Sukhpal S Sandhu

Variants in the VEGFA Gene and Treatment Outcome after Anti-VEGF Treatment for Neovascular Age-related Macular Degeneration

PURPOSE To determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD). DESIGN A prospective cohort study. PARTICIPANTS We included 201 consecutive patients receiving anti-VEGF injections for neovascular AMD. METHODS Patients were followed over 12 months. They were treated with 3 initial monthly ranibizumab or bevacizumab injections. Thereafter, the decision to retreat was made by clinicians at each follow-up visit on the basis of retreatment criteria. Seven tagged single nucleotide polymorphisms (tSNPs) in the VEGFA gene were selected and examined. Multivariate data analysis was used to determine the role of each tSNP in treatment outcome. MAIN OUTCOME MEASURES The influence of selected VEGFA tSNPs on visual acuity (VA) outcome at 6 months. RESULTS Mean baseline VA was 51±17 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Overall, the mean change in VA from baseline was +6.5±12, +4.4±13.4, and +2.3±14.6 letters at 3, 6, and 12 months, respectively. The tSNP rs3025000 was the only SNP significantly associated (P<1 × 10(-4)) with visual outcome at 6 months with multiple correction. The presence of the T allele (TC or TT genotypes) at this tSNP predicted a better outcome of +7 letters at 6 months compared with the CC genotype. In a subgroup analysis, presence of the T allele predicted a significantly higher chance of the patients belonging to the responder group (gain of ≥5 letters from baseline) after 3, 6, and 12 months treatment (odds ratio, 2.7, 3.5, and 2.4; 95% confidence interval, 1.46-5.07, 1.82-6.71, and 1.27-4.57, respectively) than any other outcome group. CONCLUSIONS Pharmacogenetic association with anti-VEGF treatments may influence the visual outcomes in neovascular AMD. In patients with the T allele in tSNP rs3025000, there was a significantly better visual outcome at 6 months and a greater chance of the patients belonging to the responder group with anti-VEGF treatment at 3, 6, and 12 months. The VA outcomes of patients harboring the T allele at SNP rs3025000 were comparable with those of the pivotal clinical trials but with fewer injections, making the treatment perhaps more cost effective in certain subgroups of patients. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Wound‐related complications and clinical outcomes following open globe injury repair

Background Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound-related issues. Design Retrospective, cohort study of consecutive open globe injuries presenting to a tertiary referral eye hospital from 1 January 2009 to 31 December 2011. Participants A total of 267 eyes of 263 patients, mainly male (82.5%) with a mean age of 44.8 (range: 4–97) years. Average follow up was 6.9 months. Methods All cases classified according to Ocular Trauma Classification Group. Main Outcome Measures Visual outcomes, risk factors for and rates of postoperative complications and endophthalmitis. Results There were 83 globe ruptures, 182 penetrating and 2 perforating eye injuries, of which 43 cases had intraocular foreign body. Factors contributing to final visual acuity (VA) <6/60 were poor presenting VA (odds ratio [OR] = 16.0, 95% confidence interval [CI]: 4.81–53.1), globe rupture (OR = 4.64, [1.99–10.8]), retinal detachment (OR = 3.40, [1.19–9.74]) and age ≥50 (OR = 2.45, [1.05–5.74]). Wound leak occurred in 44 eyes (16%). Of these, 18 (41%) proceeded to re-suturing. Factors contributing to wound leak were stellate-shaped wound (OR = 3.28, [1.39–7.73]) and delayed presentation (OR = 2.80, [1.02–7.71]). Ten eyes (3.7%) developed endophthalmitis. Factors associated with endophthalmitis were delayed presentation (OR = 8.91, [1.71–46.6]), microbial keratitis (OR = 12.5, [1.85–85.0]) and lens capsule breach (OR = 12.4, [1.85–83.1]). Conclusions Wound leak is an important postoperative complication of open globe injury repair. Delayed presentation is an important risk factor for postoperative wound leak and endophthalmitis. Prompt and meticulous wound management of open globe injury may reduce these complications.Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound‐related issues.

Paracentral acute middle maculopathy as a finding in patients with severe vision loss following phacoemulsification cataract surgery: PAMM following cataract surgery

