Jeffrey W. Kalenak

Autosomal dominant iris hypoplasia is caused by a mutation in the rieger syndrome (rieg/pitx2) gene

PURPOSE To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger syndrome (RIEG/PITX2). METHOD Mutation screening and sequence analysis was performed in a single family. RESULTS A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/ITX2 gene product. CONCLUSION Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger syndrome.

Original articleThe Ahmed Versus Baerveldt Study: One-Year Treatment Outcomes

OBJECTIVE To report the 1-year treatment outcomes of the Ahmed Versus Baerveldt (AVB) Study. DESIGN Multicenter randomized clinical trial. PARTICIPANTS A total of 238 patients were enrolled in the study, including 124 in the Ahmed group and 114 in the Baerveldt group. METHODS Patients aged 18 years or older with uncontrolled glaucoma refractory to medicinal, laser, and surgical therapy were randomized to undergo implantation of an Ahmed-FP7 valve (New World Medical, Inc., Rancho Cucamonga, CA) or a Baerveldt-350 implant (Abbott Medical Optics, Inc., Santa Ana, CA), to be followed for 5 years. MAIN OUTCOME MEASURES The primary outcome measure was failure, defined as intraocular pressure (IOP) out of target range (5-18 mmHg with ≥ 20% reduction from baseline) for 2 consecutive visits after 3 months, vision-threatening complications, additional glaucoma procedures, or loss of light perception. Secondary outcome measures included IOP, medication use, visual acuity, complications, and interventions. RESULTS There were no significant differences in baseline ocular or demographic characteristics between the study groups with the exception of sex. Preoperatively, the study group had a mean IOP of 31.4 ± 10.8 mmHg on a mean of 3.1 ± 1.0 glaucoma medications with a median Snellen acuity of 20/100. The cumulative probability of failure a 1-year was 43% in the Ahmed group and 28% in the Baerveldt group (P = 0.02). The mean IOP at 1 year was 16.5 ± 5.3 mmHg in the Ahmed group and 13.6 ± 4.8 mmHg in the Baerveldt group (P < 0.001). The mean number of glaucoma medications required was 1.6 ± 1.3 in the Ahmed group and 1.2 ± 1.3 in the Baerveldt group (P = 0.03). Visual acuity was similar in both groups at all visits in the first year (P = 0.66). In the first year after surgery, there were a similar number of patients who experienced postoperative complications in the 2 groups (45% Ahmed, 54% Baerveldt, P = 0.19), but a greater number of patients in the Baerveldt group required interventions (26% Ahmed vs. 42% Baerveldt, P = 0.009). CONCLUSIONS The Baerveldt-350 group had a higher success rate than the Ahmed-FP7 group after 1 year of follow-up, but required a greater number of interventions. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Expression of the Mf1 gene in developing mouse hearts: Implication in the development of human congenital heart defects

The transcription factor FKHL7 gene has recently been associated with the anterior segment dysgenesis disorder of the eye known as Axenfeld‐Rieger anomaly (ARA). A growing body of evidence indicates that mutations in FKHL7 cause not only defects in the anterior segment of the eye but defects in the heart valves and septa as well. In order to evaluate its contribution to normal heart septation and valve formation, expression of the mouse homologue Mf1 in embryonic hearts was analyzed by in situ hybridization. A weak but significant level of Mf1 expression could be detected in the endocardium of mouse embryos as early as day 8.5 post‐conception (p.c.). Mf1 expression was undetectable in the hearts of day 9.5 p.c. embryos, but by day 10.5–11 p.c., Mf1 transcripts could be found again in the endocardium of both the atrium and ventricle and a relatively strong signal was observed in the dorsal portion of the septum primum, in what appeared to be the spinal vestibule. At day 13 p.c. when aortic and pulmonary trunks are separated, relatively more Mf1 transcripts were detected in the leaflets of aortic, pulmonary, and venous valves, the ventral portion of the septum primum, as well as in the single layer of cells on the edges of the atrioventricular cushion tissues. Surprisingly, there was no signal detected in the developing interventricular septum. At day 15 p.c., overall Mf1 signals were greatly decreased. However, significant levels of expression could still be observed in the atrial septum, the tricuspid valve, the mitral valve, and in the venous valve but not in the interventricular septum. The temporal and spatial expression patterns of the Mf1 gene in developing mouse hearts suggest that Mf1 may play a critical role in the formation of valves and septa with the exception of the interventricular septum. This is further supported by our studies showing that mutations in the FKHL7 gene were associated with defects in the anterior segment of the eye as well as atrial septal defects or mitral valve defects. Dev Dyn 1999;216:16–27.

