Clinical presentation and treatment paradigms of brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia

OBJECTIVEPatients with hereditary hemorrhagic telangiectasia (HHT) are known to suffer from high rates of cerebral arteriovenous malformations (AVMs). The authors performed a systematic review and meta-analysis of the literature examining prevalence rates, characteristics, and clinical presentation of cerebral AVMs in the HHT population.METHODSTo identify studies on AVM prevalence and characteristics in the HHT population, 4 databases (MEDLINE, EMBASE, Scopus and Web of Science) were searched by a reference librarian with over 30 years experience in systematic reviews and meta-analysis. The search period was January 1, 1990–March 2016. The following search terms were used: hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome, AVM, brain AVM, arteriovenous malformation, arteriovenous fistula, prevalence, and epidemiology. The authors identified studies that examined the prevalence rates, characteristics, and clinical presentation of cerebral AVMs in patients with HHT. They assessed overall AVM prevalence rates as well as prevalence rates by age, sex, HHT type, and country/region. They also systematically reviewed the characteristics of AVMs, including rupture status, location, clinical presentation, angioarchitecture, and Spetzler-Martin grade. Data were analyzed using a random-effects meta-analysis model.RESULTSThirty-nine studies were included in this meta-analysis. Thirty studies examined brain AVM prevalence rates in various HHT patient populations, and 18 studies examined AVM clinical and angiographic characteristics (9 studies examined both prevalence rates and AVM characteristics). The prevalence of brain AVMs in HHT patients was 10.4% (95% CI 7.9%–13.0%) with no significant difference between males (8.5%, 95% CI 4.9%–12.0%) and females (11.0%, 95% CI 5.9%–16.1%). Patients with HHT Type 1 (HHT1) had a significantly higher brain AVM prevalence (13.4%, 95% CI 9.5%–17.4%) compared with those with HHT Type 2 (HHT2) (2.4%, 95% CI 1.0%–3.8%) (p < 0.0001). In 55.2% (95% CI 38.3%–72.1%) of cases, the AVMs were symptomatic. Spetzler-Martin grade was 2 or less in 86.9% (95% CI 67.5%–95.2%) of patients.CONCLUSIONSThe prevalence of brain AVMs in the HHT population is about 10%. HHT1 patients are significantly more likely to have brain AVMs than HHT2 patients. Most AVMs in the HHT population are symptomatic. The Spetzler-Martin grade for these lesions is 2 or less in nearly 90% of patients.

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Abstract 50: Evaluation of Candidate Polymorphisms for Association With Brain Arteriovenous Malformations and Intracranial Hemorrhage in Hereditary Hemorrhagic Telangiectasia

Stroke ◽

10.1161/str.47.suppl_1.50 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Ludmila Pawlikowska ◽

Jeffrey Nelson ◽

Diana E Guo ◽

Charles E McCulloch ◽

Michael T Lawton ◽

...

Keyword(s):

