A core-lab adjudicated analysis of single-stent assisted coiling of wide-neck bifurcation aneurysms.

BACKGROUND AND PURPOSE: Core-lab adjudicated data regarding the efficacy of the single-stent assisted aneurysm coiling technique 'L-stenting' are lacking. We present a multicenter, core-lab adjudicated study evaluating the safety and effectiveness of single-stent assisted coiling in the treatment of wide-neck bifurcation aneurysms (WNBAs). METHODS: Consecutive patients who underwent L-stenting for WNBAs at three academic institutions between 2015 and 2019 were included in this retrospective study. Clinical safety and efficacy outcomes were gathered from the patient chart, and angiographic imaging was evaluated by core lab analysis. Safety and efficacy outcomes were summarized and predictors of safety and efficacy were calculated. RESULTS: Of 128 patients treated, 124 had angiographic outcome data at last follow-up. Of those, 110 had adequate (core-lab adjudicated modified Raymond Roy (mRR) score of 1 or 2) occlusion (88.7%). During follow-up, 19 patients (14.8%) required retreatment. There were 17 complications experienced in 12 patients: intraoperative (n=8, 6.25%), perioperative (n=5, 3.9%), or delayed (n=6; n=4 attributed to device/procedure, 3.1%). Significant predictors of complete occlusion were smaller aneurysm size and use of the jailing technique (P=0.0276). Significant predictors of retreatment were larger size, neck size, and larger dome to neck ratio (P=0.0008). CONCLUSION: This study provides multicenter, core-lab adjudicated angiographic data regarding the efficacy of single-stent assisted coiling for WNBAs. This study acts as a validated comparator for future studies investigating novel devices or techniques for treating this challenging subgroup of aneurysms.

The Impact of Preprocedural Platelet Function Testing on Periprocedural Complication Rates Associated With Pipeline Flow Diversion: An International Multicenter Study.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel. METHODS: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant. RESULTS: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9). CONCLUSION: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.

Transcranial Doppler cerebrovascular reactivity: Thresholds for clinical significance in cerebrovascular disease.

BACKGROUND AND PURPOSE: Thresholds for abnormal transcranial Doppler cerebrovascular reactivity (CVR) studies are poorly understood, especially for patients with cerebrovascular disease. Using a real-world cohort with cerebral arterial stenosis, we sought to describe a clinically significant threshold for carbon dioxide reactivity (CO2R) and vasomotor range (VMR). METHODS: CVR studies were performed during conditions of breathing room air normally, breathing 8% carbon dioxide air mixture, and hyperventilation. The mean and standard deviation (SD) of CO2R and VMR were calculated for the unaffected side in patients with unilateral stenosis; a deviation of 2 SDs below the mean was chosen as the threshold for abnormal. Receiver operating characteristic (ROC) curves for both sides for patients with unilateral and bilateral stenosis were evaluated for sensitivity (Sn) and specificity (Sp). RESULTS: A total of 133 consecutive CVR studies were performed on 62 patients with stenosis with mean±SD age 55±16 years. Comorbidities included hypertension (60%), diabetes (15%), stroke (40%), and smoking (35%). In patients with unilateral stenosis, mean±SD CO2R for the unaffected side was 1.86±0.53%, defining abnormal CO2R as <0.80%. Mean±SD CO2R for the affected side was 1.27±0.90%. The CO2R threshold predicted abnormal acetazolamide single-photon emission computed tomography (SPECT) (Sn = .73, Sp = .79), CT/MRI perfusion abnormality (Sn = .42, Sp = .77), infarction on MRI (Sn = .45, Sp = .76), and pressure-dependent exam (Sn = .50, Sp = .76). For the unaffected side, mean±SD VMR was 39.5±15.8%, defining abnormal VMR as <7.9%. For the affected side, mean±SD VMR was 26.5±17.8%. The VMR threshold predicted abnormal acetazolamide SPECT (Sn = .46, Sp = .94), infarction on MRI (Sn = .27, Sp = .94), and pressure-dependent exam (Sn = .31, Sp = .90). CONCLUSIONS: In patients with multiple vascular risk factors, a reasonable threshold for clinically significant abnormal CO2R is <0.80% and VMR is <7.9%. Noninvasive CVR may aid in diagnosing and risk stratifying patients with stenosis.

