Category: Peer-reviewed

Ultrasound Biomicroscopy of the Ciliary Body in Ocular/Oculodermal Melanocytosis

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Purpose: To describe the ultrasound biomicroscopy (UBM) findings of the ciliary body in patients with ocular/oculodermal melanocytosis.Design: Retrospective observational case series study.Methods: A retrospective chart and imaging database review was conducted for patients with unilateral ocular/oculodermal melanocytosis who underwent UBM examination at the Ocular Oncology Clinic of Princess Margaret Hospital. Radial images of the ciliary body at the 3-, 6-, 9-, and 12-o’clock positions were obtained in both eyes. UBM characteristics included ciliary body thickness and reflectivity. The eye with ocular/oculodermal melanocytosis was compared with the contralateral unaffected eye as a control. Statistical significance was analyzed with Student t test.Results: Twelve patients were included. All patients showed unilateral diffuse pigmentation involving episclera and anterior chamber angle. The iris showed diffuse pigmentation in 10 cases and sectorial in 2. Mean ciliary body thickness of the affected eyes was 0.581 ± 0.058 mm (range 0.489-0.744) compared with 0.475 ± 0.048 mm (range 0.406-0.622) in the contralateral eye, which was found to be a statistically significant difference (P < .001). The affected ciliary body showed hyperreflectivity when compared with the unaffected eye. All affected eyes were graded as medium to high reflectivity compared with the unaffected eyes that showed a medium to medium/low reflectivity.Conclusion: Ciliary body involvement in ocular/oculodermal melanocytosis presents as increased thickness and higher ultrasound reflectivity on UBM when compared with the unaffected eye. UBM is helpful in imaging clinically undetectable areas of melanocytosis involving the ciliary body.

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Surgical Outcomes of Medial Rectus Recession in Esotropia with Cerebral Palsy

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Purpose:
To determine the outcome of a reduced amount of medial rectus (MR) muscle recession in esotropes with cerebral palsy (CP) and to compare the surgical response with that of normal controls.

Design:
Retrospective cohort study.

Participants:
Thirty esotropes with CP and 60 age-matched esotropes without CP who underwent a unilateral or bilateral MR muscle recession.

Methods:
The surgical amount of MR muscle recession was reduced by 1 mm per muscle in patients with CP.

Main Outcome Measures:
Success rates, surgical response, cumulative probabilities of success, and factors affecting surgical responses evaluated by generalized linear mixed models.

Results:
In patients with CP, the initial success rate was higher (P = 0.037) and the rate of undercorrection was lower (P = 0.037) compared with patients without CP. At the final visit, success rates were not significantly different between both groups. However, the rate of overcorrection was higher (P = 0.003) compared with patients without CP. The rate of overcorrection per person-year during follow-up was 11% in patients with CP and 2% in patients without CP. Patients with CP showed a greater surgical response than did those without CP, at about 1.3 prism diopters per millimeter of MR muscle recession (P<0.001).

Conclusions:
Even with the reduced amount of recession, esotropes with CP showed a greater surgical response to MR muscle recession than did those without CP, and the incidence of late overcorrection was significantly higher compared with that of patients without CP.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Reversal of Lamina Cribrosa Displacement after Intraocular Pressure Reduction in Open-Angle Glaucoma

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Purpose:
To compare the change in lamina cribrosa (LC) displacement in response to intraocular pressure (IOP) lowering in patients with open-angle glaucoma (OAG) using spectral-domain optical coherence tomography (SD-OCT).

Design:
Observational case series.

Participants:
One hundred eyes of 100 patients with OAG in whom IOP at the follow-up examination had decreased by at least 20% compared with the baseline IOP.

Methods:
Serial horizontal B-scan images of the optic nerve head (ONH) were obtained from each eye using enhanced depth imaging SD-OCT. Approximately 65 B-scans covering the optic discs were obtained before and 3 to 6 months after lowering IOP. The baseline and follow-up LC depths (the distance from the Bruch’s membrane opening plane to the level of the anterior LC surface) were measured in B-scan images from each eye.

