William F. Astle

Mutations in CYP1B1, the Gene for Cytochrome P4501B1, Are the Predominant Cause of Primary Congenital Glaucoma in Saudi Arabia

The autosomal recessive disorder primary congenital glaucoma (PCG) is caused by unknown developmental defect(s) of the trabecular meshwork and anterior chamber angle of the eye. Homozygosity mapping with a DNA pooling strategy in three large consanguineous Saudi PCG families identified the GLC3A locus on chromosome 2p21 in a region tightly linked to PCG in another population. Formal linkage analysis in 25 Saudi PCG families confirmed both significant linkage to polymorphic markers in this region and incomplete penetrance, but it showed no evidence of genetic heterogeneity. For these 25 families, the maximum combined two-point LOD score was 15.76 at a recombination fraction of .021, with the polymorphic marker D2S177. Both haplotype analysis and homozygosity mapping in these families localized GLC3A to a 5-cM critical interval delineated by markers D2S2186 and D2S1356. Sequence analysis of the coding exons for cytochrome P4501B1 (CYP1B1) in these 25 families revealed three distinctive mutations that segregate with the phenotype in 24 families. Additional clinical and molecular data on some mildly affected relatives showed variable expressivity of PCG in this population. These results should stimulate a study of the genetic and environmental events that modify the effects of CYP1B1 mutations in ocular development. Furthermore, the small number of PCG mutations identified in this Saudi population makes both neonatal and population screening attractive public health measures.

Telemedicine approach to screening for severe retinopathy of prematurity: a pilot study

PURPOSE To evaluate the use of remote reading of digital retinal photographs in the diagnosis of severe (referral-warranted) retinopathy of prematurity (ROP) during longitudinal screening for ROP. STUDY DESIGN Prospective, longitudinal cohort study. SUBJECTS Forty-four consecutive premature infants at risk for ROP. METHODS All infants were examined longitudinally, over a series of examinations, by indirect ophthalmoscopy (gold standard) and digital photography using the RetCam-120 Digital Retinal Camera (Massie Research Laboratories Inc., Dublin, CA) equipped with an ROP lens. Images were stored and read remotely by a masked reader. Referral-warranted ROP was defined as ROP in zone 1, the presence of plus disease or the presence of any stage 3 ROP. We determined whether and when referral-warranted ROP was diagnosed for each eye, of each infant, on each examination, during the course of each of the infants screening. RESULTS Severe (referral-warranted) ROP was diagnosed in 23 eyes by indirect ophthalmoscopy during their series of examinations. Digital photography had a sensitivity of 100% and a specificity of 96% in detecting referral-warranted ROP. The positive predictive value of digital photography was 92%, and the negative predictive value was 100%. In 87% of eyes, referral-warranted ROP was diagnosed by digital photography before or at the same time as indirect ophthalmoscopy. CONCLUSIONS Longitudinal remote reading of digital photographs using the RetCam-120 system has excellent specificity and sensitivity in detecting referral-warranted ROP. This pilot study has shown that remote reading of digital photographs has promise for telemedicine strategies in ROP screening.

Effect of Age on Response to Amblyopia Treatment in Children

OBJECTIVE To determine whether age at initiation of treatment for amblyopia influences the response among children 3 to less than 13 years of age with unilateral amblyopia who have 20/40 to 20/400 amblyopic eye visual acuity. METHODS A meta-analysis of individual subject data from 4 recently completed randomized amblyopia treatment trials was performed to evaluate the relationship between age and improvement in logMAR amblyopic eye visual acuity. Analyses were adjusted for baseline amblyopic eye visual acuity, spherical equivalent refractive error in the amblyopic eye, type of amblyopia, prior amblyopia treatment, study treatment, and protocol. Age was categorized (3 to <5 years, 5 to <7 years, and 7 to <13 years) because there was a nonlinear relationship between age and improvement in amblyopic eye visual acuity. RESULTS Children from 7 to less than 13 years of age were significantly less responsive to treatment than were younger age groups (children from 3 to <5 years of age or children from 5 to <7 years of age) for moderate and severe amblyopia (P < .04 for all 4 comparisons). There was no difference in treatment response between children 3 to less than 5 years of age and children 5 to less than 7 years of age for moderate amblyopia (P = .67), but there was a suggestion of greater responsiveness in children 3 to less than 5 years of age compared with children 5 to less than 7 years of age for severe amblyopia (P = .09). CONCLUSIONS Amblyopia is more responsive to treatment among children younger than 7 years of age. Although the average treatment response is smaller in children 7 to less than 13 years of age, some children show a marked response to treatment.

