Norman A. Zabriskie

CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD

Background Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear. Methods and Findings We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). Conclusion Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case–control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 × 10−3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10−8; and Boston: P = 2.1 × 10−2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.

A comparison of patient comfort during cataract surgery with topical anesthesia versus topical anesthesia and intracameral lidocaine

OBJECTIVE To determine whether intraocular lidocaine increases patient comfort during cataract surgery while under topical anesthesia. DESIGN Prospective, randomized, double-masked, placebo-controlled clinical trial. PARTICIPANTS Both men and women between 45 and 85 years of age who were scheduled for elective cataract surgery while under topical anesthesia participated. Sixty-eight patients were randomized to each group. INTERVENTION Patients were randomized to receive either topical anesthesia plus intracameral 1% preservative-free lidocaine or intracameral balanced salt solution. MAIN OUTCOME MEASURES Patient assessment of pain during delivery of the anesthesia, surgery, and after surgery using a visual analog pain scale was measured. Patients also recorded the degree to which they were bothered by tissue manipulation and the microscope light. Surgeon assessments of operative conditions, patient cooperation, and intraoperative complications were recorded. The attending anesthesiologist recorded any required supplemental intravenous sedation and any increase in pulse or increase in blood pressure. RESULTS There was no significant difference in patient-reported pain scores for delivery of anesthesia (P = 0.902), surgery (P = 0.170), or after surgery (P = 0.680). Patients in the lidocaine group reported being less bothered by tissue manipulation (P = 0.021). The surgeon assessment showed more patient cooperation in the lidocaine group (P = 0.043). CONCLUSIONS Both topical anesthesia alone and topical anesthesia plus intracameral lidocaine provide good operative conditions for the surgeon and comfortable surgical circumstances for the patient. Injection of intraocular lidocaine increases patient cooperation and decreases the degree to which patients are bothered by tissue manipulation, two outcomes that justify its use.

HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA . This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

Apparent central nervous system depression in infants after the use of topical brimonidine

PURPOSE To report two cases in which topical brimonidine resulted in apparent central nervous system depression and unresponsiveness in an infant. METHODS Review of two patients. An 11-day-old infant became lethargic and apneic after a single drop of brimonidine. These symptoms were reproduced after a second administration of brimonidine. A 5-month-old infant became lethargic and poorly responsive after receiving 1 drop of brimonidine in each eye. RESULTS The first patient required admission to the hospital for medical stabilization. He recovered without sequelae. The second patient recovered spontaneously approximately 2.5 hours after administration of brimonidine. CONCLUSIONS Topical brimonidine may be associated with central nervous system depression in infants. The use of brimonidine is not recommended in these patients until further data are available.

Genetic association of LOXL1 gene variants and exfoliation glaucoma in a Utah cohort.

Exfoliation glaucoma (XFG) is the commonest identifiable cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar proteins in the anterior segment of the eye. We investigated LOXL1 gene variants previously identified to confer susceptibility to exfoliation glaucoma (XFG) in a Utah Caucasian cohort. After a standard eye examination protocol we genotyped SNPs rs2165241 and rs3825942 in 62 XFG or XFS patients and 170 normal controls. Genotype frequency distribution, odds ratios (ORs), and population attributable risks were calculated for the risk alleles. The SNP rs2165241 was significantly associated with XFG and XFS (p=4.13x10-9 for an additive model, ORhet=4.42 (2.30-8.50), ORhom=34.19 (4.48-261.00); T allele: 83.1% in cases versus 52.4% in controls). Significant association was also found for rs3825942: (p=1.89x10-6). Our findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XFG. This information will potentially guide glaucoma monitoring efforts by targeting individuals whose genetic profiles put them at higher risk for XFG.