Deconstructive repair of a direct carotid-cavernous fistula via a posterior circulation retrograde approach.

We report a case of a 24-year-old patient who presented after a head trauma with a traumatic occlusion of his left internal carotid artery. He underwent diagnostic cerebral angiogram and was found to have a direct left carotid-cavernous fistula (CCF) with retrograde filling from the posterior circulation across the posterior communicating artery. Because of the severe injury to the left internal carotid artery (ICA), reconstructive repair of the ICA was not possible. The patient underwent deconstructive repair of the CCF by coil embolization using a posterior retrograde approach. Coils were successfully placed in the cavernous sinus and back into the left ICA with complete cure of the CCF and restoration of cerebral perfusion distal to the treated CCF. We review the types of CCFs, their clinical presentation, and their endovascular treatments. Retrograde access of a direct CCF is rarely reported in the literature, and we believe this approach offers a viable alternative in appropriately selected patients.

Characterizing coma in large vessel occlusion stroke.

BACKGROUND: Coma is an unresponsive state of disordered consciousness characterized by impaired arousal and awareness. The epidemiology and pathophysiology of coma in ischemic stroke has been underexplored. We sought to characterize the incidence and clinical features of coma as a presentation of large vessel occlusion (LVO) stroke. METHODS: Individuals who presented with LVO were retrospectively identified from July 2018 to December 2020. Coma was defined as an unresponsive state of impaired arousal and awareness, operationalized as a score of 3 on NIHSS item 1a. RESULTS: 28/637 (4.4%) patients with LVO stroke were identified as presenting with coma. The median NIHSS was 32 (IQR 29-34) for those with coma versus 11 (5-18) for those without (p < 0.0001). In coma, occlusion locations included basilar (13), vertebral (2), internal carotid (5), and middle cerebral (9) arteries. 8/28 were treated with endovascular thrombectomy (EVT), and 20/28 died during the admission. 65% of patients not treated with EVT had delayed presentations or large established infarcts. In models accounting for pre-stroke mRS, basilar occlusion location, intravenous thrombolysis, and EVT, coma independently increased the odds of transitioning to comfort care during admission (aOR 6.75; 95% CI 2.87,15.84; p < 0.001) and decreased the odds of 90-day mRS 0-2 (aOR 0.12; 95% CI 0.03,0.55; p = 0.007). CONCLUSIONS: It is not uncommon for patients with LVO to present with coma, and delayed recognition of LVO can lead to poor outcomes, emphasizing the need for maintaining a high index of suspicion. While more commonly thought to result from posterior LVO, coma in our cohort was similarly likely to result from anterior LVO. Efforts to improve early diagnosis and care of patients with LVO presenting with coma are crucial.

Neurovascular Interventions for Neurotrauma: From Treatment of Injured Vessels to Treatment of the Injured Brain?

Traumatic brain injury is often associated with a direct or secondary neurovascular pathology. In this review, we present recent advancements in endovascular neurosurgery that enable accurate and effective vessel reconstruction with emphasis on its role in early diagnosis, the expanding use of flow diversion in pseudoaneurysms, and traumatic arteriovenous fistulas. In addition, future directions in which catheter-based interventions could potentially affect traumatic brain injury are described: targeting blood brain barrier integrity using the advantages of intra-arterial drug delivery of blood brain barrier stabilizers to prevent secondary brain edema, exploring the impact of endovascular venous access as a means to modulate venous outflow in an attempt to reduce intracranial pressure and augment brain perfusion, applying selective intra-arterial hypothermia as a neuroprotection method mitigating some of the risks conferred by systemic cooling, trans-vessel wall delivery of regenerative therapy agents, and shifting attention using multimodal neuromonitoring to post-traumatic vasospasm to further characterize the role it plays in secondary brain injury. Thus, we believe that the potential of endovascular tools can be expanded because they enable access to the "highways" governing perfusion and flow and call for further research focused on exploring these routes because it may contribute to novel endovascular approaches currently used for treating injured vessels, harnessing them for treatment of the injured brain.