Risk of amblyopia recurrence after cessation of treatment.

BACKGROUND Although amblyopia can be successfully treated with patching or atropine, there have been few prospective studies of amblyopia recurrence once treatment is discontinued. METHODS We enrolled 156 children with successfully treated anisometropic or strabismic amblyopia (145 completed follow-up), who were younger than 8 years of age and who received continuous amblyopia treatment for the previous 3 months (prescribed at least 2 hours of daily patching or prescribed at least one drop of atropine per week) and who had improved at least 3 logMAR levels during the period of continuous treatment. Patients were followed off treatment for 52 weeks to assess recurrence of amblyopia, defined as a 2 or more logMAR level reduction of visual acuity from enrollment, confirmed by a second examination. Recurrence was also considered to have occurred if treatment was restarted because of a nonreplicated 2 or more logMAR level reduction of visual acuity. RESULTS Recurrence occurred in 35 (24%) of 145 cases (95% confidence interval 17% to 32%) and was similar in patients who stopped patching (25%) and in patients who stopped atropine (21%). In patients treated with moderately intense patching (6 to 8 hours per day), recurrence was more common (11 of 26; 42%) when treatment was not reduced prior to cessation than when treatment was reduced to 2 hours per day prior to cessation (3 of 22; 14%, odds ratio 4.4, 95% confidence interval 1.0 to 18.7). CONCLUSIONS Approximately one fourth of successfully treated amblyopic children experience a recurrence within the first year off treatment. For patients treated with 6 or more hours of daily patching, our data suggest that the risk of recurrence is greater when patching is stopped abruptly rather than when it is reduced to 2 hours per day prior to cessation. A randomized clinical trial of no weaning versus weaning in successfully-treated amblyopia is warranted to confirm these observational findings.

A randomized trial of atropine vs patching for treatment of moderate amblyopia: Follow-up at age 10 years

OBJECTIVE To determine the visual acuity outcome at age 10 years for children younger than 7 years when enrolled in a treatment trial for moderate amblyopia. METHODS In a multicenter clinical trial, 419 children with amblyopia (visual acuity, 20/40-20/100) were randomized to patching or atropine eyedrops for 6 months. Two years after enrollment, a subgroup of 188 children entered long-term follow-up. Treatment after 6 months was at the discretion of the investigator; 89% of children were treated. MAIN OUTCOME MEASURE Visual acuity at age 10 years with the electronic Early Treatment Diabetic Retinopathy Study test. APPLICATION TO CLINICAL PRACTICE Patching and atropine eyedrops produce comparable improvement in visual acuity that is maintained through age 10 years. RESULTS The mean amblyopic eye acuity, measured in 169 patients, at age 10 years was 0.17 logMAR (logarithm of the minimum angle of resolution) (approximately 20/32), and 46% of amblyopic eyes had an acuity of 20/25 or better. Age younger than 5 years at entry into the randomized trial was associated with a better visual acuity outcome (P < .001). Mean amblyopic and sound eye visual acuities at age 10 years were similar in the original treatment groups (P = .56 and P = .80, respectively). CONCLUSIONS At age 10 years, the improvement of the amblyopic eye is maintained, although residual amblyopia is common after treatment initiated at age 3 years to younger than 7 years. The outcome is similar regardless of initial treatment with atropine or patching.

