Publications (30) View all
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Article: Hereditary hemorrhagic telangiectasia: How accurate are the clinical criteria?
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ABSTRACT: The clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria. Three out of four criteria are required for a definite clinical diagnosis HHT, two criteria are considered "possible" HHT, and 0 or 1 criterion makes the diagnosis unlikely. However, these consensus diagnostic criteria have not been validated. We report on the diagnostic accuracy of the clinical criteria. A total of 450 consecutive persons ≥16 years of age were screened for HHT between May 2004 and September 2009, including a chest CT to screen for pulmonary arteriovenous malformations (AVMs). We selected 263 first-degree relatives of disease-causing mutation carriers who underwent mutation analysis. Genetic test results were considered the gold standard. The family mutation was present in 186 patients (mean age 42.9 ± 14.6 yr; 54.8% female). A clinical diagnosis was definite, "possible", and unlikely in 168 (90.3%), 17 (9.1%), and 1 (0.5%) patient, respectively. In 77 persons the family mutation was absent (mean age 37.1 ± 12.3 yr, 59.7% female). In this group a clinical diagnosis was definite, possible, and unlikely in 0, 35 (45.5%), and 42 (54.5%) persons, respectively. The positive predictive value of a definite clinical diagnosis was 100% (95% CI 97.8-100), the negative predictive value of an unlikely diagnosis 97.7% (95% CI 87.9-99.6). Of 52 patients with "possible" HHT, 17 (32.7%) displayed an HHT-causing mutation. The Curaçao clinical criteria have a good diagnostic performance. Genetic testing is particularly helpful in patients with a "possible" clinical diagnosis HHT. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 03/2013; 161(3):461-6. · 2.39 Impact Factor -
Article: Grade of pulmonary right-to-left shunt on contrast echocardiography and cerebral complications; a striking association.
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ABSTRACT: BACKGROUND: A pulmonary right-to-left shunt (RLS) carries the risk of cerebral paradoxical embolization and severe neurological complications. Recognising patients at risk is important to facilitate appropriate management strategies, but a direct relation between pulmonary shunt size and risk of complications remains controversial. OBJECTIVE: This study evaluated the potential relation between pulmonary shunt size on transthoracic contrast echocardiography (TTCE) and prevalence of cerebral manifestations in persons screened for hereditary haemorrhagic telangiectasia (HHT). METHODS: We conducted a two-center, cross-sectional study of all consecutive persons screened for HHT between 2004 and 2011. Pulmonary shunt grading was performed according to contrast opacification of the left ventricle on TTCE (grade 0, no microbubbles; 1, <30 microbubbles; 2, 30-100 microbubbles; 3, >100 microbubbles). Cerebral manifestations were defined as ischemic stroke, transient ischemic attack or brain abscess, diagnosed by a neurologist and confirmed by appropriate imaging techniques. RESULTS: A pulmonary RLS was present in 530 out of 1038 patients (51.1%, mean age 44.3±15.6 years, 58.6% women). The presence of a cerebral manifestation (n=51) differed significantly between pulmonary shunt grades on TTCE; 1.4%, 0.4%, 6.5% and 20.9% for grade 0, 1, 2 and 3 respectively. Pulmonary shunt grade 1 was not associated with an increased prevalence of cerebral manifestations (OR 0.44, 95%CI 0.05-4.13, p=0.47), while pulmonary shunt grade 2 (OR 4.78, 95%CI 1.14-20.0, p=0.03) and grade 3 (OR 10.4, 95%CI 2.4-45.3, p=0.002) were both independent predictors for the prevalence of a cerebral ischemic event or brain abscess. CONCLUSION: Pulmonary RLS grade on TTCE is strongly associated with the prevalence of cerebral complications in patients screened for HHT.Chest 02/2013; · 5.25 Impact Factor -
Article: Relation between migraine and size of echocardiographic intrapulmonary right-to-left shunt.
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ABSTRACT: An increased prevalence of intrapulmonary right-to-left shunt (RLS) has been shown in patients with migraine. The aim of this study was to determine whether the size of intrapulmonary RLS was associated with migraine with aura (MA+) and migraine without aura (MA-) in subjects screened for hereditary hemorrhagic telangiectasia. A total of 462 consecutive subjects were screened for hereditary hemorrhagic telangiectasia and underwent transthoracic contrast echocardiography. A pulmonary shunt was established when contrast appeared in the left atrium after 4 cardiac cycles. Shunt size was assessed semiquantitatively as small (<30 microbubbles), moderate (30 to 100 microbubbles), or large (>100 microbubbles). A headache questionnaire was completed by 420 subjects (91%). Two independent neurologists diagnosed migraine according to the International Headache Society criteria. Of 420 screened subjects (mean age 43.4 ± 15.4 years, 61.4% women), 44 (10.5%) had MA+ and 45 (10.7%) had MA-. MA+ was an independent predictor for an intrapulmonary RLS (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.36 to 6.47, p=0.006) in multivariate analysis. MA- was not correlated with RLS (OR 1.21, 95% CI 0.56 to 2.64, p=0.60). When comparing patients with MA+ to those without migraine in a multivariate analysis, the presence of an intrapulmonary shunt predicted MA+ (OR 2.5, 95% CI 1.2 to 5.2, p=0.01), as did female gender (OR 3.15, 95% CI 1.29 to 7.65, p<0.01). The correlation of MA+ and RLS could be entirely attributed to large intrapulmonary shunts (OR 7.61, 95% CI 3.11 to 18.61, p<0.001), as small (OR 0.6, 95% CI 0.13 to 2.78, p=0.52) and moderate (OR 1.33, 95% CI 0.35 to 5.02, p=0.68) shunts did not appear to be risk factors for MA+. In conclusion, patients with large intrapulmonary RLS have an increased risk for MA+.The American journal of cardiology 03/2011; 107(9):1399-404. · 3.58 Impact Factor -
Article: Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.Nature medicine 04/2010; 16(4):420-8. · 27.14 Impact Factor -
Article: Is hereditary haemorrhagic telangiectasia rare in the black race? The first sub-Saharan mutation.
Haemophilia 01/2011; 17(1):e244. · 2.60 Impact Factor
