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.

Reproducibility of oxygen saturation monitoring during six-minute walk test and exercise stress test in patients with pulmonary arteriovenous malformations associated with hereditary hemorrhagic telangiectasia.

Patients with pulmonary arteriovenous malformations (PAVMs) are at risk for multiple complications and require close follow-up. We investigated the reproducibility of the 6-minute walk test (6MWT) and exercise stress test (EST) for the evaluation of low oxygen saturation in patients with PAVMs. Twenty-two patients with PAVMs, most of whom had hereditary hemorrhagic telangiectasia (HHT), participated in a Human Investigations Committee-approved protocol. Patients ranged from 9 to 74 years of age (mean 28) and had a broad spectrum of anatomic subtypes of PAVMs, including focal and diffuse. Standard 6MWT and cycle ergometry EST were both performed twice with adequate rest between tests. Heart rate (HR) and oxygen saturation were measured at the beginning and end of each test. Distance walked and maximum resistance was also recorded. The intraclass correlation coefficients (r(i)) at the end of 6MWT were as follows: HR (r(i) = 0.940; 95% confidence interval [CI] 0.863-0.975), oxygen saturation (r(i) = 0.973; 95% CI 0.933-0.989), and distance (r(i) = 0.942; 95% CI 0.867-0.975). The r(i)s at the end of EST were as follows: HR (r(i) = 0.941; 95% CI 0.865-0.975), oxygen saturation (r(i) = 0.993; 95% CI 0.982-0.997), and maximum resistance (r(i) = 0.941; 95% CI 0.864-0.975). 6MWT and EST were reproducible measures of exercise capacity and oxygen saturation and are potential adjunct tests in the follow-up assessment for patients with PAVMs.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.

Comparison of four embolic materials at uterine artery embolization by using postprocedural MR imaging enhancement.

PURPOSE: To test the hypothesis that not all embolic materials are equivalent by using postprocedural magnetic resonance (MR) imaging enhancement of uterine fibroids in patients treated with uterine artery embolization (UAE). MATERIALS AND METHODS: Approval and a waiver of consent from the institutional human investigations committee was received for this study. The study was HIPAA compliant. A total of 84 women who underwent 6-month MR imaging follow-up constituted this retrospective study. Within this group, 25 women were treated with Contour polyvinyl alcohol (PVA) particles, 23 were treated with Contour SE particles, 19 were treated with Embosphere microspheres, and 17 were treated with Bead Block microspheres. Pre- and postprocedural MR imaging results were analyzed for the total number of fibroids present in the uterus of each patient and for the percentage of individual fibroid enhancement. Enhancement of individual fibroids was measured with quartile intervals. Greater than 25% residual enhancement of a fibroid after embolization was considered an incomplete infarction. The overall percentage change in enhancement was calculated for each patient. Bivariate analysis by using generalized linear modeling and one-way analysis of variance was used to assess differences in infarction with different embolic materials. RESULTS: Among patients treated with Contour and Embosphere, there was a mean reduction in enhancement by 76.60% and 83.07%, respectively, compared with a mean reduction of 52.53% and 49.78% in patients treated with Bead Block and Contour SE, respectively. There was a significant difference in postembolization enhancement between Bead Block and Embosphere, Bead Block and Contour, Contour SE and Embosphere, and Contour SE and Contour. CONCLUSION: Patients treated with Bead Block or Contour SE demonstrated a reduced degree of infarction at follow-up MR imaging compared with patients treated with Contour or Embosphere.

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.

Pulmonary arteriovenous malformations: how do I embolize?

Pulmonary arteriovenous malformations (PAVM) are high-flow, low-pressure shunts, consisting of a single feeding artery connecting via an aneurysmal sac to a draining vein. The aneurysmal connection is referred to as an aneurysmal sac. The "filter capacity" of the pulmonary capillaries is lost and results in predisposition to brain abscess, stroke, and transient ischemic attack and, when multiple, dyspnea, because of right-to-left shunting and hypoxemia. PAVM are markers of hereditary hemorrhagic telangiectasia (HHT). Up to 30% of patients with HHT have PAVM complicating their disorder. Left untreated, 50% of patients with PAVM will develop disabling or fatal complications. In addition to stroke and transient ischemic attack syndromes due to passage of paradoxical emboli through the PAVM, rupture of the aneurysmal sac, particularly in the third trimester of pregnancy, can lead to fatal hemoptysis or hemothorax. Finally, brain abscess or more obscure musculoskeletal or spinal infections may be secondary to PAVM. Since detachable silicone balloons are no longer available, we have developed precise techniques for closing pulmonary malformations using pushable fibered coils. It is not the coil that is so important, but it is the use of coaxial or triaxial catheters that allow for precise placement of the coil. Cross-sectional occlusion is essential for embolization of PAVM and this is achieved using the "anchor" or "scaffold" technique. Our recent results indicate permanent involution of treated malformations with a 3% recurrence rate. All patients should be assessed for other manifestations of HHT before treatment and they are best followed in one of the 20 HHT Centers worldwide (www.hht.org).

