Krings, Timo

The cerebrofacial metameric syndromes are a group of congenital syndromes that result in vascular malformations throughout specific anatomical distributions of the brain, cranium and face. Multiple reports of patients with high-flow or low-flow vascular malformations following a metameric distribution have supported this idea. There has been much advancement in understanding of segmental organization and cell migration since the concept of metameric vascular syndromes was first proposed. We aim to give an updated review of these embryological considerations and then propose a more detailed classification system for these syndromes, predominately incorporating the contribution of neural crest cells and somitomeres to the pharyngeal arches.

Background: Accurate and reliable models of intracranial hemorrhage (ICH) risk in the untreated course of brain arteriovenous malformation (BAVM) patients are needed to help weigh the risk-benefit of treatment. We present preliminary estimates of rates and risk factors for ICH or death in the Multicenter AVM Research Study (MARS), which is the largest individual patient data meta-analysis (IPDMA) of cohort studies of unruptured BAVM. Methods: Longitudinal data from 9 cohorts comprising 2,839 unruptured BAVM at time of diagnosis were included: UCSF (n=557), Macquarie (n=462), Kaiser Permanente Northern California (n=354), Columbia (n=335), Barrow Neurological Institute (n=324), Tiantan Hospital (n=303), Mayo Clinic-Rochester (n=244), Scottish Intracranial Vascular Malformation Study (n=194), and Toronto Western Hospital (n=66). Clinical and angiographic data were collected using standardized definitions across cohorts. Cox proportional hazards analysis of time-to-event (ICH or death) in the untreated course after diagnosis was performed, censoring at first treatment or last visit. Baseline hazard rates were stratified by cohort to account for different rates and follow-up times. Results: The combined cohort was 49% female, 72% white race, and 17% Hispanic ethnicity; mean age at diagnosis was 37±17 years and mean follow-up was 3.4±7.0 years. The most common presenting symptom was seizures (43%). Mean AVM size was 3.5±1.9 cm and 46% were Spetzler-Martin grade I-II. Overall, 123 ICH and 131 deaths occurred over 9,608 person-years (PY) for an event rate of 2.64 per 100 PY [95% CI: 2.34-2.99]. Cox regression analyses adjusting for age at diagnosis (HR=1.67 [1.54, 1.82], P<0.001) identified cerebellar location (HR=1.73 [1.03-2.93], P=0.040) and exclusively deep venous drainage (HR=1.83 [1.09-3.09], P=0.022) as predictors. Conclusion: Our current model identified increasing age, exclusively deep venous drainage, and cerebellar location as risk factors for ICH or death in the untreated course of unruptured bAVM patients. Review of imaging data, multiple imputation of missing angioarchitectural data, and additional data from pending cohorts will provide greater power to search for additional risk factors in this ongoing IPDMA.

Abstract Background Flow diversion is a common endovascular treatment for cerebral aneurysms, but studies comparing different types of flow diverters are scarce. Objective To perform a propensity score matched cohort study comparing the Pipeline Embolization Device (PED) and Flow Redirection Intraluminal Device (FRED) for posterior circulation aneurysms. Methods Consecutive aneurysms of the posterior circulation treated at 25 neurovascular centers with either PED or FRED were collected. Propensity score matching was used to control for age, duration of follow-up imaging, adjunctive coiling, and aneurysm location, size, and morphology; previously ruptured aneurysms were excluded. The two devices were compared for the following outcomes: procedural complications, aneurysm occlusion, and functional outcome. Results A total of 375 aneurysms of the posterior circulation were treated in 369 patients. The PED was used in 285 (77.2%) and FRED in 84 (22.8%) procedures. Aneurysms treated with the PED were more commonly fusiform and larger than those treated with FRED. To account for these important differences, propensity score matching was performed resulting in 33 PED and FRED unruptured aneurysm pairs. No differences were found in occlusion status and neurologic thromboembolic or hemorrhagic complications between the two devices. The proportion of patients with favorable functional outcome was higher with FRED (100% vs 87.9%, p=0.04). Conclusion Comparative analysis of PED and FRED for the treatment of unruptured posterior circulation aneurysms did not identify significant differences in aneurysm occlusion or neurologic complications. Variations in functional outcomes warrant additional investigations.

