Kuldev Singh

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Aqueous Shunts in Glaucoma: A Report by the American Academy of Ophthalmology

OBJECTIVE To provide an evidence-based summary of commercially available aqueous shunts currently used in substantial numbers (Ahmed [New World Medical, Inc., Rancho Cucamonga, CA], Baerveldt [Advanced Medical Optics, Inc., Santa Ana, CA], Krupin [Eagle Vision, Inc, Memphis, TN], Molteno [Molteno Ophthalmic Ltd., Dunedin, New Zealand]) to control intraocular pressure (IOP) in various glaucomas. METHODS Seventeen previously published randomized trials, 1 prospective nonrandomized comparative trial, 1 retrospective case-control study, 2 comprehensive literature reviews, and published English language, noncomparative case series and case reports were reviewed and graded for methodologic quality. RESULTS Aqueous shunts are used primarily after failure of medical, laser, and conventional filtering surgery to treat glaucoma and have been successful in controlling IOP in a variety of glaucomas. The principal long-term complication of anterior chamber tubes is corneal endothelial failure. The most shunt-specific delayed complication is erosion of the tube through overlying conjunctiva. There is a low incidence of this occurring with all shunts currently available, and it occurs most frequently within a few millimeters of the corneoscleral junction after anterior chamber insertion. Erosion of the equatorial plate through the conjunctival surface occurs less frequently. Clinical failure of the various devices over time occurs at a rate of approximately 10% per year, which is approximately the same as the failure rate for trabeculectomy. CONCLUSIONS Based on level I evidence, aqueous shunts seem to have benefits (IOP control, duration of benefit) comparable with those of trabeculectomy in the management of complex glaucomas (phakic or pseudophakic eyes after prior failed trabeculectomies). Level I evidence indicates that there are no advantages to the adjunctive use of antifibrotic agents or systemic corticosteroids with currently available shunts. Too few high-quality direct comparisons of various available shunts have been published to assess the relative efficacy or complication rates of specific devices beyond the implication that larger-surface-area explants provide more enduring and better IOP control. Long-term follow-up and comparative studies are encouraged.

Trabeculectomy with intraoperative mitomycin C versus 5-Fluorouracil: Prospective randomized clinical trial

OBJECTIVE To evaluate the relative efficacy and safety of 5-fluorouracil (5-FU) and mitomycin C (MMC) when used as adjuncts with primary trabeculectomy in eyes not at high risk for failure. DESIGN Prospective multicenter, randomized clinical trial. PARTICIPANTS One hundred thirteen patients with primary open-angle, pseudoexfoliative, pigmentary, or angle-closure glaucoma undergoing primary trabeculectomy were recruited. METHODS One eye of each patient was randomized to receive either 5-FU (50 mg/ml for 5 minutes) or MMC (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES Intraocular pressure (IOP), visual acuity, complications, and interventions were documented at fixed intervals after surgery. The study also examined progression of visual field loss, long-term complications, and bleb appearance 3 years after surgery. RESULTS Of the 108 patients with complete perioperative information, 54 eyes received 5-FU and 54 received MMC. The proportion of patients reaching different predefined target IOPs after surgery was slightly higher in the MMC group than in the 5-FU group. This difference was less than 25%, which would have been necessary to achieve statistical significance with a power of 0.8 and the sample size used. Likewise, there was no statistically significant difference between the groups with regard to mean preoperative IOP, complications, or interventions. Mean postoperative follow-up was 309 and 330 days in the 5-FU and MMC groups, respectively (P = 0.593). CONCLUSIONS 5-Fluorouracil and MMC were found to be equally safe and effective adjuncts to primary trabeculectomy in the short- and medium-term postoperative periods.

Novel Glaucoma Procedures: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. DESIGN Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA). METHODS Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. MAIN OUTCOME MEASURES These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence. RESULTS All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. CONCLUSIONS The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.

The effect of cataract extraction on intraocular pressure.