Anterior Lens Capsule Rupture Caused by Air Bag Trauma

PURPOSE To report a child with anterior lens capsule rupture caused by air bag inflation. METHODS A 10-year-old girl sustained a rupture of the right anterior lens capsule secondary to air bag deployment during a minor automobile accident. The evaluation included orbital ultrasound and orbital computed tomography. RESULT The right eye underwent lens aspiration with intraocular lens placement. Postoperatively, the patient did well with 20/25 best-corrected visual acuity. CONCLUSION Our case, in which the patients lens capsule was ruptured by air bag inflation, illustrates that air bag deployment, even in minor low-speed accidents, can cause severe blunt trauma to the eye.

A comparison of topical and retrobulbar anesthesia for trabeculectomy.

PurposeTo compare the safety and efficacy of topical versus retrobulbar anesthesia for primary trabeculectomy MethodsA prospective study of 36 consecutive patients undergoing trabeculectomy who were randomized to receive topical (n = 18) or retrobulbar (n = 18) anesthesia. Operating conditions, patient comfort, and surgical outcome were evaluated. SettingsTertiary-care university hospital ambulatory surgical center. ResultsThere were no differences in operating conditions (P = 0.14), pain during (P = 0.54) or after (P = 0.76) surgery, or supplemental anesthesia required (P = 0.34) between the two groups. Very few patients in either group were bothered by touch sensation, tissue manipulation, or the microscope light. Chemosis, subconjunctival hemorrhage and eyelid hemorrhage were seen exclusively in the retrobulbar group (P <0.03), and were all attributable to the injection. Inadvertent eye movement was present more frequently in the topical group (P = 0.01), although this did not pose a problem to the surgeon. No surgical complications were encountered in either group. ConclusionTopical anesthesia is a safe and effective alternative to retrobulbar anesthesia for primary trabeculectomy.

Topical versus retrobulbar anesthesia for combined phacotrabeculectomy: prospective randomized study

Purpose: To compare the safety and efficacy of topical and retrobulbar anesthesia for combined phacotrabeculectomy. Setting: Tertiary‐care university hospital ambulatory surgical center. Methods: In this prospective study, 40 consecutive patients having combined phacotrabeculectomy were randomized to receive topical (n = 20) or retrobulbar (n = 20) anesthesia. Operating conditions, patient comfort, and surgical outcome were evaluated. Results: There was no significant between‐group difference in operating conditions (P = .56), pain during (P = .41) or after (P = .23) surgery, or supplemental anesthesia required (P = .49). Few patients in either group were bothered by tissue manipulation or the microscope light, although more patients in the topical group were slightly bothered by touch sensation (P = .05). Chemosis, subconjunctival hemorrhage, and eyelid hematoma were seen almost exclusively in the retrobulbar group (P < .05). Inadvertent eye movement was present more frequently in the topical group (P = .04), although this did not pose a problem to the surgeon. Conclusion: Topical anesthesia is a safe and effective alternative to retrobulbar anesthesia for combined phacotrabeculectomy.

Comparison of brimonidine/ latanoprost and timolol/ dorzolamide: Two randomized, double-masked, parallel clinical trials

Two double-masked, randomized, parallel, multicenter trials of similar design were conducted to compare the IOP-lowering efficacy of dual therapy with brimonidine 0.2% and latanoprost 0.005% with the fixed combination of timolol 0.5%/dorzolamide 2% in patients with glaucoma or ocular hypertension. The combination of brimonidine and latanoprost produced significantly greater mean IOP reductions at each visit in both trials. In study 1, the mean reduction at peak drug effect after 6 weeks was 9.2 mm Hg (34.7%) with brimonidine and latanoprost and 6.7 mm Hg (26.1%) with timolol/dorzolamide (P=.024); respective reductions at week 12 were 9.0 mm Hg (33.9%) and 6.5 mm Hg (25.3%) (P=.044). At the month 1 visit in study 2, the mean peak IOP reduction was 10.6 mm Hg (39.0%) with dual therapy and 6.3 mm Hg (25.1%) with the fixed combination (P=.001). After 3 months, reductions were 9.1 mm Hg (33.4%) and 6.6 mm Hg (26.3%) (P=.047). In these studies, the combination of brimonidine and latanoprost provided IOP control superior to that of the fixed combination of timolol/dorzolamide.