Main Outcome Measures:
The mean and maximum amount of reductions in LC depth measured in the 7 selected B-scan images.

Results:
Intraocular pressure decreased from 21.2±9.1 to 10.5±2.6 mmHg. The percent of IOP reduction was significantly related to the untreated IOP (P < 0.001). There was a significant decrease in the LC depth at the follow-up examination compared with the baseline value (P < 0.001). The magnitude of LC depth reduction was significantly associated with younger age, higher untreated IOP, higher baseline IOP, and greater percent of IOP reduction (all P < 0.02).

Conclusions:
Reversal of the LC displacement was observed after IOP-lowering treatment in OAG. The degree of LC displacement reversal was related to the amount of IOP lowering.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Null CYP1B1 Genotypes in Primary Congenital and Nondominant Juvenile Glaucoma

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Purpose:
To assess the mutation spectrum, enzymatic activity, and phenotypic features associated with CYP1B1 genotypes in primary congenital glaucoma (PCG) and nondominant juvenile glaucoma (ndJG).

Design:
CYP1B1 genotyping, segregation analysis, and functional evaluation of mutations in a cohort of patients.

Participants:
A total of 177 probands clinically diagnosed with PCG (161) or ndJG (16).

Methods:
Automatic DNA sequencing of the promoter (−1 to −867) and the 3 CYP1B1 exons. CYP1B1 enzymatic activity was evaluated using an ethoxyresorufin O-deethylation assay in transfected HEK-293T cells.

Main Outcome Measures:
Screening and functional evaluation of CYP1B1 mutations. Glaucoma diagnosis based on slit-lamp examination, measurement of intraocular pressure, gonioscopy, and fundus examination.

Results:
Thirty-one different mutations were identified in 56 PCG and 7 ndJG index cases. To the best of our knowledge, 3 of the identified mutations were novel (−337G>T, F123L, and I399_P400del). Approximately 56% of all mutation carriers were compound heterozygotes, 25% were homozygotes, and both groups inherited glaucoma as an autosomal recessive trait. Nineteen percent of carriers were heterozygotes and showed non-Mendelian segregation. In vitro and inferred functional analysis showed that no less than approximately 74% of the recessive genotypes result in null enzymatic activity. We detected variable expressivity in relation to age of onset and a possible case of incomplete penetrance in 3 of 6 families (50%), with more than 1 affected child or more than 1 subject carrying 2 CYP1B1 mutant alleles. Altogether, these data support that PCG is not a simple monogenic disease. In addition, most patients with PCG carrying null or putative null genotypes showed severe bilateral phenotypes featured by early disease onset, frequently at birth. The mean number of trabeculectomies per eye was significantly higher in carriers than in noncarriers.

Conclusions:
This is the largest analysis of CYP1B1 mutations performed in European patients with PCG to date. Our data show that null CYP1B1 genotypes, and therefore complete absence of CYP1B1 activity, frequently lead to severe phenotypes. Our results support that CYP1B1 glaucoma is not a simple monogenic disease and that CYP1B1 activity levels could influence the phenotype.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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The Incidence of Rhegmatogenous Retinal Detachment in The Netherlands

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Objective:
To estimate the incidence and characteristics of rhegmatogenous retinal detachment (RRD) in The Netherlands in 2009.

Design:
Retrospective, observational case series.

Participants:
All patients with RRD in the Dutch population in 2009.

Methods:
By reviewing surgical logs, cases of primary RRD repair in 2009 were identified. Exclusion criteria included RRD before 2009 and exudative, tractional, or traumatic retinal detachments. Patient demographics, date of surgery, and lens status were documented. Incidence of RRD and 95% confidence intervals (CIs) were calculated based on the Poisson distribution. Age distribution, male-to-female ratio, and proportion of RRD patients with prior cataract extraction (CE) were determined. A Student t test was used to examine differences in the incidence of RRD between groups.