The Ahmed Versus Baerveldt Study: Design, Baseline Patient Characteristics, and Intraoperative Complications

OBJECTIVE To report the design, baseline patient characteristics, and intraoperative complications of the Ahmed Versus Baerveldt (AVB) Study. DESIGN Multicenter, randomized, clinical trial. PARTICIPANTS Patients were recruited from 7 international clinical sites and treated by 10 surgeons between 2005 and 2009. Inclusion criteria required that patients be at least 18 years of age and have uncontrolled glaucoma refractory to medicinal, laser, and surgical therapy. METHODS Eligible patients were randomized to undergo implantation of an Ahmed-FP7 valve (New World Medical, Inc., Rancho Cucamonga, CA) or a Baerveldt-350 implant (Abbott Medical Optics, Inc., Santa Ana, CA) using standardized surgical technique, to be followed for 5 years. MAIN OUTCOME MEASURES The primary outcome measure was failure, defined as intraocular pressure (IOP) out of target range (5-18 mmHg with ≥ 20% reduction from baseline) for 2 consecutive visits after 3 months, vision-threatening complications, additional glaucoma procedures, or loss of light perception. Secondary outcome measures included IOP, medication use, visual acuity, complications, and interventions. RESULTS A total of 238 patients were enrolled in the study; 124 received the Ahmed-FP7 valve implant and 114 received the Baerveldt-350 implant. The 2 treatment groups did not differ in any baseline characteristics with the exception of sex. The mean age of the study group was 66 ± 16 years, and 55% were women, with a greater proportion in the Baerveldt group (P=0.01). The mean baseline IOP of the study group was 31.4 ± 10.8 on a mean of 3.1 ± 1.0 glaucoma medications. The median Snellen visual acuity was 20/100, mean number of previous laser therapies was 0.9 ± 1.1, and mean number of previous surgeries was 1.7 ± 1.2. Five (4%) patients in the Ahmed group and 4 (4%) patients in the Baerveldt group experienced significant intraoperative complications. CONCLUSIONS Aqueous drainage devices are being increasingly used for glaucoma refractory to conventional treatment, and the AVB Study compares the 2 most commonly implanted devices. The 2 groups had similar baseline characteristics, and there were a similar number of intraoperative complications for both devices. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Transscleral neodymium : YAG laser cyclocoagulation for uncontrolled glaucoma

To determine the efficacy and safety of the procedure, we reviewed the records of 25 eyes of 25 patients who had received noncontact transscleral Nd:YAG laser cyclocoagulation for a variety of uncontrolled glaucomas. Thirteen to 35 pulses (mean, 22.7 pulses) had been placed 1 mm to 2 mm behind the limbus with an energy per pulse of 3.4 J to 8.2 J (mean 4.5 J). Follow-up ranged from 6 months to 23 months, with the exception of one eye, which had to be enucleated. Nine of the 25 eyes (36%) required one or two repeat treatments. Twelve (48%) had intraocular pressures at last follow-up of less than 21 mm Hg but greater than 4 mm Hg. Ten eyes (40%) developed moderate to severe pain transiently, and 10 (40%) developed substantial, but transient, inflammation. Transscleral Nd:YAG laser cyclocoagulation appears to be relatively effective and well tolerated.

Revision for exposed anterior segment tubes.