Abstract BACKGROUND The Pipeline Embolization Device (PED; Medtronic) has been used off-label for the treatment of challenging posterior circulation aneurysms. Data on this modality are primarily limited to small retrospective single-center series. OBJECTIVE To assess safety and efficacy of this treatment by establishing an international, multicenter collaboration. METHODS Consecutive posterior circulation aneurysms treated with the PED from 2012 to 2019 across 11 neurovascular centers were retrospectively reviewed. Baseline demographics, aneurysm and treatment characteristics, complications, occlusion status, and functional outcome were assessed. RESULTS There were 149 posterior circulation aneurysms treated with PED in 146 patients. A total of 24 (16.4%) patients presented with subarachnoid hemorrhage. Most aneurysms were dissecting/blister (36.2%) in morphology, followed by saccular (35.6%) and fusiform (28.2%). The most common locations were the vertebral (51.7%) and basilar arteries (22.8%). Complete or near-complete occlusion (>90%) was achieved in 90.9% of aneurysms at a median follow-up of 12 mo. Dissecting/blister aneurysms were most likely to occlude ( P = .06). Symptomatic neurologic complications occurred in 9.4% of aneurysms, associated with larger size, ruptured presentation, presentations with brain stem compression, cranial nerve palsy, or stroke. Favorable functional outcome (modified Rankin Score 0-2) was achieved in 86.2% of patients. There were 6 fatalities of which 4 occurred in aneurysmal subarachnoid hemorrhage patients. CONCLUSION This multicenter study shows that PED for the treatment of posterior circulation is preferentially used for the treatment of fusiform and dissecting/blister aneurysm morphologies. Despite the challenges presented by these less-common morphologies, flow diversion may be performed with a neurologic complication rate of about 10% and favorable long-term aneurysm occlusion rates.

Background and purpose The Alberta Stroke Program Early CT Score (ASPECTS) is a commonly used scoring system to select patients with stroke for endovascular treatment (EVT). However, the inter- and intra-reader variability is high. Objective To determine whether the inter- and intra-reader variability is different for various regions of the ASPECTS scoring system by evaluating the interobserver variability of ASPECTS between different readers in a per-region analysis. Materials and methods All patients with acute ischemic stroke who proceeded to EVT in our institutions over a 4-year period were retrospectively identified from a prospectively maintained database. Images were reviewed by two experienced neuroradiologists, who recalculated the ASPECTS independently. We examined each region of the ASPECTS system to evaluate agreement between the raters in each area. Results 375 patients were included. The median total ASPECTS was 9 (IQR 8–9). The most common region showing ischemic change was the insula, with the M6 region being least commonly affected. Overall interobserver agreement for ASPECTS using Cohen’s κ was 0.56 (95% CI 0.51 to 0.61). The region with the highest agreement was the insula (κ=0.56; 0.48 to 0.64). The region with the lowest agreement was M3 (κ=0.34; 0.12 to 0.56). Agreement was relatively good when ASPECTS were dichotomized into 0–5 versus 6–10 (κ=0.66; 0.49 to 0.84). Conclusions Substantial interobserver variability is found when calculating ASPECTS. This variability is region dependent, and practitioners should take this into account when using ASPECTS for treatment decisions in patients with acute stroke.

Background Preliminary clinical studies on the safety and efficacy of the pipeline embolization device (PED) for the treatment of small/medium aneurysms have demonstrated high occlusion rates with low complications. Objective To evaluate the safety and effectiveness of the PED for treatment of wide necked small and medium intracranial aneurysms. Methods PREMIER is a prospective, multicenter, single arm trial. Patients were treated with the PED for unruptured wide necked aneurysms, measuring ≤12 mm along the internal carotid artery or vertebral artery, between July 2014 and November 2015. At 1 year post-procedure, the primary effectiveness endpoint was complete occlusion (Raymond grade 1) without major parent vessel stenosis (≤50%) or retreatment, and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurologic death. Results A total of 141 patients were treated with PEDs (mean age 54.6±11.3 years, 87.9% (124/141) women). Mean aneurysm size was 5.0±1.92 mm, and 84.4% (119/141) measured <7 mm. PED placement was successful in 99.3% (140/141) of patients. Mean number of PEDs implanted per patient was 1.1±0.26; a single PED was used in 92.9% (131/141) of patients. At 1 year, 97.9% (138/141) of patients underwent follow-up angiography with 76.8% (106/138) of patients having met the study’s primary effectiveness endpoint. The combined major morbidity and mortality rate was 2.1% (3/140). Conclusions Treatment of wide necked small/medium aneurysms with the PED results in high rates of complete occlusion without significant parent vessel stenosis and low rates of permanent neurologic complications. Trial registration NCT02186561 .

