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.

Factors Contributing to Major Neurological Complications From Vein of Galen Malformation Embolization.

Importance: Major neurological complications from the embolization of vein of Galen malformations (VOGMs) are poorly understood. We provide a detailed analysis of contributors to periprocedural neurological complications and lessons learned. Objective: To assess the rate of major periprocedural neurological complications following VOGM embolization with major procedural and strategic contributors. Design, Setting, and Participants: This retrospective cohort study was conducted at a quarternary referral pediatric hospital (Hospital for Sick Children; Toronto, Ontario, Canada) from January 1999 to December 2018 with a mean clinical follow-up of 44.7 months; all children with VOGM diagnosed and/or treated were eligible (n = 48). Thirty-three patients who underwent endovascular treatment were included. Interventions: Endovascular staged transarterial embolization performed in 33 patients over 91 sessions. Main Outcomes and Measures: The primary outcome was the rate of periprocedural neurological complications (occurring within 1 week of embolization). The secondary outcomes were mortality, long-term neurological outcomes, and contributing anatomical and management factors to neurological complications. Results: Of 33 patients who underwent embolization (31 boys [64.6%]; 17 girls [35.4%]; median age at first embolization, 4 months [range, 0-29 months]), 10 patients (30.3%) developed major periprocedural neurological complications. Five of these patients died. Univariate logistic regression analyses identified internal cerebral vein drainage to the main venous sac of the VOGM and use of a microcatheter with a distal outer diameter of more than 2.0F as significant predictors of poor neurological outcomes. Lessons learned from our experience include the need to assess the internal cerebral vein drainage pattern on preprocedural magnetic resonance venography, avoidance of excessive embolization into the venous sac, treatment of more distal fistulae before proximal fistulae to avoid a sump effect, and preferably use of smaller (<2.0F outer diameter) microcatheters in neonatal embolization procedures. Conclusions and Relevance: In this cohort, 10 patients with VOGM treated with embolization (30.3%) experienced major periprocedural neurological complications, half of whom died. While these outcomes are superior to historic conservative and surgical treatment results, ongoing improvements in treatment and pretreatment diagnostic approaches are needed. Awareness of the lessons learned from our experience can help to avoid similar complications in the future for this vulnerable population.

An ACVRL1 gene mutation presenting as vein of Galen malformation at prenatal diagnosis.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease. The diagnostic criteria of HHT, or Curaçao criteria, include the following: recurrent epistaxis or nighttime nose bleeding, mucocutaneous telangiectases, visceral arteriovenous malformation, or an appropriate family history. The diagnosis is classified as definite if three criteria are present, possible if two criteria are present, and unlikely if only one is present. Nowadays, the confirmation of HHT diagnosis is based on molecular genetic studies. It has been showed that only mutations of genes encoding proteins within the transforming growth factor beta signaling pathway were responsible for the manifestation of the disease. The vein of Galen malformation (VOGM) as a presenting sign of HHT is rare. The prenatal diagnosis of HHT is even rarer. Herein, we present a case of prenatally diagnosed case of HHT based on the presence of VOGM in the fetus. To our knowledge, it is the first time that the gene mutation discovered in this case manifested as VOGM in the fetal life.

Vein of Galen Malformation, a cause of Intracranial Calcification: Case Report and Review of Literature.

Intracranial calcifications in the pediatric population can have many etiologies including neoplastic, infectious, neurodegenerative, metabolic, or cerebrovascular abnormalities. We present the case of a 2-year-old boy with vein of Galen malformation, a rare cause of intracranial calcifications with a review of literature.

Malformación arteriovenosa de la vena de Galeno. Serie de casos / Vein of Galen aneurysmal malformation. A case series

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Vein of Galen Aneurysmal Malformation: Advances in Management and Endovascular treatment.

BACKGROUND: Vein of Galen aneurysmal malformation (VGAM) is a rare congenital vascular malformation representing <1% of all arteriovenous malformations. The knowledge and strategies in the management are constantly evolving. OBJECTIVE: To review our series of postneonatal VGAM patients treated over 11-yr period. METHODS: Retrospective analysis of 113 VGAM treated between January 2004 and April 2015. After exclusions, 45 patients were included: 33 choroidal and 12 mural types. RESULTS: Presenting symptom in the order of frequency: enlarged head circumference, antenatal diagnosis, mild CHF, and PHT at birth. Older patients were diagnosed following trauma, headache, cognitive decline, and incidentally during workup for other diseases. Hydrocephalus due to hydrodynamic disorder was present in 70% of choroidal and 58% of mural types. Only a quarter needed cerebrospinal fluid diversion procedure. Radiological cure was achieved in 82%; the outcome graded on a 5-point scale: 0 (death) to 4 (normal). A total of 66.6% are neurologically and developmentally intact with outcome score 4, 20% had outcome score of 3, and 8.9% had outcome score of 2. There was 4.4% mortality. Dural feeders to VGAM were found either in the initial or during the treatment in 22.2% in the current series. Angiogenesis from pial vessels developed after partial embolization in 17.7% that resolved completely following complete obliteration of VGAM. CONCLUSION: Technical and technological advancements in endovascular embolization along with better understanding of clinical, anatomic, and pathophysiological aspects have resulted in significantly improved outcome and prognosis in VGAM. Most patients with proper treatment can now survive and most develop normally following appropriately timed treatment.