PurposeTo discuss the clinical problem of exposed anterior segment tubes, to review the literature on revision surgery, and to present my method of revision for tube exposure. MethodsReview of the pertinent literature and tabulation of complications from the authors cases of revision surgery. ResultsThe risk of endophthalmitis requires that all cases of exposed anterior segment tube undergo revision with a patch graft. Simple conjunctival closure is inadequate. A patch graft of collagenous human autograft or allograft material is necessary to prepare the eye for complete healing and resolution of the exposure. Methods of revision from the literature are reviewed and presented, along with the authors method of revision. Complications, reported and potential, are discussed. ConclusionsAll exposed anterior segment tubes should be revised with patch graft to resolve the exposure and avoid endophthalmitis. Several methods of revision are available, and the rate of complications is low.

Prospective ultrasonographic evaluation of intraoperative and delayed postoperative suprachoroidal hemorrhage from glaucoma filtering surgery.

PurposeTo determine the incidence of, visual loss from, and perioperative risk factors for suprachoroidal hemorrhage (SCH) occurring during or after glaucoma filtering surgery. MethodsContact B-Scan ultrasonography was used to evaluate at a median of 15 days postoperatively, one eye of 158 patients who underwent various glaucoma filtering procedures during an 18 month period. ResultsUltrasonography detected SCH in 13 patients (8.2%). SCH was recognized during surgery in two cases; 11 were detected postoperatively. Preexisting aphakia (odds ratio 12.9, 95% confidence interval 3.6 to 46.2) and intraoperative anterior vitrectomy (odds ratio 5.2, 95% confidence interval 1.2 to 22.4) were significantly associated with SCH. A significant negative association was found for combined cataract/glaucoma procedures with posterior chamber intraocular lens implantation (odds ratio 0.08, 95% confidence interval 0.01 to 0.69). No significant association between SCH and age, sex, race, diabetes, obesity, systemic hypertension, right versus left eye, type of glaucoma, surgeon, number of preoperative antiglaucoma medications, 5-fluorouracil/mitomycin-C therapy-or previous vitrectomy was found. For some risk factors the power of the study may not be sufficient to establish a correlation: with SCH. Two patients with SCH had serious visual acuity loss and 2 had mild visual acuity loss. Eyes of three patients were surgically drained of SCH. Most patients with SCH did not experience pain, and only one presented-with elevated intraocular pressure at the time SCH was recognized. ConclusionPre-existing aphakia and concurrent vitrectomy were significant risk factors identified. Combined cataract and glaucoma filtering procedures correlated negatively with suprachoroidal hemorrhage. Most patients with suprachoroidal hemorrhage experienced little or no visual loss, pain, or intraocular pressure elevation.

Anti–Vascular Endothelial Growth Factor Injections and Intraocular Pressure Measurement: Should We Throw the Baby out with the Bath Water?

