Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia.

INTRODUCTION: Systemic bevacizumab is a novel targeted therapy for severe epistaxis and chronic gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT), but published data are very limited. AIM: We conducted a survey-based study to characterize current treatment practices and physician-reported safety and effectiveness of systemic bevacizumab for bleeding in (HHT). METHODS: A 27-item survey was sent to physician centre directors of 31 International HHT Centers of Excellence. RESULTS: Response rate was 84%. Approximately half of centres had treated >10 HHT patients with systemic bevacizumab for chronic bleeding for a total of 291 patients treated. All centres utilize a 5 mg/kg dose for induction treatment and most administer six doses (range, 4-8) every 2 weeks. However, maintenance regimens varied considerably between centres. Bevacizumab was highly effective, with 86% reporting significant (>50%) improvement in GI bleeding and/or epistaxis and haemoglobin rise in most patients treated with bevacizumab; 52% reported haemoglobin normalization in most patients. All centres reported adverse event rates <30% and two-thirds of centres reported adverse event rates <10%. Discontinuation for adverse events or inefficacy was rare. Bleeding severity thresholds for initiation of bevacizumab were highly variable, and it is typically administered by haematologists (76% of centres). Two-thirds of centres reported obtaining insurance approval for bevacizumab for most or all patients but 48% reported difficulty in obtaining coverage. CONCLUSION: Systemic bevacizumab is widely used to treat bleeding in HHT with excellent physician-reported effectiveness and safety. There is considerable variation in maintenance treatment practices and thresholds for initiation of bevacizumab among HHT centres.

Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial.

IMPORTANCE: Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain. OBJECTIVE: To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis. DESIGN, SETTING, AND PARTICIPANTS: The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014. INTERVENTIONS: Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline). MAIN OUTCOMES AND MEASURES: The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure. RESULTS: Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits. CONCLUSIONS AND RELEVANCE: Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01408030.

Current Practice: Rationale for Screening Children with Hereditary Hemorrhagic Telangiectasia for Brain Vascular Malformations.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias, recurrent epistaxis, and organ vascular malformations including in the brain, which occur in about 10% of patients. These brain vascular malformations include high-flow AVMs and AVFs as well as low-flow capillary malformations. High-flow lesions can rupture, causing neurologic morbidity and mortality. STATE OF PRACTICE: International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia recommend screening children for brain vascular malformations with contrast enhanced MR imaging at hereditary hemorrhagic telangiectasia diagnosis. Screening has not been uniformly adopted by some practitioners who contend that screening is not justified. Arguments against screening include application of short-term data from the adult A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial of unruptured sporadic brain AVMs to children with hereditary hemorrhagic telangiectasia as well as concerns about administration of sedation or IV contrast and causing patients or families increased anxiety. ANALYSIS: In this article, a multidisciplinary group of experts on hereditary hemorrhagic telangiectasia reviewed data that support screening guidelines and counter arguments against screening. Children with hereditary hemorrhagic telangiectasia have a preponderance of high-flow lesions including AVFs, which have the highest rupture risk. The rupture risk among children is estimated at about 0.7% per lesion per year and is additive across lesions and during a lifetime. ARUBA, an adult clinical trial of expectant medical management versus treatment of unruptured brain AVMs, favored medical management at 5 years but is not applicable to pediatric patients with hereditary hemorrhagic telangiectasia given the life expectancy of a child. Additionally, interventional, radiosurgical, and surgical techniques have improved with time. Experienced neurovascular experts can prospectively determine the best treatment for each child on the basis of local resources. The "watch and wait" approach to imaging means that children with brain vascular malformations will not be identified until a potentially life-threatening and deficit-producing intracerebral hemorrhage occurs. This expert group does not deem this to be an acceptable trade-off.

Hereditary hemorrhagic telangiectasia: diagnosis and management.