Direct Versus Indirect Revascularization for Moyamoya: a Large Multicenter Study.

BACKGROUND: Moyamoya is a chronic occlusive cerebrovascular disease of unknown etiology causing neovascularization of the lenticulostriate collaterals at the base of the brain. Although revascularization surgery is the most effective treatment for moyamoya, there is still no consensus on the best surgical treatment modality as different studies provide different outcomes. OBJECTIVE: In this large case series, we compare the outcomes of direct (DR) and indirect revascularisation (IR) and compare our results to the literature in order to reflect on the best revascularization modality for moyamoya. METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational studies in Epidemiology guidelines of moyamoya affected hemispheres treated with DR and IR surgeries across 13 academic institutions predominantly in North America. All patients who underwent surgical revascularization of their moyamoya-affected hemispheres were included in the study. The primary outcome of the study was the rate of symptomatic strokes. RESULTS: The rates of symptomatic strokes across 515 disease-affected hemispheres were comparable between the two cohorts (11.6% in the DR cohort vs 9.6% in the IR cohort, OR 1.238 (95% CI 0.651 to 2.354), p=0.514). The rate of total perioperative strokes was slightly higher in the DR cohort (6.1% for DR vs 2.0% for IR, OR 3.129 (95% CI 0.991 to 9.875), p=0.052). The rate of total follow-up strokes was slightly higher in the IR cohort (8.1% vs 6.6%, OR 0.799 (95% CI 0.374 to 1.709) p=0.563). CONCLUSION: Since both modalities showed comparable rates of overall total strokes, both modalities of revascularization can be performed depending on the patient's risk assessment.

Informed consent practices for acute stroke therapy: principles, challenges and emerging opportunities.

IMPORTANCE: Informed consent (IC) plays a crucial yet underexplored role in acute stroke treatment, particularly in the context of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). This narrative review examines data on current IC practices in acute ischemic stroke management, specifically for patients treated with IVT or EVT, with the aim of identifying areas for improvement and strategies to enhance the IC process. OBSERVATIONS: IC practices for IVT vary significantly among hospitals and physicians with the frequency of always requiring consent ranging from 21 to 37%. Factors influencing IC for IVT include patient decision-making capacity, standard of care, time sensitive nature of treatments, legal and moral obligations, risk of complications, physician age and speciality, treatment delays, and hospital size. Consent requirements tend to be stricter for patients presenting within the 3-4.5-h window. The content and style of information shared as part of the IC process revealed discrepancies in the disclosure of stroke diagnosis, IVT mechanism, benefits, and risks. Research on IC practices for EVT is scarce, highlighting a concerning gap in the available evidence base. CONCLUSIONS AND RELEVANCE: This review underscores the significant variability and knowledge gaps in IC for EVT and IVT. Challenges related to decision-making capacity assessment and the absence of standardised guidance substantially contributes to these gaps. Future initiatives should focus on simplifying information delivery to patients, developing formal tools for assessing capacity, standardising ethical frameworks to guide physicians when patients lack capacity and harmonizing IC standards across sites. The ultimate goal is to enhance IC practices and uphold patient autonomy, while ensuring timely treatment initiation.

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Intracranial stenting compared to medical treatment alone for intracranial atherosclerosis patients: An updated meta-analysis.

Objective: Stroke is the second-leading cause of death globally. Intracranial atherosclerotic stenosis (ICAS) represents 10-15% of ischemic strokes in Western countries and up to 47% in Asian countries. Patients with ICAS have an especially high risk of stroke recurrence. The aim of this meta-analysis is to reassess recurrent stroke, transient ischemic attack (TIA), and other outcomes with stenting versus best medical management for symptomatic ICAS. Methods: The search protocol was developed a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The OVID Medline, Embase, Web of Science, and Cochrane Library databases were searched from inception to August 14th, 2022. Results: This Meta-analysis Included Four Randomized Controlled Trials (Rcts), With A Total Number Of 991 Patients. The Mean Age Of Participants Was 57 Years. The Total Number Of Intracranial Stenting Patients Was 495, And The Number Of Medical Treatment Patients Was 496. The Included Studies Were Published Between 2011 And 2022. Two Studies Were Conducted In The Usa, And The Other Two In China. All Included Studies Compared Intracranial Stenting To Medical Treatment For Icas. Conclusions: In patients with ischemic stroke due to symptomatic severe intracranial atherosclerosis, the rate of 30-day ischemic stroke, 30-day intracerebral hemorrhage, one-year stroke in territory or mortality favored the medical treatment alone without intracranial stenting. The risk of same-territory stroke at last follow-up, disabling stroke at last follow-up, and mortality did not significantly favor either group. Intracranial stenting for atherosclerosis did not result in significant benefit over medical treatment.

