found 229 differentially expressed genes in aneurysms versus controls and 1489 in ruptured versus unruptured aneurysms. The differential expression of all 8 genes selected for digital polymerase chain reaction validation was confirmed. Extracellular matrix pathways were enriched in aneurysms versus controls, whereas pathways involved in immune response and the lysosome pathway were enriched in ruptured versus unruptured aneurysms. Immunoglobulin genes were expressed in aneurysms, but showed no expression in controls. CONCLUSIONS: For rupture of intracranial aneurysms, we identified the lysosome pathway as a new pathway and found further evidence for the role of the immune response. Our results also point toward a role for immunoglobulins in the pathogenesis of aneurysms. Immune-modifying drugs are, therefore, interesting candidate treatment strategies in the prevention of aneurysm development and rupture.

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease.

BACKGROUND: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. SUMMARY: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. KEY MESSAGE: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions.

Vessel wall perforation mechanism of the excimer laser-assisted non-occlusive anastomosis technique.

The excimer laser assisted non-occlusive anastomosis (ELANA) technique is used to make anastomoses on intracerebral arteries. This end-to-side anastomosis is created without temporary occlusion of the recipient artery using a 308-nm excimer laser with a ring-shaped multi-fiber catheter to punch an opening in the arterial wall. Over 500 patients have received an ELANA bypass. However, the vessel wall perforation mechanism of the laser catheter is not known exactly and not 100 % successful. In this study, we aimed to understand the mechanism of ELANA vessel perforation using specialized imaging techniques to ultimately improve its effectiveness. High-speed imaging, high-contrast imaging, and high-sensitivity thermal imaging were used to study the laser wall perforation mechanism and reveal the mechanical and thermal effects involved. In vitro, rabbit arteries were exposed with the special designed laser catheter in a setup representative for the clinical setting, in which blood was replaced with a transparent UV absorbing liquid for visualization. We observed that laser vessel wall perforation was caused by explosive vapor bubbles tearing through the vessel wall, mostly within the first 20 of the total 200 pulses. Thermal effects were minimal. Unsymmetrical tension in the vessel wall inducing migration of the flap during laser exposure was observed in case of unsuccessful wall perforations. The laser wall perforation mechanism in the ELANA technique is primarily mechanical. Symmetric tension in the recipient vessel wall is essential and should be trained by neurosurgeons.

Novel Application of Postmortem CT Angiography for Evaluation of the Intracranial Vascular Anatomy in Cadaver Heads.

OBJECTIVE: Postmortem CT angiography is a common procedure used to visualize the entire human vasculature. For visualization of a specific organ's vascular anatomy, casting is the preferred method. Because of the permanent and damaging nature of casting, the organ cannot be further used as an experimental model after angiography. Therefore, there is a need for a minimally traumatic method to visualize organ-specific vascular anatomy. The purpose of this study was to develop and evaluate a contrast enhancement technique that is capable of visualizing the intracranial vascular anatomy while preserving the anatomic integrity in cadaver heads. MATERIALS AND METHODS: Seven human heads were used in this study. Heads were prepared by cannulating the vertebral and internal carotid arteries. Contrast agent was injected as a mixture of tap water, polyethylene glycol 600, and an iodinated contrast agent. Postmortem imaging was executed on a 64-MDCT scanner. Primary image review and 3D reconstruction were performed on a CT workstation. RESULTS: Clear visualization of the major cerebral arteries and smaller intracranial branches was achieved. Adequate visualization was obtained for both the anterior and posterior intracranial circulation. The minimally traumatic angiography method preserved the vascular integrity of the cadaver heads. CONCLUSION: A novel application of postmortem CT angiography is presented here. The technique can be used for radiologic evaluation of the intracranial circulation in cadaver heads. After CT angiography, the specimen can be used for further experimental or laboratory testing and teaching purposes.

"STA-MCA bypass with encephalo-duro-myo-synangiosis combined with bifrontal encephalo-duro-periosteal-synangiosis" as a one-staged revascularization strategy for pediatric moyamoya vasculopathy.

PURPOSE: Moyamoya vasculopathy progressively compromises cerebral blood flow resulting in chronic hypoperfusion. The middle cerebral artery (MCA) territory and the bifrontal areas are the regions most frequently affected. Although most techniques aim to only revascularize the MCA territory, augmentation of blood flow of the bifrontal areas is of importance in the pediatric moyamoya population since these regions play an important role in cognition, intellectual development, and in lower extremity and sphincter function. We recently described a one-staged surgical procedure combining revascularization of three regions, the MCA territory unilaterally and the frontal areas bilaterally. The purpose of this article is to report our surgical experience in eight children and to emphasize the rational for bifrontal revascularization. METHODS: We report a case series consisting of eight children where the following surgical strategy was applied: (1) a direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass with encephalo-duro-myo-synangiosis (EDMS) for unilateral MCA revascularization; in combination with (2) a bifrontal encephalo-duro-periosteal-synangiosis (EDPS) for bifrontal revascularization. Patients' characteristics and 30-day follow-up data are reported. RESULTS: The patient group consisted of six girls and two boys (mean age 10.0, range 4.2-17.5 years): six children presented with moyamoya disease, two with moyamoya syndrome. We performed a one-staged revascularization of one MCA territory and both frontal areas in all patients. No significant complications occurred. Two patients experienced postoperative focal seizures, successfully treated with anti-epileptic medication. CONCLUSIONS: The single-staged STA-MCA bypass with EDMS combined with bifrontal EDPS allowed revascularization of three regions (the MCA territory unilaterally and the frontal areas bilaterally) and may serve as an alternative and safe treatment option for pediatric moyamoya patients.

Comparing five simple vascular storage protocols.

BACKGROUND: We aim to find a storage protocol for vessels that preserves their dimensional, histologic, and mechanical characteristics to facilitate reproducible anastomosis experiments and microsurgical training with constant quality. MATERIALS AND METHODS: We compared stored rabbit aortas, harvested in a slaughterhouse, using five different protocols with fresh controls. Aortas were preserved for 125 d in (1) NaCl 0.9% at -18°C, (2) Roswell Park Memorial Institute 1640 90% with 10% dimethyl sulfoxide (RPMI/DMSO) at -18°C, (3) RPMI/DMSO at -70°C, (4) glycerol 85% at 4°C, and (5) glycerol in stepwise increased concentrations until 85% at 4°C. After preservation, we measured vessel diameter, wall thickness, and Young's Modulus indicating stiffness. Neurosurgeons compared stored vessels with fresh vessels, blinded for preservation subgroup. We performed histologic assessment blinded for preservation subgroup. RESULTS: Fresh rabbit aortas showed a mean diameter of 2.65 ± 0.14 mm, a mean wall thickness of 126 ± 22 µm, and a Young's Modulus of 11.4 ± 2.4 N/mm(2). NaCl 0.9%-preserved aortas showed a significantly increased vessel diameter and decreased stiffness. RPMI/DMSO-preserved aortas showed no significant differences from fresh aortas in dimensions and mechanical characteristics. Glycerol-preserved tissue showed a significant increase in wall thickness, a related significant decrease in diameter, and increase in stiffness. Neurosurgeons regarded RPMI/DMSO tissue as most comparable with fresh tissue. Histologic assessment revealed no differences between the different protocols and fresh control group. CONCLUSIONS: Storage of rabbit aortas in RPMI/DMSO most adequately preserves their dimensional and mechanical properties.