Purpose of review To review the current ophthalmic literature regarding the impact of modern cataract surgery on intraocular pressure (IOP). Recent findings Many articles in the literature demonstrate a modest, long-lasting decrease in IOP following phacoemulsification and posterior chamber intraocular lens implantation in patients with primary open-angle glaucoma and ocular hypertension. The mechanism of this average pressure-lowering effect has yet to be elucidated. The IOP reductions obtained in patients with angle closure glaucoma are often more pronounced than those seen in patients with open angles. Patients with higher levels of preoperative IOP obtain greater average reductions in IOP, although this phenomenon may partially be explained by a statistical effect known as regression to the mean. Summary Although it is well recognized that phacoemulsification may result in a modest sustained reduction in IOP, there are several limitations in the studies that have assessed the magnitude of this effect. The implications of such IOP reduction with cataract surgery on the medical and surgical algorithms for care in patients with open-angle glaucoma and coexistent cataract remain unclear. In contrast, the substantial benefits of cataract surgery in patients with acute and chronic angle-closure glaucoma have been well studied and are generally widely accepted. An improved understanding of the pathophysiological mechanisms of IOP lowering after cataract extraction may help us better predict which patients are most likely to benefit from simple cataract extraction, obviating the need for combined cataract and glaucoma surgical procedures in such circumstances.

Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery

PURPOSE To determine the efficacy of reducing conjunctival bacterial flora with topical ofloxacin when given for 3 days compared with 1 hour before surgery. DESIGN Prospective, randomized, controlled trial. PARTICIPANTS Ninety-two eyes from 89 patients were randomized to a control group (48 eyes) or study group (44 eyes). METHODS All patients from both groups received topical ofloxacin 0.3% 1 hour before surgery and a 5% povidone iodine scrub of the periorbital area before surgery. The patients in the study group received additional ofloxacin four times daily for 3 days before surgery. MAIN OUTCOME MEASURES Conjunctival cultures were obtained at five separate time points and were inoculated in solid and liquid culture media. The presence of bacteria was determined, quantified, and identified. RESULTS Forty-two percent of eyes in the control group had positive conjunctival culture immediately before surgery, compared with 19% of eyes in the study group (P < 0.05). Immediately after surgery, 34% and 14% of eyes had positive cultures in the control and study groups, respectively (P < 0.05). Quantitatively, fewer bacteria were isolated from eyes in the study group compared with those in the control group for culture samples that were obtained both before povidone iodine scrub and at the conclusion of surgery (P </= 0.05). CONCLUSIONS The application of topical ofloxacin for 3 days before surgery appears to be more effective in eliminating bacteria from the conjunctiva than an application of ofloxacin 1 hour before surgery.

Cyclophotocoagulation: A report by the American Academy of Ophthalmology

OBJECTIVE This document describes cyclophotocoagulation procedures for glaucoma and examines the evidence to answer key questions about patient selection, and efficacy of transscleral and endoscopic techniques. METHODS A literature search conducted for the years 1968 to 2000 retrieved 130 citations. The author reviewed 34 of these articles and selected 19 for the panel methodologist to review and rate according to the strength of evidence. A Level I rating is assigned to properly conducted, well-designed, randomized clinical trials; a Level II rating is assigned to well-designed cohort and case-control studies; and a Level III rating is assigned to case series and poorly designed prospective and retrospective studies, including case-control studies. RESULTS The predominant problem with all studies on cyclophotocoagulation is the lack of a uniform definition of success, which makes comparisons difficult. One randomized controlled trial (Level I evidence) compared the efficacy of transscleral cyclophotocoagulation with noncontact Nd:YAG and semiconductor diode laser. It found no significant difference between the two, although a significant problem was the variability allowed with laser parameters. Most of the literature consists of noncomparative case series that provide evidence that is limited and often not convincing. CONCLUSION Cyclophotocoagulation is indicated for patients with refractory glaucoma who have failed trabeculectomy or tube shunt procedures, patients with minimal useful vision and elevated intraocular pressure, and patients who have no visual potential and need pain relief (based on Level III evidence). It may be useful for patients whose general medical condition precludes invasive surgery or who refuse more aggressive surgery (i.e., filter or tube). It is also useful in emergent situations, such as the acute onset of neovascular glaucoma. There is insufficient evidence to definitively compare the relative efficacy of the cyclophotocoagulation procedures for glaucoma. It is the panels opinion, however, that semiconductor diode systems appear to possess the best combination of effectiveness (based on Level III evidence), portability, expense, and ease of use at this time.