The Impact of Dual Antiplatelet Therapy Duration on Unruptured Aneurysm Occlusion After Flow Diversion: A Multicenter Study.

OBJECTIVE: Endoluminal flow diversion reduces blood flow into intracranial aneurysms, promoting thrombosis. Postprocedural dual antiplatelet therapy (DAPT) is necessary for the prevention of thromboembolic complications. The purpose of this study is to therefore assess the impact that the type and duration of DAPT has on aneurysm occlusion rates and iatrogenic complications after flow diversion. METHODS: A retrospective review of a multicenter aneurysm database was performed from 2012 to 2020 to identify unruptured intracranial aneurysms treated with single device flow diversion and ≥12-month follow-up. Clinical and radiologic data were analyzed with aneurysm occlusion as a function of DAPT duration serving as a primary outcome measure. RESULTS: Two hundred five patients underwent flow diversion with a single pipeline embolization device with 12.7% of treated aneurysms remaining nonoccluded during the study period. There were no significant differences in aneurysm morphology or type of DAPT used between occluded and nonoccluded groups. Nonoccluded aneurysms received a longer mean duration of DAPT (9.4 vs 7.1 months, P = 0.016) with a significant effect of DAPT duration on the observed aneurysm occlusion rate (F(2, 202) = 4.2, P = 0.016). There was no significant difference in the rate of complications, including delayed ischemic strokes, observed between patients receiving short (≤6 months) and prolonged duration (>6 months) DAPT (7.9% vs 9.3%, P = 0.76). CONCLUSIONS: After flow diversion, an abbreviated duration of DAPT lasting 6 months may be most appropriate before transitioning to low-dose aspirin monotherapy to promote timely aneurysm occlusion while minimizing thromboembolic complications.

Treatment of a posterior cerebral artery aneurysm in the context of complex cardio-cerebrovascular variations using the Tubridge flow diverter.

We present a case of intracranial aneurysm located in the P1 segment of left posterior cerebral artery in the context of tetralogy of Fallot. Complex variations included right aortic arch with abnormal branching. Also, the bilateral vertebral arteries were absent, with a type I persistent proatlantal intersegmental artery of the left side. The aneurysm was treated with endovascular intervention with a Tubridge flow diverter and was noted to be completely cured on 6-month follow-up. We discuss the many considerations in this patient including developmental and modern-era treatment.

Direct Burr Hole Access for Transverse-Sigmoid Junction DAVF Embolization: A Case Report.

Dural arteriovenous fistulas (DAVFs) are rare intracranial vascular malformations that present with a variety of clinical signs and symptoms. Among these, intracranial hemorrhage is a severe complication. A 72-year-old male presented with headache and pulsatile tinnitus. Cerebral angiography revealed a Borden II/Cognard IIa+b DAVF. He underwent stage 1 transarterial embolization of the occipital artery which reduced shunting by 30%. Several attempts were made to access the fistula during stage 2 transvenous embolization, but it was not possible to access the left transverse sinus fistula site since there was no communication across the torcula from the right transverse sinus and the left inferior sigmoid-jugular bulb was occluded. Therefore, a single burr hole was drilled and direct access to the DAVF was achieved with a micropuncture needle under neuronavigational guidance. The left transverse-sigmoid sinus junction was then embolized with coils. After the procedure, angiography revealed that the DAVF was cured with no residual shunting. This case demonstrates how minimally invasive surgery provides an alternative method to access a DVAF when conventional transarterial and/or transvenous embolization treatment options are not possible. Each DAVF case has unique anatomy and physiology, and creative multi-disciplinary strategies can often yield the best results.