Intracranial Hemorrhage ◽

Hereditary Hemorrhagic Telangiectasia ◽

Arteriovenous Malformations ◽

Nucleotide Polymorphisms ◽

Genetic Modifiers ◽

Association Analyses ◽

Brain Arteriovenous Malformations ◽

Significance Threshold ◽

Common Genetic Variants ◽

Brain Avm

Introduction: Brain arteriovenous malformations (AVM) are an important cause of intracranial hemorrhage (ICH) in young adults. Most are sporadic, but also occur in inherited diseases such as hereditary hemorrhagic telangiectasia (HHT). ICH presentation of brain AVM in both sporadic and HHT cases is a marker of high ICH risk. In order to investigate whether the same genetic modifiers influence sporadic and HHT brain AVM, we evaluated candidate genetic polymorphisms reported as associated with sporadic brain AVM, with ICH presentation or ICH during clinical course, in HHT patients. Methods: We genotyped 8 polymorphisms ( APOE E2/3/4 [rs7412, rs429358], ANGPTL rs116724, EPHB4 rs314308, IL6 -174G>C [rs1800795], IL1B -31T>C [rs1143627], ITGB8 rs10486391, TNF -238G>A[rs361525]) in 753 Caucasian HHT patients enrolled by the Brian Vascular Malformation Consortium (BVMC). Genotypes were collapsed into risk allele carriers vs. other for analysis, as published for sporadic AVM. APOE E2/3/4 haplotypes were assigned based on genotypes of the 2 APOE polymorphisms. Association of genotype with phenotype was evaluated by multivariable logistic regression adjusted for age, gender and accounting for family clustering. We used a nominal significance threshold of p=0.05, requiring the same direction of effect as in sporadic brain AVM (odds ratio for risk genotype [OR]>1). Results: Among 753 HHT patients, 155 (21%) had brain AVM, of whom 26 (17%) presented with ICH. Two additional brain AVM patients had ICH during follow-up. None of the 7 variants (6 single nucleotide polymorphisms and APOE haplotype) were significantly associated with brain AVM (OR=0.6-1.3), with ICH presentation of brain AVM (OR=0.4-1.9), or with any brain AVM ICH in HHT patients (OR=0.5-2.1). Conclusions: Common genetic variants previously reported to be associated with sporadic brain AVM were not associated with brain AVM nor with ICH in the BVMC HHT cohort, suggesting different genetic modifiers may influence sporadic and HHT brain AVM. However, the number of ICH cases in the cohort is small, so the confidence intervals are wide and we cannot rule out clinically important associations. The BVMC is enrolling additional HHT patients to expand the cohort and increase power for association analyses.

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Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene-phenotype correlations

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.35622 ◽

2012 ◽

Vol 158A (11) ◽

pp. 2829-2834 ◽

Cited By ~ 36

Author(s):

Takeo Nishida ◽

Marie E. Faughnan ◽

Timo Krings ◽

Murali Chakinala ◽

James R. Gossage ◽

...

Keyword(s):

Hereditary Hemorrhagic Telangiectasia ◽

Arteriovenous Malformations ◽

Brain Arteriovenous Malformations

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Seizure Presentation in Patients With Brain Arteriovenous Malformations Treated With Stereotactic Radiosurgery: A Multicenter Study

Neurosurgery ◽

10.1093/neuros/nyz310_804 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Ching-Jen Chen ◽

Leah Shabo ◽

Dale Ding ◽

Natasha Ironside ◽

Douglas Kondziolka ◽

...

Keyword(s):

Stereotactic Radiosurgery ◽

Arteriovenous Malformations ◽

Clinical Presentation ◽

Study Cohort ◽

Factors Associated ◽

Common Presentation ◽

Multiple Factors ◽

Brain Arteriovenous Malformations ◽

Common Clinical Presentation ◽

Multivariable Models

Abstract INTRODUCTION Seizures are the second most common clinical presentation in patients with brain arteriovenous malformations (AVMs), and they are the most common presentation of unruptured AVMs. The aim of this multicenter, retrospective cohort study was to identify predictors of seizure presentation in AVM patients treated with stereotactic radiosurgery (SRS). METHODS We performed a retrospective review of AVM patients treated with SRS at 8 participating International Radiosurgery Research Foundation sites. Patient and AVM characteristics were compared between those with versus without a seizure presentation in univariable and multivariable models. Subgroup analysis of patients with cortical AVMs was performed. RESULTS The study cohort comprised 2333 AVM patients, including 419 (18%) with and 1914 (82%) without a seizure presentation. Prior AVM resection (OR = 7.65, P = .001), lack of prior AVM hemorrhage (OR = 0.004, P < .001), cortical AVM location (OR = 1559.42, P < .001), lower Spetzler-Martin (SM) grade (OR = 0.51, P = .007), and higher Virginia Radiosurgery AVM Score (VRAS; OR = 1.46, P = .008) were independent predictors of seizure presentation. The rate of seizure presentation in patients with cortical AVMs was 27%. Prior AVM resection (OR = 8.36, P < .001), lack of prior AVM hemorrhage (OR = 0.004, P < .001), and temporal AVM location (OR = 4.15, P < .001) were independent predictors of seizure presentation for cortical AVMs. CONCLUSION We identified multiple factors associated with seizure presentation in AVM patients selected to undergo SRS. Prior AVM resection, cortical AVM location, and lack of prior AVM hemorrhage were the strongest predictors of pre-SRS seizures. SM grade and VRAS may have a role in seizure risk stratification. Among cortical AVMs, temporal lobe localization was predictive of seizure presentation.

