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

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.

Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

Background Patients with hereditary hemorrhagic telangiectasia have liver vascular malformations that can cause high-output cardiac failure (HOCF). Known sequelae include pulmonary hypertension, tricuspid regurgitation, and atrial fibrillation. Methods and Results The objectives of this study were to describe the clinical, echocardiographic, and hemodynamic characteristics and prognosis of hereditary hemorrhagic telangiectasia patients with HOCF who were found to have a subaortic membrane (SAoM). A retrospective observational analysis comparing patients with and without SAoM was performed. Among a cohort of patients with HOCF, 9 were found to have a SAoM in the left ventricular outflow tract by echocardiography (all female, mean age 64.8±4.0 years). The SAoM was discrete and located in the left ventricular outflow tract 1.1±0.1 cm below the aortic annular plane. It caused turbulent flow, mild obstruction (peak velocity 2.8±0.2 m/s, peak gradient 32±4 mm Hg), and no more than mild aortic insufficiency. Patients with SAoM (n=9) had higher cardiac output (12.1±1.3 versus 9.3±0.7 L/min, P=0.04) and mean pulmonary artery pressures (36±3 versus 28±2 mm Hg, P=0.03) compared with those without SAoM (n=19) during right heart catheterization. Genetic analysis revealed activin receptor-like kinase 1 mutations in each of the 8 patients with SAoM who had available test results. The presence of a SAoM was associated with a trend towards higher 5-year mortality during follow-up. Conclusions SAoM with mild obstruction occurs in patients with hereditary hemorrhagic telangiectasia and HOCF. SAoM was associated with features of more advanced HOCF and poor outcomes.

Results of exercise stress testing in patients with diffuse pulmonary arteriovenous malformations.

Patients with diffuse pulmonary arteriovenous malformations (PAVMs) are subject to frequent complications and need to be followed closely. As part of this follow-up, we have employed exercise stress testing (EST) as an aid to assess their status. Twenty patients from a cohort of 35 with diffuse PAVMs have undergone EST using a standard cycle ergometer test. All patients had previously undergone pulmonary angiography, noncontrast chest computed tomography (CT), and repair of large focal PAVMs, prior to EST. Mean room air oxygen saturation at baseline and at maximum exercise (85% of maximum heart rate) were tabulated. Serial studies in six children and young adults were plotted by year and compared using the patient as their own control. Fourteen females and six males ranging in age from 4 to 50 years (mean 22 years) were studied. Baseline mean oxygen saturation was 84% and fell to 73% at maximum exercise. There was no significant difference between those with unilateral and bilateral involvement (P = 0.09). In four of the six patients with serial EST, the baseline and exercise oxygen saturations were quite stable. In the two patients who became symptomatic, with age, growth, and more activity, complete embolization of one or more segments of the lung improved their EST and functionality. Based on our previous work in patients with diffuse PAVMs, EST appears to offer a relatively safe and noninvasive method for assessing these patients. Our limited experience with serial EST suggests a good correlation with decreased functionality in these patients.

New definition and natural history of patients with diffuse pulmonary arteriovenous malformations: twenty-seven-year experience.

BACKGROUND: Patients with diffuse pulmonary arteriovenous malformations (PAVM), a small but important subset of the PAVM population, have significant morbidity and mortality rates. METHODS: Thirty-six patients (21 female and 15 male) with diffuse PAVM from a cohort of 821 consecutive patients with PAVM were evaluated. Diffuse PAVM were categorized angiographically: involvement of one or more segmental pulmonary arteries in one or both lungs. Hereditary hemorrhagic telangiectasia (HHT) status, gender, presence or absence of large (> or = 3-mm diameter artery) focal PAVM, oxygen saturations, complications including hemoptysis, years of follow-up, and survival were tabulated. RESULTS: HHT was present in 29 of 36 patients (81%), and diffuse PAVM were more commonly bilateral (26 of 36 patients, 72%) than unilateral (10 of 36 patients, 28%) [p = 0.02]. Female gender was associated with bilateral diffuse PAVM (19 of 26 patients, 73%) [p = 0.01]. Focal PAVM were present in both groups but more commonly in patients with bilateral involvement (16 of 26 patients, 62%) [p = 0.02]. Initial oxygen saturations (pulse oximetry, standing) of patients with unilateral and bilateral diffuse PAVM were 87 +/- 7% and 79 +/- 8% (mean +/- SD), respectively (p = 0.02). The last or current values for patients with unilateral and bilateral involvement are 95 +/- 3% and 85 +/- 7%, respectively (p < 0.0001). Nine deaths occurred, and all were in patients with bilateral involvement. Deaths were due to hemoptysis of bronchial artery origin (n = 2), hemorrhage from duodenal ulcer (n = 1), spontaneous liver necrosis (n = 3), brain hemorrhage (n = 1), brain abscess (n = 1), and operative death during attempted lung transplant (n = 1). CONCLUSIONS: Patients with diffuse PAVM are a high-risk group, and yearly follow-up is recommended.