Main Outcome Measures:
Annual RRD incidence in the population and per gender-adjusted age category and proportion of RRD patients with prior CE.

Results:
The annual RRD incidence was 18.2 per 100 000 people (95% CI, 11.4–18.8), with a peak incidence of 52.5 per 100 000 people (95% CI, 29.4–56.8) between 55 and 59 years of age. The Bilateral RRD rate was 1.67%. Macula-off presentation occurred in 54.5% of all RRD patients. Prior CE was noted in 33.5% of RRD eyes. The male-to-female ratio was 1.3:1, and RRD incidence was statistically significantly more frequent in males (P<0.0001).

Conclusions:
Rhegmatogenous retinal detachment is predominantly a disease of the population older than 50 years, and males are more susceptible to RRD. The annual RRD incidence is highly dependent on demographic characteristics.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Aqueous Levels of Fluocinolone Acetonide after Administration of Fluocinolone Acetonide Inserts or Fluocinolone Acetonide Implants

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Purpose:
To compare aqueous levels of fluocinolone acetonide (FAc) after administration of FAc inserts or FAc implants (Retisert; Bausch & Lomb, Rochester, NY).

Design:
Comparison of pharmacokinetics from 2 prospective, interventional, clinical trials.

Participants:
Thirty-seven patients with diabetic macular edema (DME) (Fluocinolone Acetonide in Human Aqueous [FAMOUS] Study, C-01-06-002) and 7 patients with uveitis (NA-00019318).

Methods:
Aqueous FAc was measured after administration of FAc implants or 0.2 μg/day (low dose, ILUVIEN; Alimera Sciences Inc., Alpharetta, GA) or 0.5 μg/day (high dose) FAc inserts.

Main Outcome Measures:
The primary end point was aqueous levels of FAc.

Results:
At 1 month after administration for subjects who received 1 treatment, mean aqueous FAc levels were 2.17 (low dose) and 3.03 ng/ml (high dose) for FAc inserts and 6.12 ng/ml for FAc implants with maximum levels of 3.83, 6.66, and 13.50 ng/ml, respectively. At 3 months, mean FAc levels were 1.76, 2.15, and 6.12 ng/ml, respectively. Between 6 and 36 months after low-dose inserts, aqueous levels of FAc were remarkably stable, ranging from 1.18 to 0.45 ng/ml. After high-dose inserts, mean FAc levels were stable between 6 and 24 months, ranging from 1.50 to 0.84 ng/ml and then decreasing to 0.35 ng/ml at 30 months and 0.15 ng/ml at 36 months. In implant-containing eyes, mean FAc levels remained >6 ng/ml through 15 months, the last time point with measurements from at least 6 eyes.

Conclusions:
Low- and high-dose FAc inserts both provide stable long-term release of FAc with comparable peak levels in the aqueous: slightly >2 ng/ml for approximately 3 months followed by steady-state levels between 1.0 and 0.5 ng/ml through 36 months for low-dose inserts versus levels between 1.5 and 1.1 ng/ml through 24 months for high-dose inserts. Steady-state aqueous levels after FAc implants were >6 ng/ml. These results provide new insights that aid in the interpretation of efficacy trials and indicate that there is a dose effect for steroid-induced ocular hypertension. In susceptible patients, prolonged aqueous levels of FAc >1 ng/ml moderately increased the risk of glaucoma and levels >6 ng/ml posed a markedly increase risk.

Financial Disclosure(s):
Proprietary or commercial disclosure may be found after the references.