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Human genetics and molecular mechanisms of vein of Galen malformation.

Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas between the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation-arteriovenous malformation syndrome ( RASA1) and hereditary hemorrhagic telangiectasia ( ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attributable in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients' families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.

Fistulous-type vein of Galen malformation phantom model for endovascular training and research.

INTRODUCTION: Vein of Galen malformation (VGM), a high-flow intracranial arteriovenous shunt, is among the most severe neurovascular diseases in childhood. In many cases untreated children die or survive only severely disabled. Endovascular embolization is the preferred treatment. OBJECTIVE: To develop a simple fistulous-type VGM phantom model for teaching and training of different endovascular treatment methods and to investigate new treatment options and devices. METHODS: An experimental in vitro pulsatile phantom model was developed imitating a high-flow fistulous-type VGM, which is typical, especially in the neonatal phase. Pressure measurements at different arterial sites were performed before and after closure of the VGM. Closure of the VGM was achieved by coiling using a combined microcatheter-based transvenous and transarterial approach called 'kissing microcatheter technique'. RESULTS: The behaviour of the phantom model in vitro under fluoroscopy and under angiographic runs was extremely similar to that in in vivo conditions in children. The results showed that intra-arterial pressures changed and increased statistically significantly at all measurement sites after embolization, as in human arteriovenous malformation. We also demonstrated different and complementary visualizations of hemodynamics and angioarchitecture by antegrade and retrograde microcatheter injections. CONCLUSIONS: Our phantom model behaves like a typical fistulous-type VGM and can be used in vitro for teaching and training and for further research. It offers a new and better understanding of hemodynamics and angioarchitecture in the endovascular management of VGM.

Decreased Superior Sagittal Sinus Diameter and Jugular Bulb Narrowing Are Associated with Poor Clinical Outcome in Vein of Galen Arteriovenous Malformation.

BACKGROUND AND PURPOSE: Few clinical and imaging findings are known to be associated with poor outcome in neonates and infants with vein of Galen arteriovenous malformations. In the present consecutive series of 35 patients, we evaluated both the diameter of the superior sagittal sinus at onset and the diameter of the jugular bulb on follow-up as potential factors related to poor outcome. MATERIALS AND METHODS: Thirty-five consecutive neonates and infants who were prospectively collected in a single-center data base were included in this review. Outcome was assessed by using the Bicêtre Outcome Score. Both the absolute diameter of the superior sagittal sinus and its ratio to the biparietal diameter were measured at onset, compared with age-matched controls, and correlated to patient outcome. RESULTS: The diameter of the superior sagittal sinus at onset and its ratio to the biparietal diameter were significantly smaller in the vein of Galen arteriovenous malformation population compared with the matched population (P = .0001) and were correlated significantly with a risk of poor clinical outcome (P = .008). Development of jugular bulb narrowing was also related to poor clinical outcome (P < .0001). CONCLUSIONS: Decreased superior sagittal sinus diameter may reflect a decrease of cerebral blood flow due to cerebral arterial steal and intracranial hydrovenous disorders. This finding may be considered cerebral blood flow deterioration and thus taken into consideration in the management decisions for patients with vein of Galen arteriovenous malformations. Likewise, our data suggest that progressive jugular bulb narrowing may indicate earlier intervention to prevent severe narrowing.

Occlusion of Posterior Fossa Dural Sinuses in Vein of Galen Malformation.

BACKGROUND AND PURPOSE: Spontaneous or progressive occlusion of the posterior fossa dural sinuses is often observed in patients with vein of Galen malformation, which can affect the clinical course. The aim of this study was to examine the patency of the posterior fossa dural sinuses in patients with vein of Galen malformation and to analyze the clinical and angiographic course of this condition. MATERIALS AND METHODS: We retrospectively reviewed 61 consecutive children with vein of Galen malformations. Clinical presentation, management, outcome, and angiographic change were analyzed for the patients with attention paid to all dural sinus occlusions. RESULTS: Twenty patients (32.8%) demonstrated spontaneous sinus occlusion, mostly in the sigmoid sinus. This condition was not observed in neonates and was first discovered during infancy or childhood. Progression of sinus occlusion was seen in 10 patients, and the conditions of 6 of them deteriorated in accordance with the progression of sinus occlusion. After total or subtotal obliteration of the malformation by transarterial glue embolization, 13 patients recovered to healthy, 3 patients had only mild developmental delay, and 4 patients remained neurologically disabled. CONCLUSIONS: Spontaneous sinus occlusion is not a rare condition and can result in neurologic deterioration in the natural history of untreated vein of Galen malformation. If signs of progressive sinus occlusion are noticed, early arteriovenous shunt reduction or elimination by transarterial glue embolization is expected to prevent permanent brain damage.

Varying clinical and imaging outcomes in patients with spontaneous thrombosis of vein of Galen malformation--a report of two cases.