Management of Adult Unruptured Brain Arteriovenous Malformations: An Updated Network Meta-Analysis.

The management of unruptured brain arteriovenous malformations (ubAVMs) is a complex challenge to neurovascular practitioners. This meta-analysis aimed to identify the optimal management of ubAVMs comparing conservative management, embolization, radiosurgery, microsurgical resection, and multimodality. The search strategy was developed a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the Ovid Medline, Embase, Web of Science, and Cochrane Library databases to identify relevant papers. Using R version 4.1.1., a frequentist network meta-analysis was conducted to compare different management modalities for the ubAVMs. Overall, the conservative group had the lowest risk of rupture (P-score=0.77), and the lowest rate of complications was found in the conservative group (P-score=1). Among different interventions, the multimodality group had the highest rupture risk (P-score=0.34), the lowest overall complications (P-score=0.75), the best functional improvement (P-score=0.65), and the lowest overall mortality (P-score=0.8). However, multimodality treatment showed a significantly higher risk of rupture (odds ratio [OR]=2.13; 95% confidence interval [95% CI]=1.18-3.86) and overall complication rate (OR=5.56; 95% CI=3.37-9.15) compared to conservative management; nevertheless, there were no significant differences in overall mortality or functional independence when considered independently. Conservative management is associated with the lowest rupture risk and complication rate overall. A multimodal approach is the best option when considering mortality rates and functional improvement in the context of existing morbidity/symptoms. Microsurgery, embolization, and radiosurgery alone are similar to the natural history in terms of functional improvement and mortality, but have higher complication rates.

FRED Jr stent for acute flow diversion in ruptured cerebral aneurysms arising from small-caliber vessels: a clinical case series.

OBJECTIVE: Treatment of ruptured aneurysms arising from small-caliber (< 2.5 mm) or distal vessels beyond the circle of Willis is considered challenging with all treatment modalities. Recently, the Flow Re-Direction Endoluminal Device Junior (FRED Jr) stent, designed for flow diversion in small arteries, was approved in the United States for the treatment of nonruptured aneurysms. Here, the authors report their experience using this device in the setting of subarachnoid hemorrhage (SAH). METHODS: Clinical and radiological records of patients sustaining SAH treated with a FRED Jr stent between June 2020 and October 2022 were reviewed. Treatment course, including antiplatelet therapy, external ventricular drain (EVD) management, and vasospasm, and clinical outcomes were analyzed. Angiographic results were assessed according to the O'Kelly-Marotta (OKM) grading scale. RESULTS: Nine patients at a median age of 62 (range 27-75) years were included. The median Hunt and Hess grade was II (IQR I) and the median modified Fisher grade was 4 (IQR 1). Aneurysm morphology types included saccular (6 patients), blister (1 patient), and dissecting (2 patients), and the aneurysms were located at the anterior communicating artery complex (n = 3) at the A2/A3 (n = 3), M2/M3 (n = 1), V4 (n = 1), and P2 (n = 1) arterial segments. All stents were deployed successfully with no intraprocedural complications. Postoperatively, no rebleeding events were encountered. Vasospasm therapy was initiated in 6 patients, and no symptomatic EVD-related hematomas were observed. Postoperative ischemic events were encountered in 2 patients. The median 3-month modified Rankin Scale score was 2 (IQR 1) for the 7 surviving patients, and 3-month radiographic follow-up revealed OKM grade D in 4 of 7 patients. CONCLUSIONS: Flow diversion using the FRED Jr stent is feasible as a potential treatment strategy for acutely ruptured aneurysms arising from small-caliber vessels. The complication profile reported in this series is comparable to those of historical microsurgical cohorts, and effective protection was conferred by this treatment modality. Therefore, our small cohort provides a glimpse into a new tool for successfully achieving acute flow diversion for this subset of difficult-to-treat aneurysms.

Azygos anterior cerebral artery shield masquerading as an aneurysm.