Hereditary hemorrhagic telangiectasia is an uncommon autosomal dominant disease that occurs in approximately one in 5,000 to 8,000 persons. This multisystem disorder can affect the nose, skin, gastrointestinal tract, lungs, liver, and brain. Epistaxis is the most common presenting problem, occurring in 90 percent of affected patients. Approximately 15 to 30 percent of patients with hereditary hemorrhagic telangiectasia will have an arteriovenous malformation in the lungs and more than 10 percent will have one in the brain. The symptoms of hereditary hemorrhagic telangiectasia are often unrecognized. Many patients, even those with affected family members, may go undiagnosed. Hereditary hemorrhagic telangiectasia is a clinical diagnosis that is based on the presence of three of four criteria (i.e., epistaxis, telangiectasias, visceral arteriovenous malformations, or family history of the disease). Screening and treatment recommendations have been created in an attempt to limit the morbidity and mortality associated with this disease. Patients with confirmed or suspected hereditary hemorrhagic telangiectasia should be screened for brain and lung arteriovenous malformations using magnetic resonance imaging of the brain and contrast echocardiography. Pulmonary arteriovenous malformations can be treated with embolization. Patients with a history of pulmonary arteriovenous malformations or those who have not been screened should use antibiotic prophylaxis before dental treatment, endoscopy, or other procedures that could cause bacteremia because of the risk of paradoxical brain embolism or infection.

Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers.

BACKGROUND: Systemic bevacizumab is a novel targeted anti-angiogenic therapy for high-output cardiac failure (HOCF) in hereditary hemorrhagic telangiectasia (HHT) but published data is limited. This survey-based study measured physician-reported safety, effectiveness and current treatment practices for systemic bevacizumab in HHT-HOCF. METHODS: A 27-item survey was sent to center directors of 31 international HHT Centers of Excellence. RESULTS: Response rate was 74% with centers reporting 150 total patients receiving systemic bevacizumab for HHT-HOCF. Approximately two-thirds of centers had treated ≥5 patients. All centers utilize a 5 mg/kg dose for induction treatment and most administer 6 doses (range, 4-6) every 2 weeks, although maintenance regimens varied considerably. Center directors reported bevacizumab to be effective, with 55% reporting significant improvement in cardiac index and HOCF symptoms in most patients treated with bevacizumab, although normalization of cardiac parameters was uncommon. Adverse events were uncommon with three-quarters of centers reporting adverse event rates < 10%. Discontinuation for adverse events or ineffectiveness was rare. Bevacizumab was typically administered by hematologists and pulmonologists (50 and 39% of centers, respectively), with highly variable thresholds for initiation. Although half the centers reported difficulty with the insurance approval process, 70% of centers were ultimately able to obtain coverage for most or all of their patients. CONCLUSIONS: Systemic bevacizumab is a widely-used therapy for HHT-HOCF with reasonable safety and effectiveness. HHT centers appear to vary considerably in maintenance treatment practices and disease severity thresholds for initiation of bevacizumab in HHT-related HOCF.

Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary.

OBJECTIVE: A prospective, qualitative study was conducted to develop a patient-reported outcome measure (PROM) for daily administration via electronic diary (eDiary) to assess the severity of nosebleeds in patients with hereditary hemorrhagic telangiectasia (HHT), in accordance with Food and Drug Administration (FDA) PROM guidance criteria. METHODS: Three expert clinicians who treat patients with HHT provided input during instrument development, which comprised: 1) Peer-reviewed literature and instrument review; 2) Development of draft Nosebleed Diary items; 3a) Three rounds of qualitative interviews (two with a paper-based diary, one with an eDiary) with patients with documented severe epistaxis related to HHT, for concept elicitation and cognitive debriefing; 3b) Face validity and translatability assessment; 3c) Patient evaluation of the usability and acceptability of the eDiary device; and 4) Preparation of the final Nosebleed eDiary and conceptual framework. RESULTS: No existing instruments were identified that evaluate HHT-related nosebleed severity daily and meet FDA PROM guidance criteria. Frequency, duration, and/or speed of flow (i.e., intensity) were reported by most participants with HHT when asked to describe their nosebleed severity. The Nosebleed eDiary was refined based on 17 patient interviews, clinical expert input and the face validity and translatability assessment. The final four-item eDiary was acceptable to patients with HHT. CONCLUSION: The Nosebleed eDiary is "fit for purpose" to assess the severity of HHT-related nosebleeds, and has established face and content validity. Further adaptation may be required for use in mild or moderate HHT populations. Psychometric testing to evaluate construct validity and reliability are recommended next steps. LEVEL OF EVIDENCE: 2c "Outcomes research".

Dilation efficacy: is 1% cyclopentolate enough?