Liver involvement in hereditary hemorrhagic telangiectasia: CT and clinical findings do not correlate in symptomatic patients.

OBJECTIVE: The purpose of our study was to report the multiphasic CT findings in patients with symptomatic liver involvement by hereditary hemorrhagic telangiectasia (HHT) and to correlate the CT findings with the type of clinical presentation. CONCLUSION: Patients with symptomatic HHT liver disease have diffuse hepatic telangiectases, a dilated common hepatic artery, and a high incidence of biliary abnormalities. Multiphasic CT is useful in diagnosing liver involvement due to HHT; however, no strong correlation was seen between CT findings and the clinical subtype of HHT liver disease.

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 1st balloon valvuloplasty: an historical note.

Balloon valvuloplasty (BV) is currently the treatment of choice for pulmonic stenosis in humans and dogs. Before permission was obtained to attempt the 1st BV in a child in 1982, the safety and efficacy of the procedure were tested in 1980 in an English Bulldog with spontaneous pulmonic stenosis. A fatal outcome would have caused indefinite postponement of BV in human patients, a procedure that currently benefits over 25,000 patients a year worldwide. This article describes the initial test procedure and its fortunate outcome in spite of unrecognized coronary anomalies in the bulldog. A small balloon was used in the test procedure, and fatal disruption of the anomalous left coronary artery (CA) did not occur as it has in several bulldogs since that time.

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.

Hemothorax due to rupture of pulmonary arteriovenous malformation: an interventional emergency.

Spontaneous hemothorax as a result of a ruptured pulmonary arteriovenous malformation (PAVM) is a life-threatening event and requires immediate interventional therapy. We present two patients who survived following emergent embolization. Definitive thoracentesis was delayed until embolization was performed. The tamponade provided by the hemothorax may have prevented exsanguination, suggesting to us that drainage of blood from the pleural space should be delayed until the PAVM has been treated. Hemorrhage from a PAVM may be the first manifestation of hereditary hemorrhagic telangiectasia. Genetic testing and screening for other family members should be considered.

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.

Comparison of MRI outcomes of uterine artery embolization for uterine leiomyoma using tris-acryl gelatin microspheres, polyvinyl alcohol spheres, and polyvinyl alcohol particles.

OBJECTIVE: Comparison of recurrence of magnetic resonance imaging (MRI) enhancement of uterine fibroids treated with uterine artery embolization (UAE) among embolic agents: polyvinyl alcohol (PVA), spherical PVA (SPVA), and tris-acryl gelatin microspheres (GM). METHODS: Pre/post-UAE gadolinium-enhanced MRIs were evaluated for residual enhancement of fibroids after UAE. Data were analyzed using 2-tail Fisher exact test to determine the likelihood of recurrence of enhancement post-UAE among embolic agents. RESULTS: One hundred one women underwent UAE. A total of 24 (41%) of 59 embolized with PVA, 18 (75%) of 24 with SPVA, and 4 (22%) of 18 with GM showed residual enhancement in some or all fibroids. Statistically significant differences in presence of residual enhancement on follow-up were found between SPVA and PVA (P = 0.0072), and SPVA and GM (P = 0.0015), but not between PVA and GM (P = 0.1756). CONCLUSIONS: Patients embolized with SPVA have a higher risk of having residual enhancement on follow-up MRI than those embolized with PVA or GM.

Value of Micronester coils in port-catheter implantation for continuous hepatic arterial infusion chemotherapy with fixed catheter tip method.

To retrospectively evaluate the use of Micronester coils in port-catheter implantation with the fixed catheter tip method in comparison with other previously used coils. The cohort of this study was 143 consecutive patients with unresectable advanced liver cancer for whom a port-catheter system was percutaneously implanted. In the most recent 32 patients, Micronester coils were used for catheter tip fixation. Details of embolic agents for fixation, persistent blood flow beyond the distal end of the indwelling catheter, and complications were compared between cases without and with Micronester coils. In all, percutaneous port-catheter placement was successful. Mean number of coils used for fixation was 4.2 without Micronester coils vs. 2.5 with Micronester coils. N-butyl cyanoacrylate (NBCA)-Lipiodol was additionally used for catheter tip fixation in 85.6% of 111 procedures without Micronester coils and in 50% of 32 using Micronester coils. The gastroduodenal artery beyond the distal end was not detected at the final examination after any procedure. Catheter dislocation occurred in five and hepatic arterial obstruction or severe stenosis in eight. The number of coils used and necessity of NBCA-Lipiodol could be decreased with usage of Micronester coils without decreasing fixation ability compared to other coils.