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Initial Experience of a Hereditary Hemorrhagic Telangiectasia Center of Excellence

Ear Nose & Throat Journal ◽

10.1177/014556131709600607 ◽

2017 ◽

Vol 96 (6) ◽

pp. E33-E36

Author(s):

Christopher F. Thompson ◽

Jeffrey D. Suh ◽

Justin McWilliams ◽

Gary Duckwiler ◽

Marilene B. Wang

Keyword(s):

Interventional Radiology ◽

Hereditary Hemorrhagic Telangiectasia ◽

Arteriovenous Malformations ◽

Clinical Presentation ◽

Comprehensive Care ◽

Initial Experience ◽

Early Screening ◽

Common Procedure ◽

Center Of Excellence ◽

Severe Epistaxis

Our objectives in reviewing the initial experience of a hereditary hemorrhagic telangiectasia center of excellence (HHT COE) were to better understand the interventions being performed in the comprehensive care of these patients and to present the early data as a reference for other tertiary centers considering starting an HHT COE. We conducted a retrospective review of consecutive patients referred to our newly developed HHT COE for evaluation and treatment between May 2010 and June 2013. Clinical presentation, otolaryngologic treatments, and other operative interventions were analyzed. One hundred forty-four of the 198 patients (73%) evaluated at the HHT COE had definite HHT based on the Curaçao diagnostic criteria, with 20 additional patients possibly having HHT and undergoing further evaluation to confirm the diagnosis. Sixteen of the 31 patients (52%) referred to otolaryngology required intervention in the operating room for epistaxis. Seventy-two of the 164 (44%) patients with definite or possible HHT required other interventions for internal organ arteriovenous malformations (AVMs), with interventional radiology embolization of pulmonary AVMs being the most common procedure. An HHT COE is important in providing comprehensive care for patients with this rare disease, which has significant clinical sequelae. Having an HHT COE allows for early screening and subspecialty referral within a system of specialists experienced in preventing the morbidity and mortality associated with severe epistaxis and internal organ AVMs.

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Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice

Journal of Neurosurgery ◽

10.3171/2021.6.jns21717 ◽

2021 ◽

pp. 1-12

Author(s):

Chul Han ◽

Michael J. Lang ◽

Candice L. Nguyen ◽

Ernesto Luna Melendez ◽

Shwetal Mehta ◽

...

Keyword(s):

Transgenic Mice ◽

Prussian Blue ◽

Hereditary Hemorrhagic Telangiectasia ◽

Arteriovenous Malformations ◽

Gene Deletion ◽

Blue Staining ◽

Prussian Blue Staining ◽

Brain Arteriovenous Malformations ◽

Group 3 ◽

Brain Avms

OBJECTIVE Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. METHODS Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. RESULTS Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). CONCLUSIONS Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.

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Angioarchitecture and clinical presentation of brain arteriovenous malformations

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2009000200031 ◽

2009 ◽

Vol 67 (2a) ◽

pp. 316-321 ◽

Cited By ~ 12

Author(s):

Marcio Luiz Tostes dos Santos ◽

Zeferino Demartini Júnior ◽

Luiz Afonso Dias Matos ◽

Antonio Ronaldo Spotti ◽

Waldir Antônio Tognola ◽

...

Keyword(s):

Neurological Deficit ◽

Arteriovenous Malformations ◽

Clinical Presentation ◽

Multivariate Analyses ◽

Morphological Features ◽

Feeding Artery ◽

Focal Neurological Deficit ◽

Brain Arteriovenous Malformations ◽

Clinical Presentations ◽

Martin Grade

The purpose of this study was to correlate the angioarchitecture of brain arteriovenous malformations (AVM) with their clinical presentation. A total of 170 patients with AVM 78 males and 92 females, were studied. Univariate and multivariate analyses were conducted in order to test the associations between morphological features and clinical presentation. The most frequent clinical presentations at diagnosis were hemorrhage in 89 (52%) patients, headache in 79 (46%), focal neurological deficit in 54 (32%), and seizure in 52 (31%). According to the Spetzler-Martin classification, grade I was found in 15 patients, II in 49, III in 55, IV in 41, and grade V in 10 patients. AVM with small nidus size, single feeding artery and single draining vein were associated with hemorrhage. Hemorrhage was positively associated with Spetzler-Martin grade I and negatively with grade V. The association between seizure and large nidus size was positive, however negative with small nidus size.

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