BACKGROUND: Pediatric eye examinations include cycloplegia and dilation. Most clinicians use 2 or 3 different medications in drop or spray form to ease instillation. We studied whether a single drop of a cycloplegic agent would provide effective dilation as well. METHODS: Children between the ages of 1 and 7 years, who presented for a routine eye examination, were recruited to participate. Each child received 1% cyclopentolate in the right eye (group A), and either tetracaine with cyclopentolate (group B) or tetracaine with cyclopentolate with phenylephrine (group C) in the left eye. At the completion of the examination, a digital picture was taken of the patient's pupils. A separate observer measured the pupil diameter and classified iris color. RESULTS: The mean pupil size for all subjects was: 6.19 mm +/- 1.33 mm, for group A, 6.56 mm +/- 1.25 for group B; and 6.47 mm +/- 1.12 for group C. Light-colored iris patients had greater dilation as a group and darker iris patients had less dilation as a group. Evaluation of the paired eyes pupil diameter found no statistical difference. CONCLUSIONS: One drop of 1% cyclopentolate provides cycloplegia and effective pupil dilation for completion of a pediatric eye examination. One drop is easier to instill than multiple drops and should be considered for use in a pediatric eye examination.

Endophthalmitis following pediatric cataract surgery with a good outcome.

Endophthalmitis is a rare but potentially devastating complication following intraocular surgery. Endophthalmitis following intraocular surgery in children often has a poor outcome. We report a case of endophthalmitis after cataract extraction in a 6-year-old girl with a good visual result.

Corneal astigmatic effects of conventional recession vs suspension recession ("hang-back") strabismus surgery: a pilot study.

INTRODUCTION: Changes in refractive error after strabismus surgery occur secondary to changes in corneal curvature. The change in refractive error is usually transient but may lead to a temporary decrease in vision. We compared the change in corneal curvature following strabismus surgery in eyes utilizing a suspension (so-called "hang-back") recession technique to eyes undergoing conventional recession surgery. METHODS: Sixteen patients undergoing bilateral medial or lateral rectus recessions were prospectively entered into the study. One eye was randomly selected to undergo conventional strabismus surgery and the other eye underwent strabismus surgery using the suspension technique. Keratometry measurements were taken in the operating room immediately prior to and immediately after surgery. The change in corneal curvature was calculated and analyzed for each technique. RESULTS: The mean change in corneal curvature was -0.06 diopters (D) for the suspension group and +0.18 D for the conventional group, confirming prior reports. However, all eyes undergoing suspension surgery had a change within 1 D whereas only 75% of those eyes undergoing conventional surgery fell within the same range. Overall there was twice the variation in the degree of astigmatism in the conventional group when compared with the suspension group. CONCLUSIONS: No eye undergoing suspension surgery experienced a change in corneal curvature greater than 1 D while 25% of those undergoing conventional surgery did. Therefore, possible benefits to the suspension recession technique might include less overall variability of astigmatism change and decreased amounts of induced astigmatism. Patients undergoing strabismus surgery using a suspension technique may be less likely to notice a change in their vision in the immediate postoperative period.

High AC/A Ratio Esotropia: Do We Really Need to Be Using Bifocals?

INTRODUCTION AND PURPOSE: Most strabismus specialists use bifocals for patients with convergence excess esotropia whose distance deviation is small. While this is a popular treatment modality, there is actually no good data to indicate that this should be considered a standard of care. PATIENTS AND METHODS: In patients for whom the distance deviation is small enough to allow for the development of binocular vision, my preference is to simply observe these patients. Most will improve with time. For those who do not, or who decompensate, surgery may be indicated. RESULTS: A careful review of the literature shows a lack of evidence to suggest that bifocals provide an effective treatment for this problem. Some data and theoretical concern may raise a concern over their use. Time and observation may be all that is necessary. There may be a role for surgical correction in these patients as well. CONCLUSION: While there are theoretical advantages to the use of bifocals in patients with convergence excess esotropia, current data does not support the actual need for active treatment of these patients.

Validity of ophthalmology surgical competency assessment rubric for strabismus surgery in resident training.