Photorefractive keratectomy in children

Purpose: To evaluate photorefractive keratectomy (PRK) in pediatric patients who fail traditional methods of treatment for myopic anisometropic amblyopia and high myopia. Setting: Nonhospital surgical facility with follow‐up in a hospital clinic setting. Methods: Photorefractive keratectomy was performed in 40 eyes of 27 patients. The patients were divided into 4 groups based on the type of myopia: myopic anisometropic amblyopia (15 eyes/13 patients), bilateral high myopia (20 eyes/10 patients), high myopia post‐penetrating keratoplasty (3 eyes/2 patients), and combined corneal scarring and anisometropic amblyopia (2 eyes/2 patients). All procedures were performed under general anesthesia using the VISX 20/20 B laser and a multizone, multipass ablation technique. Appropriate corneal fixation was achieved with appropriate head positioning (turn and tilt) and an Arrowsmith fixation ring. Myopia was as high as −25.00 diopter (D) spherical equivalent (SE), but no treatment was for more than −17.50 D SE. Results: The mean SE decreased from −10.68 D to −1.37 D at 1 year, a mean change of −9.31 D. At 1 year, the mean best corrected visual acuity improved from 20/70 to 20/40 in the entire group. Forty percent of eyes were within ±1.0 D of the targeted refraction. There was no haze in 59.5% of eyes. Three eyes initially had 3+ haze; 1 improved to 2+ and 2 required repeat PRK with significant haze reduction. Five eyes (3 patients) with greater than −17.00 D SE myopia before PRK (range −17.50 to −25.00 D) had 3.42 D more effect than predicted (range 0.50 to 5.50 D). A functional vision survey demonstrated a positive effect on the childrens ability to function in their environments after the laser treatment. Conclusion: Photorefractive keratectomy in children represents another method of providing long‐term resolution of bilateral high myopia and myopic anisometropic amblyopia.

Surgical outcomes of primary foldable intraocular lens implantation in children: understanding posterior opacification and the absence of glaucoma.

PURPOSE: To evaluate visual and stereoscopic performance after pediatric cataract extraction with intraocular lens (IOL) implantation performed by the same surgeon over 24 years and to review the complications. SETTING: The Alberta Childrens Hospital, Calgary, Alberta, Canada. METHODS: This retrospective review comprised children aged 1 month to 18 years who had small‐incision cataract extraction with foldable posterior chamber IOL implantation from 1995 to 2008. RESULTS: The postoperative follow‐up was 6 months to 12 years. Posterior capsule opacification (PCO) requiring secondary surgical membranectomy developed in 22.7% of the children. Younger children developed PCO more often than older children. The PCO rate was 70.8% in children younger than 1 year and decreased steadily to 6.1% in children older than 7 years. The mean onset of PCO was 6.1 months postoperatively. Other complications were vitreous tags (12.0%), IOL dislocation (4.7%), and loose corneal sclera sutures (2.7%). Of the eyes in which vision could be recorded, 89.5% had improved corrected visual acuity, with no eye losing acuity. Stereopsis was present in 35% of testable children preoperatively and 91% postoperatively. CONCLUSIONS: Cataract surgery in children younger than 2 years should be considered a 2‐stage procedure in view of the higher incidence of PCO. Secondary glaucoma decreased significantly when surgery was performed after 30 days of age and the eye was left pseudophakic after surgery. Further improvements in IOL design, surgical instrumentation, and implantation techniques will continue to improve the ability to visually rehabilitate children.

Laser-assisted subepithelial keratectomy for anisometropic amblyopia in children: outcomes at 1 year.