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Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase I/II Study

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Purpose: To evaluate the safety and bioactivity of MP0112, a designed ankyrin repeat protein (DARPin) that specifically binds vascular endothelial growth factor (VEGF) in patients with diabetic macular edema (DME). DARPins are a novel class of proteins selected for specific, high-affinity binding to a target protein.Design: Phase I/II, open-label, multicenter dose-escalation trial.Methods: After a single intravitreal injection of MP0112, the main outcomes were safety assessments, aqueous MP0112 levels, change in best-corrected visual acuity (BCVA), and foveal thickness measured by optical coherence tomography. Six cohorts were planned, but only 3 were enrolled (0.04, 0.15, 0.4 mg), because a maximally tolerated dose of 1.0 mg was identified in a parallel age-related macular degeneration trial.Results: Median aqueous concentration of MP0112 was 555 nM 1 week and >10 nM in 3 of 4 patients 12 weeks post injection of 0.4 mg. Median BCVA improvement at week 12 was 4, 6, and 10 letters in cohorts 1, 2, and 3. Ocular inflammation was observed in 11 patients (61%) and was severe in 1. High-resolution chromatography separated proinflammatory impurities from MP0112, resulting in a new formulation.Conclusions: A single intraocular injection of 0.4 mg MP0112 resulted in levels above the half-maximal inhibitory concentration and neutralization of VEGF in aqueous humor for 8-12 weeks. Despite inflammation in several patients, there was prolonged edema reduction and improvement in vision in several patients. The source of the inflammation was eliminated from a new preparation that is being tested in an ongoing clinical trial.

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Incidence of Herpes Zoster Ophthalmicus: Results from the Pacific Ocular Inflammation Study

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Purpose:
To provide a population-based estimate of the incidence of herpes zoster ophthalmicus (HZO) with comparisons across racial, sex, and age groups, as well as to estimate the frequency of postherpetic neuralgia (PHN).

Design:
Retrospective, population-based cohort study.

Participants:
All patients enrolled in the Kaiser Permanente Hawaii health plan during the study period (N = 217 061).

Methods:
All patient encounters between January 1, 2006, and December 31, 2007, in the electronic medical record of Kaiser Permanente Hawaii were queried for International Classification of Diseases, 9th edition (ICD-9) codes corresponding to HZO. Charts were reviewed to confirm a diagnosis of HZO and to collect information about specific ocular manifestations. Demographic data and information on PHN were collected electronically. Incidence rates were calculated per 100 000 person-years for the entire population and for age-, sex-, and race-specific subgroups.

Main Outcome Measures:
Clinical diagnosis of HZO during the study period.

Results:
A total of 134 cases of HZO were identified in this population of 217 061 people. The overall incidence was 30.9 per 100 000 person-years (95% confidence interval [CI], 25.9–36.6). The incidence rate for the population aged ≥65 years was 104.6 per 100 000 person-years (95% CI, 79.0–135.9), approximately 5 times the remainder of the population (P < 0.001). The most common manifestation of HZO was dermatitis, followed by keratitis and conjunctivitis. The incidence of HZO for Pacific Islanders was 19.0 per 100 000 person-years (95% CI, 12.4–28.3), which was significantly lower than the rate for non–Pacific Islanders (P = 0.007). Twenty-one percent of patients with HZO developed PHN. Older age and HZO with keratitis, conjunctivitis, or uveitis were found to be risk factors for PHN.

Conclusions:
This study provides a population-based estimate of HZO and highlights differences across various age and racial groups. It also suggests that demographic characteristics may be useful in determining the risk of developing HZO.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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The Cost–Utility of Telemedicine to Screen for Diabetic Retinopathy in India

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Purpose:
To assess the cost-effectiveness of a telemedicine diabetic retinopathy (DR) screening program in rural Southern India that conducts 1-off screening camps (i.e., screening offered once) in villages and to assess the incremental cost-effectiveness ratios of different screening intervals.

Design:
A cost–utility analysis using a Markov model.

Participants:
A hypothetical cohort of 1000 rural diabetic patients aged 40 years who had not been previously screened for DR and who were followed over a 25-year period in Chennai, India.