The Accreditation Council for Graduate Medical Education (ACGME) requires US residency programs to assess ophthalmology residents for competency in 6 core areas. Ophthalmic surgical skills are currently part of the ACGME "Patient Care" competency, although some have advocated for a seventh competency, "Surgical Skills." The Ophthalmology Surgical Competency Assessment Rubric for Strabismus Surgery in Resident Training ( OSCAR: Strabismus) tool was designed to aid in the assessment of surgical skills using procedure specific behavioral anchors. The present study evaluated inter-rater agreement of the OSCAR: Strabismus tool in the assessment of resident performance. OSCAR: Strabismus evaluations of resident surgical strabismus cases were performed by a multinational group of faculty strabismus surgeons. Cronbach α statistical analysis of the completed evaluations revealed high inter-rater agreement, indicating the OSCAR: Strabismus is a reliable tool to facilitate assessment of resident strabismus surgical skills.

The effect of media press coverage on parental preferences in amblyopia treatment.

BACKGROUND: Amblyopia has traditionally been treated by full-time occlusion of the sound eye. Recent studies have looked at the efficacy of atropine penalization and less patching in the treatment of amblyopia. These studies have drawn much attention from the lay press. This media attention may influence parent treatment preferences. METHODS: We distributed two news releases recently published by national newspapers to parents presenting to an outpatient pediatric eye clinic. They were then asked to rank atropine drops, 2-hour, 6-hour, and full-time patching (FTP) in order of preference. We then supplied additional information published in the scientific studies, but not mentioned in the lay press, and parents were asked to rerank their preferences. RESULTS: A total of 53 surveys were completed. The frequency with which each method (atropine, 2-hour, 6-hour, FTP) was initially ranked #1 was 66, 21, 2, and 11%, respectively. The frequency each was ranked #1 in the follow-up survey was 30, 26, 8, and 38%, respectively. The Wilcoxon matched-pair signed-ranks test demonstrated significant changes in treatment preferences (atropine, z = -4.204, P < 0.0001; 2-hour patch, z = -2.574, P = 0.0101; 6-hour patch, z = 4.484, P < 0.0001; FTP, z = 3.703, P = 0.0002). CONCLUSION: After having read press releases regarding amblyopia treatment, parents' preferences favored atropine and less patching. After being given additional information about the results of these studies, there was a strong shift in opinions in favor of more patching and away from atropine. The media appear to play an important role in influencing parent treatment preferences.

Unilateral anterior transposition and resection of the inferior oblique muscle for the treatment of hypertropia.

BACKGROUND: Anterior transposition of the inferior oblique muscle generally is restricted to bilateral cases because of reports of postoperative ipsilateral hypotropia or significant limitation of elevation when performed unilaterally. We performed unilateral anterior transposition of the inferior oblique muscle in patients with vertical and horizontal strabismus who were at risk of anterior segment ischemia. PATIENTS AND METHODS: Six patients underwent unilateral anterior transposition of the inferior oblique muscle in combination with a resection of the inferior oblique muscle. Two patients had lost an inferior rectus muscle in a previous procedure, and four patients had coexistent horizontal and vertical strabismus of various etiologies as well as poor unilateral vision. RESULTS: All six patients achieved vertical alignment within 10 prism diopters. CONCLUSIONS: Unilateral anterior transposition of the inferior oblique muscle appears to be a useful procedure in selected patients with vertical strabismus.

Complications of Strabismus Surgery.

All surgeries carry risks of complications, and there is no way to avoid ever having a complication. Strabismus surgery is no different in this regard. There are methods to reduce the risk of a complication during or after surgery, and these steps should always be taken. When a complication occurs, it is important to first recognize it and then manage it appropriately to allow for the best outcome possible. This article will discuss some of the more common and/or most devastating complications that can occur during or after strabismus surgery as well as thoughts on how to avoid them and manage them should they happen.

Comparison of the Icare rebound tonometry with the Goldmann applanation tonometry in a pediatric population.

We report the results of a comparative study at a single center on 214 eyes of 109 pediatric patients in whom IOP was measured using the Icare rebound tonometer and Goldmann applanation tonometry. Measurements from the two modalities demonstrated a correlation coefficient of 0.83 (P < 0.001), with Icare measuring on average 1.38 mm Hg higher. Compared to Goldmann, the Icare was more easily tolerated in the children studied. In 37 eyes that tolerated pachymetry, central corneal thickness was positively correlated with Icare measurements.

Reading disorders in children.

Reading difficulties are a complex set of disorders. Current research indicates that these disorders are not caused by vision abnormalities. Treatment of these disorders requires a multidisciplinary approach involving educators, psychologists, and physicians. Parents, physicians, and school officials should understand that there are no quick cures for these children.