Introduction: Accurately balancing risks of interventional treatment and intracranial hemorrhage (ICH) in the untreated course of unruptured brain arteriovenous malformation (uBAVM) patients is critical for optimal management. Observational studies of uBAVM afford an opportunity to address important gaps and previous criticisms of randomized data to help guide treatment decisions and assess long-term risk/benefit ratio. We previously published an individual patient data meta-analysis (IPDMA) in 4 MARS cohorts and identified ICH presentation and increasing age as significant predictors of ICH during follow-up, but was not powered to detect predictors in those with uBAVM. Thus, the goals of this project are to identify risk factors for ICH in uBAVMs, to estimate the risk with precision, and to create personalized, risk-prediction models. Methods: MARS is an international, multi-center study of 11 cohorts with target enrollment of 4,500 uBAVM patients ascertained through population-based or referral-based studies. We are harmonizing both retrospective and prospective data, including clinical, lifestyle, imaging, and angiographic factors. Treatments, complications, and functional outcomes (physician and patient-reported) will be updated annually between 2018-2022. We propose to: 1) identify predictors of outcome in uBAVMs using IPDMA; 2) test whether long-term outcomes differ by treatment using statistical approaches for causal inference and unbiased estimates; 3) compare treatment outcomes in randomized and non-randomized data to address generalizability; and 4) validate models and provide a novel tool for calculating individualized risks. Eligible sites have: a) prior BAVM publications; b) data from a minimum of 100 uBAVM patients; c) agree to random outcome adjudication; and d) agree to MARS data sharing policy. Discussion: The NIH-funded MARS consortium will provide important and comprehensive characterization of the untreated and treated course of uBAVMs, using large observational datasets and sophisticated epidemiological approaches. The data and models generated will be a useful resource for decision-making. We welcome participation from eligible sites with longitudinal data on uBAVM patients

Background and purpose Thoracolumbar and sacral spinal epidural arteriovenous fistulas (SEDAVFs) are an increasingly recognized form of spinal vascular malformation. The purpose of this study was to perform a systematic review of the demographics, clinical presentation and treatment results of thoracolumbar SEDAVFs. Materials and methods Pubmed, Scopus and Web of Science databases were searched from January 2000 to January 2018 for articles on treatment of SEDAVFs. Pooled data of individual patients were analyzed for demographic and clinical features of SEDAVFs as well as treatment outcomes. Results There were 125 patients from 11 studies included. Mean age was 63.5 years. There was a male sex predilection (69.6%). Sensory symptoms including pain or numbness were the most frequently presenting symptoms. Fistula location was the lumbosacral spine in 79.2% and the thoracic spine in 20.8%. Involvement of intradural venous drainage was more common than extradural venous drainage only (89.6% vs 10.4%). Of the 123 treated patients, endovascular therapy was performed in 67.5% of patients, microsurgery in 23.6%, and combined treatment in 8.9%. The overall complete obliteration rate was 83.5% and did not differ between groups. Clinical symptoms improved in 70.7% of patients, were stable in 25%, and worsened in 1.7% with no difference between treatment modalities. Conclusions Thoracic and lumbosacral SEDAVFs often present with symptoms secondary to congestive myelopathy or compressive symptoms. Both endovascular and microsurgical treatments were associated with high obliteration rates and good clinical outcomes.

Background and purpose Spinal arterial aneurysms are a rare cause of spinal subarachnoid hemorrhage (SAH). We performed a retrospective review of spinal arterial aneurysms not associated with spinal arteriovenus shunts from three institutions in order to better understand the clinical and imaging characteristics of these lesions. Materials and methods We performed a retrospective review of spinal arterial aneurysms managed at three North American institutions. For each patient, the following information was collected: demographic data, clinical presentation, comorbidities, imaging findings, and neurological status at the last follow-up. Treatment strategies and outcomes were reported. Results 11 patients were included; 7 were women and median age was 60 years. The most common presentation was sudden back pain (81.8%). We found 3 aneurysms on the radiculomedullary artery and 8 along the radiculopial arteries. Of the 3 aneurysms on the radiculomedullary artery, 1 was treated conservatively, 1 was treated with coiling of the aneurysm and sacrifice of the radiculomedullary artery, and 1 was treated with surgical trapping. The 8 aneurysms on the radiculopial artery were treated endovascularly in 4 cases, surgically in 1 case, and conservatively in 3 cases. One surgically treated patient had a spinal subdural hematoma. There were no other complications. Mean clinical follow-up time was 20 months, and 87.5% of patients were functionally independent. Conclusions Spinal arterial aneurysms are lesions which commonly present with sudden back pain and spinal SAH. Conservative, surgical, and endovascular treatment options are safe and effective. Long term outcomes in these patients are generally good.