Hemorrhage Rates From Brain Arteriovenous Malformation in Patients With Hereditary Hemorrhagic Telangiectasia
Background and Purpose—Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs).
Methods—We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis.
Results—The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0–70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42–2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25–31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11–1.73%).
Conclusions—Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease caused by mutations in transforming growth factor-β signaling genes (ENG, ALK1, or SMAD4). HHT is characterized by mucocutaneous telangiectasia, frequent epistaxis, and organ arteriovenous malformations (AVMs). Patients with HHT often have multiple brain AVMs (BAVMs), which is highly predictive of HHT diagnosis.1 Previous series have suggested that patients with HHT-BAVM may have a lower risk of intracranial hemorrhage (ICH) than patients with sporadic BAVM.2 We describe hemorrhage rates and characteristics in patients with HHT-BAVM enrolled in a multicenter study.
Patients with HHT (n=932) were enrolled in the Brain Vascular Malformation Consortium (BVMC) HHT Project between April 2010 and June 2014 from 14 HHT centers of excellence (Table I in the online-only Data Supplement).3 Eligible patients with HHT either had a genetic diagnosis (ENG, ALK1, or SMAD4 mutation) or a definite clinical diagnosis (≥3 following Curaçao criteria)4: (1) spontaneous recurrent nosebleeds; (2) mucocutaneous telangiectasia (lips, oral cavity, fingers, or nose); (3) visceral AVM involvement (pulmonary, hepatic, or brain); or (4) affected first-degree relative by the same criteria. All patients with HHT were screened for BAVM regardless of symptoms; BAVM was diagnosed by angiography, magnetic resonance imaging, or surgical resection.
Data were collected retrospectively at study enrollment using AVM-reporting guidelines,5 including age, sex, race, HHT gene mutation, presentation symptoms, hemorrhage at BAVM diagnosis or during follow-up (assessed retrospectively and prospectively from the time of enrollment), and BAVM treatment type and date (Table). All patients were also prospectively followed annually for ICH events, new symptoms, and any new treatments up to 4 years after enrollment. ICH events are determined from clinicians during medical history, chart review, and imaging where available.
A total of 194 enrolled patients with HHT had BAVM and 153 had follow-up data. Follow-up time started after the date of BAVM diagnosis until the date of hemorrhage, censoring at the date of first treatment, death, or last follow-up, and truncated at 15 years from diagnosis. ICH rates (number of first ICH events/patient-years at risk×100) and 95% confidence intervals (CIs) were calculated using Stata (StataCorp version 13.1; College Station, TX). Kaplan–Meier survival curves are presented by ICH presentation, and log-rank test exact P values were calculated using StatXact.6 To assess the effect of missing data on ICH rates, we performed multiple imputation using chained equations in Stata,7 allowing us to include all 194 patients with HHT-BAVM (Figure I in the online-only Data Supplement).
Characteristics of our HHT-BAVM cohort are shown in Table and are similar to other HHT populations.8,9 The mean follow-up time was 3.2±4.3 years after BAVM diagnosis, and mean age at BAVM diagnosis was 31±19 years (range, 0–70), with 61% of cases diagnosed from asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented initially with ICH.
A total of 5 ICH events occurred over 493 patient-years, yielding an overall ICH rate of 1.02% (95% CI, 0.42–2.44%) per year. The ICH rate was significantly higher (P=0.003) for ruptured than unruptured cases at presentation (Figure). In ruptured cases, the annual ICH rate was 10.07% (95% CI, 3.25%–31.21%), whereas the rate in unruptured cases was 0.43% (95% CI, 0.11–1.73%). Four of 5 ICH events occurred in women, but this was not statistically significant (P=0.556). Sensitivity analysis of imputed datasets resulted in similar ICH rates and 95% CIs (Figure I in the online-only Data Supplement).
This is the largest study to date examining hemorrhage risk in HHT patients with BAVM. Despite the small number of hemorrhages, the upper bound of our 95% CI limits the overall annual ICH rate in patients with HHT-BAVM to <2.5% per year, which is consistent with ICH rates from 4 large sporadic BAVM populations of 2.3% (95% CI, 2.0%–2.7%).10 A similar pattern is also observed in patients with sporadic BAVM with an almost 4-fold higher ICH rate in ruptured (4.8%; 95% CI, 3.9%–5.9%) than unruptured (1.3%; 95% CI, 1.0%–1.7%) BAVMs at presentation.10
Only one previous study has directly quantified ICH risk in patients with HHT-BAVM; Willemse et al2 identified 22 Dutch HHT patients with BAVMs (of 196 screened) and reported an overall ICH rate of 0.41% to 0.72% per year. The apparently lower ICH rate in HHT-BAVM has led some to speculate that the risk may be lower than for patients with sporadic BAVM and more similar to that of unruptured sporadic BAVMs (1.3%10 to 2.2% per year8). However, the HHT-BAVM and sporadic BAVM populations are markedly different with respect to how BAVMs are ascertained. In reported HHT populations, BAVMs are frequently identified on asymptomatic screening after HHT diagnosis, contributing to the lower ICH rates. This study is the first to demonstrate a significant association with specific features of BAVM, specifically that patients with HHT-BAVM presenting ruptured have higher rerupture rates, similar to that seen for patients with sporadic BAVM. Thus, depending on additional BAVM features, there may be subgroups of patients with HHT-BAVM at higher or lower risk for hemorrhage. For example, patients with HHT-BAVM often display multiple lesions as well as a range of other neurovascular phenotypes.1,9
Our study had several limitations. The small number of ICH events precluded us from evaluating additional ICH risk factors, for example, angiographic characteristics. Second, our results may be subject to selection bias, which may affect ICH rates. However, our calculations based on patient-years of risk reflect current treatment practices for HHT-BAVM, and we observed similar patterns of ICH risk as for patients with sporadic BAVM. In addition, imputation analysis of missing data yielded strikingly similar ICH rates as those observed. Finally, our analysis did not consider per-lesion risk of hemorrhage at this time, which may also alter risk.
In summary, we found that patients with ruptured HHT-BAVM have a higher risk of subsequent hemorrhage compared with those who present unruptured, similar to patients with sporadic BAVM.
BVMC HHT Investigator Group
Murali Chakinala, Marie E. Faughnan, James R. Gossage, Katharine Henderson, Vivek Iyer, Raj Kasthuri, Helen Kim, Timo Krings, Michael T. Lawton, Doris Lin, Johannes Jurgen Mager, Justin McWilliams, Jamie McDonald, Ludmila Pawlikowska, Jeffrey Pollak, Felix Ratjen, Karen Swanson, Karel terBrugge, Dilini Vethanayagam, Andrew White, Robert I. White Jr, Pearce Wilcox, William L. Young
Sources of Funding
This work was supported by BVMC/U54 NS065705 (part of the Rare Diseases Clinical Research Network and supported through collaboration between National Institutes of Health Office of Rare Diseases Research at the National Center for Advancing Translational Science, and the National Institute of Neurological Disorders and Stroke), Nelson Arthur Hyland Foundation, and Li Ka Shing Knowledge Institute (M.E. Faughnan).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.007367/-/DC1.
- Received September 8, 2014.
- Revision received February 27, 2015.
- Accepted March 12, 2015.
- © 2015 American Heart Association, Inc.
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