A Prospective Trial of Intraoperative Fluorouracil During Trabeculectomy in a Black Population

In a study population of black Africans with advanced glaucoma in Ghana we conducted a prospective study of intraoperative 5-fluorouracil alone. Eyes undergoing trabeculectomy were randomly selected either to receive or not receive a single intraoperative application of 5-fluorouracil (50 mg/ml for five minutes). Fifty-five eyes had a mean follow-up of 282 days (minimum, 92 days). Twenty of 24 eyes (83%) in the 5-fluorouracil group vs 12 of 31 eyes (39%) in the control group had postoperative intraocular pressure of 20 mm Hg or less with or without medical therapy (P = .01). Eleven of 24 eyes (46%) in the 5-fluorouracil group and five of 31 eyes (16%) in the control group had intraocular pressure of 15 mm Hg or less (P = .02). Without medical therapy, 17 of 24 eyes (71%) in the 5-fluorouracil group and ten of 31 eyes (32%) in the control group had intraocular pressure of 20 mm Hg or less (P = .02). The overall complications were similar in the two groups. In this population, intraoperative 5-fluorouracil markedly improved the ability of trabeculectomy to lower intraocular pressure. We recommend that intraoperative 5-fluorouracil be considered in glaucoma surgery with poor prognosis as an alternative to postoperative subconjunctival injections when multiple injections are not feasible.

Automated perimetry: A report by the American academy of ophthalmology

OBJECTIVE The purpose of this document is to summarize and evaluate the effectiveness of new automated perimetry tests and algorithms in diagnosing glaucoma and detecting disease progression. METHODS A literature search on automated perimetry retrieved over 300 citations from 1994 to 2001, of which 71 were selected as relevant to this assessment. The quality of the evidence obtained from these studies was assessed by the methodologist. RESULTS The four automated perimetry techniques described in this assessment are short wavelength automated perimetry (SWAP), frequency doubling technology perimetry (FDT), high-pass resolution perimetry (HPRP), and motion automated perimetry (MAP). The algorithms described are Swedish interactive threshold algorithm (SITA) and SITA fast. With the exception of SWAP, these techniques and algorithms reduce testing time and inconsistent patient performance when compared with conventional full threshold testing. CONCLUSIONS Short wavelength automated perimetry detected visual field loss earlier than standard threshold automated perimetry, with a sensitivity and specificity of about 88% and 92% respectively. However, it is a lengthy, demanding test, is sensitive to media opacities, and has a greater magnitude of long-term fluctuation compared with standard threshold automated perimetry, which make it difficult to assess disease progression accurately. When compared to standard threshold automated perimetry, FDT perimetry showed sensitivity and specificity greater than 97% for detecting moderate and advanced glaucoma, and sensitivity of 85% and specificity of 90% for early glaucoma. As FDT perimetry has a short testing time and is resistant to blur and pupil size, it may be a useful screening tool. In a longitudinal study, high-pass resolution perimetry was more effective than standard threshold automated perimetry in monitoring progressive glaucomatous loss, detecting progression at a median of 12 months earlier in 54% of patients studied. Motion automated perimetry demonstrated usefulness in detecting early glaucomatous visual loss in a longitudinal study. Studies on SITA demonstrated greater sensitivity and reproducibility and less intertest variability when compared to standard full threshold testing and a 50% reduction in testing times. A study comparing standard full threshold, SITA, and SITA fast found a sensitivity of 95% for the first two techniques and 93% for SITA fast. Long-term follow-up studies are needed to assess the ability of these techniques to detect progression of glaucoma over time.

Trabeculectomy With Intraoperative 5-Fluorouracil vs Mitomycin C

PURPOSE To compare the effectiveness of intraoperative 5-fluorouracil (5-FU) and mitomycin C used adjunctively with trabeculectomy in a black West African population. METHODS Eighty-five consecutive eyes of 85 black patients undergoing primary trabeculectomy for open-angle glaucoma were prospectively randomly assigned to receive either 5-FU (50 mg/ml for 5 minutes) or mitomycin C (0.5 mg/ml for 3 1/2 minutes) intraoperatively by soaked sponge. RESULTS Of the 81 eyes with at least a 3-month postoperative follow-up, 41 of 44 (93.2%) in the mitomycin C group and 27 of 37 (73.0%) in the 5-FU group had a final intraocular pressure of less than 21 mm Hg (P = .01). Twenty-eight of 44 eyes (63.6%) in the mitomycin C group and 18 of 37 (51.4%) in the 5-FU group had a final intraocular pressure of less than 15 mm Hg (P = .26). Mean postoperative intraocular pressure was 13.7 mm Hg in the mitomycin C group and 16.3 mm Hg in the 5-FU group (P = .05). There were no differences between the two groups in mean age, preoperative intraocular pressure, postoperative visual acuity, and complications. Mean follow-up was 10.0 +/- 4.41 months (range, 4 to 19 months). CONCLUSIONS The adjunctive use of mitomycin C with trabeculectomy is equally safe and more efficacious compared to 5-FU in this West African population. Use of mitomycin C in this study was not associated with a statistically significantly greater proportion of patients achieving low intraocular pressure (less than 15 mm Hg) compared to 5-FU.