For many years, observations in the clinic and numerous case reports have suggested that repeated intravitreal injections of antievascular endothelial growth factor drugs can lead to persistent elevation of intraocular pressure (IOP). These observations have led well-meaning investigators to wonder if large existing databases from rigorously conducted randomized trials on the efficacy and safety of the agents could be analyzed to address this issue better. Unfortunately, because change in IOP was not the primary outcome variable in these studies,onemaysuspectthat thelackofrigor withwhichdata on IOP were collected could tarnish any conclusions. Ophthalmology has published manuscripts venturing into this fraught area. Bakri et al 1 performed a post hoc analysis of the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) studies, which compared ranibizumab with verteporfin and ranibizumab with sham injection, respectively, for the treatment of age-related macular degeneration. They reported that “Most IOP measurements were made by either applanation tonometry (49.4%) or Tono-Pen (Medtronic Solan, Jacksonville, FL) (45.5%). For the remaining patients, IOP was measured by pneumotonometry [sic], the method was missing, or a combination of methods was used.” Bakri et al ignored the robust literature demonstrating that applanation and Tono-Pen (Reichert Inc., Buffalo, NY) IOP readings are neither equivalent nor interchangeable. 2 In the current issue (see page 1802), Freund et al 3 performed a similar analysis, this time examining IOP data from the VIEW (VEGF Trap: Investigation of Efficacy and Safety in Wet AMD) 1 and VIEW 2 randomized trials comparing aflibercept with ranibizumab for age-related macular degeneration.TheyconcludedthatIOPelevationwaslesslikelywith afliberceptthanranibizumab.LikeBakrietal,theycouldbeno morespecificintermsofIOPmethodologythantostatethatin some patients, IOP was measured by Goldmann tonometry and that in others, the Tono-Pen was used. The glaucoma research community has long wrestled with the vagaries of IOP measurement, which include variations and inaccuracies resulting from the use of uncalibrated tonometers, the large number of personnel involved in studies, the lack of masking for IOP measurements, and the absence of more than 1 baseline IOP. For these reasons, the major trials in glaucoma therapytookgreatcaretoadheretoprotocolsformeasuringIOP, and a consensus as to how IOP should be measured has been reached. 4 Key features of the consensus include using a calibrated Goldmann tonometer for uniformity (unless the purpose of the study is to compare the accuracy and variability of more than 1 tonometer); measurement of the IOP by 2 individuals: an operator who adjusts the tonometer dial and a reader who reads and records the results (to reduce bias); and the obtaining of at least 2 measurements at each time point (to reduce the influence of continuous IOP variability). Furthermore, measurement of central corneal thickness is now an integral part of the interpretation of the IOP measurement (but without applying a corneal correction factor to IOP), and documentation of the presence or absence of glaucoma and the use of medications to lower IOP also is important. Althoughthedesignersofthesecriticalretinastudiesrequired

Performance and Safety of a New Ab Interno Gelatin Stent in Refractory Glaucoma at 12 Months

I THANK GROVER AND ASSOCIATES FOR PUBLISHING 1-year data on the new ab interno 45-micron gelatin stent, in ‘‘Performance and safety of a new ab interno gelatin stent in refractory glaucoma at 12 months.’’ Why did the authors choose the primary performance outcome as the proportion of patients ‘‘achieving >/1⁄420% mean diurnal IOP reduction from baseline at 12 months on the same number or fewer medications.’’? Under their definition, for example, a patient starting with a preoperative intraocular pressure (IOP) of 30 mm Hg on 3 medications would be classified as ‘‘success’’ if the final IOP were 24 mm Hg on 3 medications, even though few surgeons would regard that as real operative success. The authors are aware, of course, that other long-term glaucoma surgical studies have reported outcomes subject to stricter definitions. They listed in their Table 4 the different failure definitions, but made no attempt to match those definitions for consistency. For example, the Ahmed Baerveldt Comparison (ABC) Study included either <20% IOP reduction from baseline OR outcome IOP outside the range 6-21 mm Hg in its classification of failure (not to mention additional glaucoma surgery or loss of light perception). The authors’ publication deadline perhaps did not allow them to quote the 5-year pooled data analysis of the ABC and Ahmed Versus Baerveldt (AVB) Studies by Christakis and associates. Those authors recalculated failure rates by applying several criteria (target IOP range 6-15, 6-18, and 6-21 mm Hg). The authors can do the same with their database. When one looks at the figures in the Christakis article, the pooled Baerveldt data showed a failure rate below 20% at 1 year (under the 6-21 mm Hg criterion), and just about a 20% failure rate at 1 year (under the 6-18 mm Hg criterion). Furthermore, the choice of 18 mm Hg as upper limit was not arbitrary; the authors of the ABC Study quoted the Advanced Glaucoma Intervention Study outcomes data as justification. I find the authors’ gelatin stent performance criterion, omitting an additional one or more target IOP range(s), to be a tad annoying. First, it forecloses an opportunity to make apples-to-apples data comparisons among glaucoma surgical choices. Just because the ABC and AVB Studies did not report 95% confidence intervals for their failure rates does not justify choosing more lax criteria.We cannot