Long-term complications of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia.

OBJECTIVE: Septal dermoplasty has been recommended as the treatment of choice for life-threatening epistaxis in patients with hereditary hemorrhagic telangiectasia. This study evaluates the complications of septal dermoplasty in the management of transfusion-dependent epistaxis. STUDY DESIGN: Consecutive retrospective study. SUBJECTS AND METHODS: Between 1994 and 2006, septal dermoplasty was performed on 106 consecutive patients with transfusion dependent epistaxis. Of 103 potential patients, 37 either died or were lost to follow-up, which left 66 patients for study. Data on complications and quality of life were collected on 50 (76%) of 66 patients (mean follow-up, 3.75 years) via phone interview. RESULTS: Seventy-eight percent experienced nasal odor; 72% had nasal crusting; 58% had decreased sense of smell; 30% noted worsened sinus infection; 88% could breathe through their nose; 86% stated improved quality of life. CONCLUSION: Septal dermoplasty remains an effective way of treating transfusion dependent epistaxis in patients with hereditary hemorrhagic telangiectasia and subjectively improves their quality of life.

Outcome of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia.

OBJECTIVES/HYPOTHESIS: Septal dermoplasty has been recommended as the treatment of choice for life-threatening epistaxis in patients with hereditary hemorrhagic telangiectasia. The purpose of the study was to evaluate the effectiveness and outcomes of septal dermoplasty for management of transfusion-dependent epistaxis. STUDY DESIGN: Retrospective study. METHODS: Between 1994 and 2004, septal dermoplasty was performed on 67 consecutive patients with severe epistaxis attributable to hereditary hemorrhagic telangiectasia. The numbers of units of blood received 1 year before and 1 year after septal dermoplasty were obtained. A subjective appraisal of the results of the surgery as well as second procedures after septal dermoplasty was determined. Patients were screened for pulmonary and cerebral arteriovenous malformations, gastrointestinal tract bleeding, and symptomatic liver disease. RESULTS: Data were obtained in 66 of 67 (98%) patients with a mean age of 61.5 years (mean follow-up, 3.9 y). Accurate transfusion requirements 1 year before and 1 year after septal dermoplasty were available in 32 of 66 (48%) patients. In these 32 patients, the mean units of blood received decreased from 21 units (range, 2-100 units) 1 year before septal dermoplasty to 1 unit (range, 0-10 units) in the year after septal dermoplasty (P < .001). Improved quality of life was claimed in 57 patients. Second therapies, ranging from cautery to repeat partial septal dermoplasty, were required in 15 patients during follow-up. Among the 67 patients, 31 (46%) had pulmonary arteriovenous malformation, 14 (21%) had gastrointestinal tract bleeding, 7 (10%) had symptomatic liver disease, and 5 (7%) had cerebral arteriovenous malformation. During the follow-up, 14 patients died of other complications of hereditary hemorrhagic telangiectasia (11 patients) and unrelated causes (3 patients). CONCLUSION: Septal dermoplasty remains an effective way of reducing transfusion requirements in patients with hereditary hemorrhagic telangiectasia and subjectively improves their quality of life. The otolaryngologist caring for patients with hereditary hemorrhagic telangiectasia should be familiar with other organ involvement by hereditary hemorrhagic telangiectasia to prevent complications during surgery.

The Young's procedure for severe epistaxis from hereditary hemorrhagic telangiectasia.

BACKGROUND: Surgical treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT) has historically been managed with the laser procedure or the septodermoplasty procedure. For transfusion-dependent patients with severe epistaxis we have been performing the Young's procedure or surgical closure of the nostrils. The objective of this study was to report treatment of severe epistaxis related to HHT with the Young's procedure and assess patient outcome. METHODS: Patients with severe iron or blood transfusion-dependent epistaxis who underwent a Young's procedure in three otolaryngology HHT centers were reviewed. Patients were evaluated for postoperative epistaxis and subjective outcome. RESULTS: Forty-three patients underwent a Young's procedure for severe epistaxis and were observed for a mean of 34 months. The procedure was well tolerated by all patients and 30 of 36 patients (83%) experienced complete cessation of bleeding after the Young's procedure. Patients had a mean increase in hemoglobin of 4.68 g/dL after the procedure. The average Glasgow Benefit Inventory score after surgery was 43.56. No patients requested a reversal of the procedure. CONCLUSION: The Young's procedure is a safe and efficacious procedure with complete cessation of epistaxis in most patients with severe epistaxis and HHT.