Here, we describe a case of a woman suspected to have an anterior cerebral artery (ACA) aneurysm that was ultimately found to have an azygous ACA shield. This benign entity highlights the importance of thorough investigation with cerebral digital subtraction angiography (DSA). This 73-year-old female initially presented with dyspnea and dizziness. CT angiogram of the head suggested an incidental 5 mm ACA aneurysm. Subsequent DSA demonstrated a Type I azygos ACA supplied by the left A1 segment. Also noted was a focal dilatation of the azygos trunk as it gave rise to the bilateral pericallosal and callosomarginal arteries. Three-dimensional visualization demonstrated a benign dilatation secondary to the four vessels branching; no aneurysm was noted. Incidence of aneurysms at the distal dividing point of an azygos ACA ranges from 13% to 71%. However, careful anatomical examination is imperative as findings may be a benign dilatation for which case intervention is not indicated.

Symmetric collateral pattern on CTA predicts favorable outcomes after endovascular thrombectomy for large vessel occlusion stroke.

Endovascular thrombectomy (EVT) has revolutionized large vessel occlusion (LVO) stroke management, but often requires advanced imaging. The collateral pattern on CT angiograms may be an alternative because a symmetric collateral pattern correlates with a slowly growing, small ischemic core. We tested the hypothesis that such patients will have favorable outcomes after EVT. Consecutive patients (n = 74) with anterior LVOs who underwent EVT were retrospectively analyzed. Inclusion criteria were available CTA and 90-day modified Rankin Scale (mRS). CTA collateral patterns were symmetric in 36%, malignant in 24%, or other in 39%. Median NIHSS was 11 for symmetric, 18 for malignant, and 19 for other (p = 0.02). Ninety-day mRS ≤2, indicating independent living, was achieved in 67% of symmetric, 17% of malignant, and 38% of other patterns (p = 0.003). A symmetric collateral pattern was a significant determinant of 90-day mRS ≤2 (aOR = 6.62, 95%CI = 2.24,19.53; p = 0.001) in a multivariable model that included age, NIHSS, baseline mRS, thrombolysis, LVO location, and successful reperfusion. We conclude that a symmetric collateral pattern predicts favorable outcomes after EVT for LVO stroke. Because the pattern also marks slow ischemic core growth, patients with symmetric collaterals may be suitable for transfer for thrombectomy. A malignant collateral pattern is associated with poor clinical outcomes.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Spoke-administered thrombolysis improves large vessel occlusion early recanalization: the real-world experience of a large academic hub-and-spoke telestroke network.

Introduction: Intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is increasingly controversial. Recent trials support MT without IVT for patients presenting directly to MT-capable "hub" centers. However, bypassing IVT has not been evaluated for patients presenting to IVT-capable "spoke" hospitals that require hub transfer for MT. A perceived lack of efficacy of IVT to result in LVO early recanalization (ER) is often cited to support bypassing IVT, but ER data for IVT in patients that require interhospital transfer is limited. Here we examined LVO ER rates after spoke-administered IVT in our hub-and-spoke stroke network. Methods: Patients presenting to 25 spokes before hub transfer for MT consideration from 2018-2020 were retrospectively identified from a prospectively maintained database. Inclusion criteria were pre-transfer CTA-defined LVO, ASPECTS ≥6, and post-transfer repeat vessel imaging. Results: Of 167 patients, median age was 69 and 51% were female. 76 received spoke IVT (+spokeIVT) and 91 did not (-spokeIVT). Alteplase was the only IVT used in this study. Comorbidities and NIHSS were similar between groups. ER frequency was increased 7.2-fold in +spokeIVT patients [12/76 (15.8%) vs. 2/91 (2.2%), P<0.001]. Spoke-administered IVT was independently associated with ER (aOR=11.5, 95% CI=2.2,99.6, p<0.05) after adjusting for timing of last known well, interhospital transfer, and repeat vessel imaging. Interval NIHSS was improved in patients with ER (median -2 (IQR -6.3, -0.8) vs. 0 (-2.5, 1), p<0.05). Conclusion: Within our network, +spokeIVT patients had a 7.2-fold increased ER relative likelihood. This real-world analysis supports IVT use in eligible patients with LVO at spoke hospitals before hub transfer for MT.