BACKGROUND: Vein of Galen malformations are rare congenital intracranial vascular malformations. The pathophysiological consequences usually manifest as high-output cardiac failure and neurological symptoms secondary to cerebral venous congestion and abnormal CSF flow. Management of these patients is complex. Indications and time to intervene are decided depending upon the age of child, clinical presentation, and multisystemic neonatal scores. Many of these children presenting early and who are not in cardiac failure are expectantly followed up. Spontaneous thrombosis of the vein of Galen malformation is a rare occurrence in these as such rare vascular malformations. METHODS: This review reports two cases of spontaneous thrombosis of the vein of Galen malformations with varying clinical as well as imaging outcomes. Possible pathophysiologic mechanisms are discussed with review of literature. RESULTS: This report highlights the importance of vigilant clinical and imaging follow-up even after spontaneous thrombosis in the vein of Galen malformations.

Radiological and clinical features of vein of Galen malformations.

BACKGROUND: Vein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized. OBJECTIVE: To examine the clinical and radiological features of VOGMs and the predictors of outcome in patients. METHODS: We retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by χ(2) analyses. RESULTS: Forty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at <10 days of age and elective embolization after 1 year of age. Patients commonly presented with hydrocephalus (65.9%) and congestive heart failure (61.0%). Mixed-type (31.7%) VOGM was more common in our cohort than purely mural (29.3%) or choroidal (26.8%) types. The most common feeding arteries were the choroidal and posterior cerebral arteries. Transarterial embolization with coils was the most common technique used to treat VOGMs at our institution. Functional outcome was normal or only mildly disabled in 50% of the cases at last follow-up (median=3 years, range=0-23 years). Younger age at first diagnosis, congestive heart failure, and seizures were predictive of adverse clinical outcome. The survival rate in our sample was 78.0% and complete thrombosis of the VOGM was achieved in 62.5% of patients. CONCLUSIONS: VOGMs continue to be challenging to treat and manage. Nonetheless, endovascular approaches to treatment are continuing to be refined and improved, with increasing success. The neurodevelopmental outcomes of affected children whose VOGMs are treated may be good in many cases.

Transarterial embolisation with Guglielmi detachable coils in an infant with a vein of Galen aneurysmal malformation.

Vein of Galen aneurysmal malformation is a rare entity in the paediatric population. However, it is being recognised with increasing frequency due to better diagnostic techniques. Neonates usually present with congestive heart failure, while in older infants and children it tends to manifest with seizures, hydrocephalus, intracerebral or subarachnoid haemorrhages. We present a case of ruptured vein of Galen aneurysmal malformation in a 3-month-old baby boy treated by transarterial embolisation using Guglielmi detachable coils.

Susceptibility-weighted imaging: a new tool in the diagnosis and evaluation of abnormalities of the vein of Galen in children.

We retrospectively identified 9 consecutive children, 3 males and 6 females (age 5.2 ± 6.3 years, range 1 day to 18 years), with known or suspected AVGs who underwent MR imaging, including SWI, at our institution between January 2007 and March 2011. On the SWI sequence, arterialized blood flow was considered to be present in the vein of Galen or its tributaries when these showed abnormal signal hyperintensity from arteriovenous shunting. SWI findings were correlated with findings from DSA studies or findings from time-of-flight or contrast-enhanced MR angiography sequences. SWI was found to accurately differentiate between high-flow and low-flow AVGs and was also useful in characterizing the arterial supply and venous drainage patterns associated with high-flow AVGs.

Predicting factors for the follow-up outcome and management decisions in vein of Galen aneurysmal malformations.

PURPOSE: Vein of Galen aneurysmal malformations (VGAMs) are choroidal arteriovenous malformations that develop during an early embryonic stage. Although recent reports have shown improved outcome for these patients, the overall outcome still is poor. In this study, we evaluated the clinical, imaging, and angiographic features that may predict the outcome in VGAM patients. METHODS: Twenty-five patients diagnosed with VGAM were reviewed for clinical symptoms, including neonatal scoring systems, imaging findings, angioarchitecture, treatment decision, initial treatment age, follow-up timing, and follow-up outcome. RESULTS: Factors that were significantly associated with a poor outcome (p < 0.05) included neurological symptoms at presentation, a medium-to-low overall neonatal score (<12/21), a very poor score (<2/5) in one (or more) categories, focal parenchymal changes, calcifications, tonsillar herniation, arterial steal, or more than two groups of multiple arterial feeders. The venous drainage pattern and treatment age were not significantly associated with the overall outcome. CONCLUSIONS: The presence of multiple factors that are related with poor outcome may warrant withholding aggressive treatment, while a small subgroup of carefully selected patients without any of these factors who are clinically asymptomatic may have a good outcome even with conservative management and close follow-up. For all other patients in which treatment is considered, the optimal treatment time is at 4-5 months of age; however, urgent treatment, regardless of age, should be indicated in those that do not have permanent brain damage on imaging with deteriorating congestive heart failure, evidence of arterial steal, or progressive occlusion of the venous outflow.