Initial experience with 3% sodium tetradecyl sulfate foam and fibered coils for management of adolescent varicocele.

PURPOSE: To report the results of treatment of adolescent patients with varicocele with use of 3% sodium tetradecyl sulfate foam (STS) in combination with pushable fibered coils. MATERIALS AND METHODS: From September 2004 to September 2006, 16 adolescent patients (age 12-19 y) with symptomatic varicocele, testicular atrophy, or surgical recurrence underwent embolization with STS foam and coils. The left internal spermatic vein (ISV) was coaxially catheterized from the right femoral vein. Three percent STS foam was placed distally in the ISV during compression so minimal foam entered the pampiniform plexus. A second nest of coils was placed in the ISV at a position over the sacroiliac (SI) joint that occluded most of the parallel collateral vessels. Coils were not placed above the SI joint in most instances. Additional foam was injected in the ISV at the upper level of the SI joint. The upper ISV was left unoccluded. Our standard follow-up consisting of ultrasound and/or physical examination after varicocele occlusion was performed 2-12 months after the procedure. RESULTS: All occlusions were technically successful, and 15 of 16 patients (94%) exhibited proven disappearance of the varicocele. All patients were asymptomatic except one who had pain despite disappearance of the varicocele. One patient with a bleeding disorder had 48 hours of scrotal discomfort as a result of pampiniform phlebitis caused by the deliberate passage of foam into the pampiniform plexus. CONCLUSIONS: The use of 3% STS foam in combination with pushable fibered coils is a safe and effective sclerosing procedure for adolescent subjects with varicocele.

Septectomy and septal dermoplasty for the treatment of severe transfusion-dependent epistaxis in patients with hereditary hemorrhagic telangiectasia and septal perforation.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal angiogenesis with resultant telangiectasia formation in mucocutaneous tissues, visceral organs, and the central nervous system. The most common manifestation of HHT is epistaxis resulting from trauma to thin-walled telangiectasias. Many patients with HHT experience worsened epistaxis due to the presence of a septal perforation. Septal perforation in HHT patients results from aggressive noncartilage sparing treatments such as monopolar cauterization. Although the mainstay of treatment for patients with severe transfusion-dependent HHT remains to be septal dermoplasty (SD), patients with a septal perforation are less likely to have a successful outcome. In this small subset of patients, septectomy (ST) combined with SD is proposed to eliminate this variable to improve skin graft uptake and therefore outcome. This study reviews the indications, procedure, and outcome of nine patients with severe transfusion-dependent HHT and septal perforation who underwent the combined procedure of SD/ST. METHODS: Nine HHT patients with severe transfusion-dependent epistaxis and septal perforation underwent SD/ST at our institution over a 5-year period. Quality of life, including number of daily events of epistaxis, and transfusion requirements were determined before and after surgery. Technical aspects of the procedure as well as complications were reviewed. RESULTS: The combined procedure of SD/ST resulted in a long-lasting subjective improvement in quality of life for all patients. Similarly, transfusion requirements were reduced from 22.61 to 9.57 (p < 0.05). There were no complications or increased morbidity from the procedure. CONCLUSION: Combined SD/ST is a safe and effective treatment for HHT patients with transfusion-dependent epistaxis and septal perforation.

Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations.

PURPOSE: To assess long-term clinical and imaging results of technically successful pulmonary arteriovenous malformation (AVM) embolization. MATERIALS AND METHODS: One hundred fifty-five patients with pulmonary AVMs underwent embolization during a period of 3 years. Recommended follow-up included clinical assessment, helical computed tomography, and physiologic evaluation within 1 year and then every 5 years. RESULTS: Hereditary hemorrhagic telangiectasia was present in 148 patients (95%). Four hundred fifteen pulmonary AVMs were occluded during 205 procedures. Clinical follow-up was available in all patients over 3-7 years and imaging follow-up was available in 144 patients (393 lesions) over 1-7 years (mean, 2.9 y). Problems related to pulmonary AVMs occurred in 35 patients (23%) at 42 time points: 22 patients with 23 symptomatic events and 17 patients with 19 asymptomatic events. Symptoms resulted from growth of nonembolized pulmonary AVMs (n = 19), residual embolized pulmonary AVMs (n = 5), or both (n = 2). Symptoms consisted of respiratory manifestations (n = 13), cerebral ischemia (n = 4), brain abscess (n = 5), hemoptysis (n = 3), and seizure (n = 1). Imaging showed pulmonary AVM involution in 97% of embolized lesions and 11 residual lesions (2.8%) in 10 patients (6.9%). These were caused by recanalization (n = 7), presence of an accessory feeding artery (n = 1), pulmonary collateral vessels (n = 1), and bronchial collateral vessels (n = 2). CT detected 10 of the 11 residual lesions. Imaging detected 97 previously small pulmonary AVMs that had enlarged to a significant size in 28 patients (18%), 15 of whom were symptomatic and 13 of whom were asymptomatic. CONCLUSIONS: Clinical and anatomic evaluation after pulmonary AVM embolization is important to detect persistent or reperfused lesions and enlarging lesions, with the latter more common. Patients with persistent, reperfused, or enlarging lesions often have symptoms, but a significant minority of patients are asymptomatic. More frequent assessment may improve detection before the onset of symptoms.