PURPOSE: To assess the refractive, visual acuity, and binocular results of laser‐assisted subepithelial keratectomy (LASEK) for anisomyopia, anisohyperopia, and anisoastigmatia in children with various levels of amblyopia secondary to the anisometropic causes. SETTING: Nonhospital surgical facility with follow‐up in a hospital clinic setting. METHODS: This retrospective review was of 53 children with anisometropia who had LASEK to correct the refractive difference between eyes. All LASEK procedures were performed using general anesthesia. Patients were divided into 3 groups according to their anisometropia as follows: myopic difference greater than 3.00 diopters (D), astigmatic difference greater than 1.50 D, and hyperopic difference greater than 3.50 D. The children were followed for at least 1 year, and their refractive status, visual acuity, and binocular vision were assessed and recorded at 2 and 6 months as well as 1 year. RESULTS: The mean age at treatment was 8.4 years (range 10 months to 16 years). The mean preoperative anisometropic difference was 6.98 D in the entire group, 9.48 D in the anisomyopic group, 3.13 D in the anisoastigmatic group, and 5.50 D in the anisohyperopic group. One year after LASEK, the mean anisometropic difference decreased to 1.81 D, 2.43 D, 0.74 D, and 2.33 D, respectively, and 54% of all eyes were within ±1.00 D of the fellow eye, 68% were within ±2.00 D, and 80% were within ±3.00 D. Preoperative visual acuity and binocular vision could be measured in 33 children. Postoperatively, 63.6% of children had an improvement in best corrected visual acuity (BCVA) and the remainder had no noted change. No patient had a reduction in BCVA or a loss in fusional ability after LASEK. Of the 33 children, 39.4% had positive stereopsis preoperatively and 87.9% had positive stereopsis 1 year after LASEK. CONCLUSION: Laser‐assisted subepithelial keratectomy is an effective surgical alternative to improve visual acuity in anisometropic children unable to tolerate conventional methods of treatment or in whom these methods fail.

Postoperative Glaucoma Following Infantile Cataract Surgery: An Individual Patient Data Meta-analysis

IMPORTANCE Infantile cataract surgery bears a significant risk for postoperative glaucoma, and no consensus exists on factors that may reduce this risk. OBJECTIVE To assess the effect of primary intraocular lens implantation and timing of surgery on the incidence of postoperative glaucoma. DATA SOURCES We searched multiple databases to July 14, 2013, to identify studies with eligible patients, including PubMed, MEDLINE, EMBASE, ISI Web of Science, Scopus, Central, Google Scholar, Intute, and Tripdata. We also searched abstracts of ophthalmology society meetings. STUDY SELECTION We included studies reporting on postoperative glaucoma in infants undergoing cataract surgery with regular follow-up for at least 1 year. Infants with concurrent ocular anomalies were excluded. DATA EXTRACTION AND SYNTHESIS Authors of eligible studies were invited to contribute individual patient data on infants who met the inclusion criteria. We also performed an aggregate data meta-analysis of published studies that did not contribute to the individual patient data. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Time to glaucoma with the effect of primary implantation, additional postoperative intraocular procedures, and age at surgery. RESULTS Seven centers contributed individual patient data on 470 infants with a median age at surgery of 3.0 months and median follow-up of 6.0 years. Eighty patients (17.0%) developed glaucoma at a median follow-up of 4.3 years. Only 2 of these patients had a pseudophakic eye. The risk for postoperative glaucoma appeared to be lower after primary implantation (hazard ratio [HR], 0.10 [95% CI, 0.01-0.70]; P = .02; I(2) = 34%), higher after surgery at 4 weeks or younger (HR, 2.10 [95% CI, 1.14-3.84]; P = .02; I(2) = 0%), and higher after additional procedures (HR, 2.52 [95% CI, 1.11-5.72]; P = .03; I(2) = 32%). In multivariable analysis, additional procedures independently increased the risk for glaucoma (HR, 2.25 [95% CI, 1.20-4.21]; P = .01), and primary implantation independently reduced it (HR, 0.10 [95% CI, 0.01-0.76]; P = .03). Results were similar in the aggregate data meta-analysis that included data from 10 published articles. CONCLUSIONS AND RELEVANCE Although confounding factors such as size of the eye and surgeon experience are not accounted for in this meta-analysis, the risk for postoperative glaucoma after infantile cataract surgery appears to be influenced by the timing of surgery, primary implantation, and additional intraocular surgery.

Paediatric pseudophakia: analysis of intraocular lens power and myopic shift

Background:  At the Alberta Children’s Hospital, the authors have been performing paediatric cataract extraction with intraocular lens (IOL) implant for over 10 years. The authors examined the amount of myopic shift that occurs in various age groups and cataract types, in order to evaluate the success of predicting the appropriate power of IOL to implant.