Methods:
We interviewed 249 people with diabetes using the time trade-off method to estimate utility values associated with DR. Patient and provider costs of telemedicine screening and hospital-based DR treatment were estimated through interviews with 100 diabetic patients, sampled when attending screening in rural camps (n = 50) or treatment at the base hospital in Chennai (n = 50), and with program and hospital managers. The sensitivity and specificity of the DR screening test were assessed in comparison with diagnosis using a gold standard method for 346 diabetic patients. Other model parameters were derived from the literature. A Markov model was developed in TreeAge Pro 2009 (TreeAge Software Inc, Williamstown, MA) using these data.

Main Outcome Measures:
Cost per quality-adjusted life-year (QALY) gained from the current teleophthalmology program of 1-off screening in comparison with no screening program and the cost–utility of this program at different screening intervals.

Results:
By using the World Health Organization threshold of cost-effectiveness, the current rural teleophthalmology program was cost-effective ($1320 per QALY) compared with no screening from a health provider perspective. Screening intervals of up to a frequency of screening every 2 years also were cost-effective, but annual screening was not (>$3183 per QALY). From a societal perspective, telescreening up to a frequency of once every 5 years was cost-effective, but not more frequently.

Conclusions:
From a health provider perspective, a 1-off DR telescreening program is cost-effective compared with no screening in this rural Indian setting. Increasing the frequency of screening up to 2 years also is cost-effective. The results are dependent on the administrative costs of establishing and maintaining screening at regular intervals and on achieving sufficient coverage.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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Topographic Correlation between β-Zone Parapapillary Atrophy and Retinal Nerve Fiber Layer Defect

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Objective:
To investigate whether a topographic correlation exists between β-zone parapapillary atrophy (PPA) and retinal nerve fiber layer (RNFL) defect. The location and extent of the β-zone were examined.

Design:
Retrospective, cross-sectional study.

Participants:
One hundred twenty-eight eyes from 128 consecutive patients with primary open-angle glaucoma (POAG) and a single localized RNFL defect were included.

Methods:
Digital optic disc photographs of the enrolled eyes were reviewed and eyes with β-zone PPA were identified. The topographic parameters of β-zone PPA and RNFL defect were measured on optic disc photographs and digital red-free RNFL photographs. The association between these parameters was examined statistically.

Main Outcome Measures:
Angular location and angular extent of β-zone PPA and RNFL defect, angular location of point of maximum radial extent (PMRE) of β-zone PPA, and β-zone PPA-to-disc area ratio.

Results:
Eighty-two (64.1%) of the 128 eyes with a single localized RNFL defect had β-zone PPA. Patients with β-zone PPA were younger (by 6.6 years) than those without β-zone PPA (P = 0.001). β-Zone PPA was located most commonly inferotemporally (65.9%). The RNFL defect was located in the same hemifield as the β-zone PPA in 76% of eyes and was located in the same hemifield as PMRE in 88% of eyes. The angular location of the RNFL defect showed a linear correlation with those of β-zone PPA (r = 0.390; P<0.001) and PMRE (r = 0.558; P<0.001). The angular extent of RNFL defect was not correlated significantly with that of β-zone PPA (P = 0.106), but it was associated weakly with β-zone PPA-to-disc area ratio (r = 0.197; P = 0.026). The angular extent of the RNFL defect also was correlated with the cup-to-disc ratio (r = 0.322; P<0.001) and the cup-to-disc area ratio (r = 0.337; P = 0.002).

Conclusions:
In POAG, a localized RNFL defect is correlated spatially with β-zone PPA.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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The p53 Codon 72 Polymorphism (rs1042522) Is Associated with Proliferative Vitreoretinopathy: The Retina 4 Project

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Purpose:
To compare the distribution of a p53 gene polymorphism among European subjects undergoing primary retinal detachment (RD) surgery in relation to the development of proliferative vitreoretinopathy (PVR).