Enteroscopic evaluation of the gastrointestinal tract in symptomatic patients with hereditary hemorrhagic telangiectasia.

OBJECTIVES: Hereditary hemorrhagic telangiectasia is an autosomal dominant disease in which 25% to 30% of patients will develop gastrointestinal bleeding from telangiectases. The extent of telangiectases has not been previously evaluated. This cross-sectional study compared the presence, number, and size of telangiectases in the stomach and duodenum to those in the jejunum using enteroscopy. METHODS: At the Yale University Vascular Malformation Center, 30 consecutive, symptomatic adult patients with hereditary hemorrhagic telangiectasia were evaluated using a 220-cm-length enteroscope. The number and size of the telangiectases were documented in the esophagus, proximal and distal stomach, four parts of the duodenum, and every 20 cm in the jejunum. The indication for the procedure was recorded as anemia, gastrointestinal bleeding, or anemia out of proportion to epistaxis. RESULTS: The results of 27 patients were analyzed. A total of 89% of patients had telangiectases in the first 60 cm of the jejunum. In individual patients, there was a strong correlation between the number of telangiectases in the stomach/duodenum when compared with the jejunum. In group analysis, the median number of telangiectases in the stomach and duodenum was significantly higher than in the jejunum (13 vs. 3; Wilcoxon signed rank test, P = 0.001). The presence of large (> or =5 mm) telangiectases in the stomach/duodenum did not necessarily indicate that there would be large telangiectases in the jejunum. CONCLUSIONS: The presence and number of stomach and duodenal telangiectases correlated with the presence and number of jejunal ones. However, the occurrence of large proximal telangiectases was not associated with large distal ones.

Vein of Galen technique for occluding the aneurysmal sac of pulmonary arteriovenous malformations.

In seven of 255 consecutive patients (2.7%) who underwent pulmonary arteriovenous malformation (PAVM) embolization at our center between July 1, 1996, and July 1, 2000, the feeding artery was considered too short for safe occlusion with use of standard stainless-steel coils or detachable balloons. These patients were successfully treated with use of a modified vein of Galen technique similar to the one used for managing intracranial vein of Galen aneurysms. In this article, the authors report their experience with this technique in safely occluding the aneurysmal sacs of PAVMs in patients with short (<2 cm) feeding pulmonary arteries.

Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia.

OBJECTIVE: Our aim was to report our experience with treating GI bleeding in patients with hereditary hemorrhagic telangiectasia (HHT). METHODS: Consecutive patients with GI bleeding referred to the Yale University Vascular Malformation Center underwent clinical evaluation and endoscopy. Hb and blood transfusion requirements for 1 yr before and after evaluation were documented. Patients with a mean Hb or= 12 units packed red blood cells (PRBC)/yr were defined as patients with significant bleeding. Drug therapies, including ethinyl estradiol/norethindrone, danazol, and aminocaproic acid, were prescribed on an individual patient basis. RESULTS: The study included 43 HHT patients with a mean age of 57 yr. Endoscopy revealed telangiectases in the esophagus (1/41), stomach (33/41), duodenum (33/41), jejunum (5/9), and colon (10/32). Patients with > 20 telangiectases visualized on esophagogastroduodenoscopy had a significantly lower mean Hb of 7.9, compared with 9.4 (p = 0.007), and a trend toward higher blood transfusion requirements. Non-HHT-related causes of GI bleeding were diagnosed in four patients. During a mean follow up of 18.9 months, the group of 40 patients with HHT-related bleeding had improvements in their mean Hb and blood transfusion requirements. CONCLUSIONS: Some HHT patients with GI bleeding improve on drug therapies, but others fail. Transfusion-dependent GI bleeding is difficult to manage, and optimal management may include both medical and endoscopic treatments.

Pulmonary arteriovenous malformations in children: outcomes of transcatheter embolotherapy.

OBJECTIVE: To describe outcomes of transcatheter embolotherapy (TCE) in children with pulmonary arteriovenous malformations (PAVMs). STUDY DESIGN: Chart and imaging review of all children (age