Design:
Case-controlled gene association study conducted as a component of the Retina 4 Project (a European multicenter study).

Participants and Controls:
Five hundred fifty DNA samples, 134 with PVR secondary to primary RD and 416 with RD without PVR.

Methods:
The p53 codon 72 polymorphism (rs1042522) was analyzed using allele-specific primer polymerase chain reaction. Proportions of genotypes and the proline (Pro-P) homozygote groups between subsamples from different countries were analyzed in 2 phases. In the first, subsamples from Spain and Portugal were analyzed. After significant results were found, samples from the United Kingdom (UK) and The Netherlands were analyzed (second phase). Genotypic and allelic frequencies were compared between cases and controls in the global sample.

Main Outcome Measures:
Single significant associations with PVR.

Results:
A significant difference (P<0.05, Fisher exact test) was observed regarding the p53 genotype frequencies at codon 72 between the PVR cases and the non-PVR controls in Spain and Portugal (phase I), but not in the UK or The Netherlands (phase II). Analysis of Pro homozygote carriers between cases and controls revealed differences in Spain (29.01–42.18 and 2.29–10.20, respectively), Portugal (10.49–29.50 and 1.35–8.89, respectively), and The Netherlands (16.49–31.70 and 4.51–15.09, respectively), but no differences in the UK (7.68–18.1 and 4.85–13.94, respectively). The odds ratio of Pro carriers from Spain and Portugal together was 8.12 (95% confidence interval [CI], 3.72–17.69; P<0.05), whereas the odds ratio of Pro carriers from the UK and The Netherlands was 2.12 (95% CI, 0.96–4.68; P = 0.07). All control samples were in Hardy-Weinberg equilibrium. Considering the entire sample, significant differences were found in genotype frequencies between cases (RR, 30.59%; RP, 43.28%; PP, 26.11% [R = Arg; P = Pro]) and controls (RR, 39.66%; RP, 52.64%; PP, 7.69%) and in Pro homozygote carriers between controls (Pro homozygote 95% CI, 18.67–33.52) and cases (Pro homozygote 95% CI, 5.1–10.2).

Conclusions:
Results indicate that the Pro variant of p53 codon 72 polymorphism is associated with a higher risk of PVR developing after a primary RD. Further studies are necessary to understand the role of this polymorphism in the development of PVR.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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A Randomized, Single-Center Study of Equivalence of 2 Intraocular Lenses Used in Cataract Surgery

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Purpose:
To compare the outcomes of 2 intraocular lenses (IOLs) for the treatment of age-related cataracts.

Design:
Prospective, randomized trial.

Participants:
Patients with age-related cataracts were recruited and randomized to receive phacoemulsification and implantation of either the AcrySof SA60AT lens (Alcon, Inc, Fort Worth, TX) or the low-cost Tecsoft Flex lens (Fred Hollows Foundation, Tilganga, Nepal). A total of 300 patients were available for description and analysis (148 in the AcrySof group and 152 in the Tecsoft group).

Methods:
Patients underwent phacoemulsification and implantation of the AcrySof SA60AT lens or the Tecsoft Flex lens. They were followed up and examined at baseline, 1 week, 1 month, 6 months, and 12 months after cataract surgery.

Main Outcome Measures:
Uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (BDVA), incidence of posterior capsule opacification (PCO), Visual Function Index questionnaire results, and safety of the implanted IOLs.

Results:
No significant difference (P>0.05) was found in UDVA and BDVA after surgery between the 2 groups. The equivalence test of the 95% confidence intervals showed that both lenses had an equal improvement of UDVA and BDVA as well as similar rates of PCO after cataract surgery. There was no significant difference between the 2 groups with regard to visual functioning or the incidence of adverse surgical events during (P>0.05) or after (P>0.05) the surgery.

Conclusions:
The Tecsoft Flex IOL is a low-cost suitable alternative that is similar to the AcrySof IOL in terms of safety and visual outcomes.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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