Paracentral acute middle maculopathy (PAMM) diagnosed by spectral domain optical coherence tomography (SD‐OCT) in patients with poor visual outcome post cataract surgery.Importance Paracentral acute middle maculopathy (PAMM) diagnosed by spectral domain optical coherence tomography (SD-OCT) in patients with poor visual outcome post cataract surgery. Background Case series of severe vision loss due to PAMM after cataract surgery. Design Retrospective case series. Participants Cases from five surgical centres in Victoria, Australia. Methods Retrospective analysis of cases with unexplained ‘patch-off’ vision loss post cataract surgery. All patients in our cohort had PAMM and presumed diagnosis of central or transient retinal artery occlusion. Main Outcome Measures A review of the patient histories focusing on pre-operative ocular and systemic vascular risk factors, anaesthetic and operative factors. Results Ten cases were included. All patients had 6/72 Snellen visual acuity or worse noted on day one post surgery. Three patients had features of central retinal artery occlusion consisting of retinal pallor with a ‘cherry red’ macula but absent relative afferent pupillary defect. Seven had no features of retinal pallor or attenuation of retinal arterioles. On SD-OCT, all eyes had evident PAMM. Six patients had a history of cardiovascular disease or blood dyscrasia. Conclusions and Relevance PAMM should be considered in patients with ‘patch off’ visual loss and absence of other fundal signs. We hypothesise that spasm or transient occlusion of central retinal artery leads to arterial hypoperfusion with subsequent ischaemia or infarction of the retina. Underlying arterial disease may have led to pre-existing hypoperfusion that may have been further compromised by raised intraocular pressure during the procedure itself or via raised orbital pressure from the anaesthesia.

Survey of prophylactic intracameral antibiotic use in cataract surgery in an Australian context

objectives and may be difficult for those from a different culture to identify. It is not unusual for those in charge to commit to minimum standards without any intention of implementing them. Although the reasons for this are many, the bottom line, despite protestations to the contrary, is that developing country government funding focuses on numbers rather than quality outcomes. And although there are exceptions, this is also true of many international non-governmental organizations. Some mundane aspects may be overlooked. In the desire to assist the developing world, we may forget the need for medical registration for visiting professionals: that local partners ignore such requirements does not negate this legal obligation. Finally, there is the related matter of trainees from developed countries seeking surgical experience through volunteer programs. There is nothing wrong with this if they already have skills in the techniques being used or are adequately supervised until such expertise is achieved. If local patients are used for teaching purposes (whether of local staff or visitors), the level or supervision must be high, using appropriate instrumentation such as beam splitters, observer scopes, and modern management of any complications such as vitreous loss. Being aware of some of these potential issues is an important precondition to change and development. As for how to then deal with them, we do not have a simple answer, but can testify that the blunt, but honest approach is rarely well received.

The Prevalence and Causes of Vision Loss in Indigenous and Non-Indigenous Australians: The National Eye Health Survey

PURPOSE To conduct a nationwide survey on the prevalence and causes of vision loss in Indigenous and non-Indigenous Australians. DESIGN Nationwide, cross-sectional, population-based survey. PARTICIPANTS Indigenous Australians aged 40 years or older and non-Indigenous Australians aged 50 years and older. METHODS Multistage random-cluster sampling was used to select 3098 non-Indigenous Australians and 1738 Indigenous Australians from 30 sites across 5 remoteness strata (response rate of 71.5%). Sociodemographic and health data were collected using an interviewer-administered questionnaire. Trained examiners conducted standardized eye examinations, including visual acuity, perimetry, slit-lamp examination, intraocular pressure, and fundus photography. The prevalence and main causes of bilateral presenting vision loss (visual acuity <6/12 in the better eye) were determined, and risk factors were identified. MAIN OUTCOME MEASURES Prevalence and main causes of vision loss. RESULTS The overall prevalence of vision loss in Australia was 6.6% (95% confidence interval [CI], 5.4-7.8). The prevalence of vision loss was 11.2% (95% CI, 9.5-13.1) in Indigenous Australians and 6.5% (95% CI, 5.3-7.9) in non-Indigenous Australians. Vision loss was 2.8 times more prevalent in Indigenous Australians than in non-Indigenous Australians after age and gender adjustment (17.7%, 95% CI, 14.5-21.0 vs. 6.4%, 95% CI, 5.2-7.6, P < 0.001). In non-Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (61.3%), cataract (13.2%), and age-related macular degeneration (10.3%). In Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (60.8%), cataract (20.1%), and diabetic retinopathy (5.2%). In non-Indigenous Australians, increasing age (odds ratio [OR], 1.72 per decade) and having not had an eye examination within the past year (OR, 1.61) were risk factors for vision loss. Risk factors in Indigenous Australians included older age (OR, 1.61 per decade), remoteness (OR, 2.02), gender (OR, 0.60 for men), and diabetes in combination with never having had an eye examination (OR, 14.47). CONCLUSIONS Vision loss is more prevalent in Indigenous Australians than in non-Indigenous Australians, highlighting that improvements in eye healthcare in Indigenous communities are required. The leading causes of vision loss were uncorrected refractive error and cataract, which are readily treatable. Other countries with Indigenous communities may benefit from conducting similar surveys of Indigenous and non-Indigenous populations.

Diabetic Macular Edema at the time of Cataract Surgery trial: a prospective, randomized clinical trial of intravitreous bevacizumab versus triamcinolone in patients with diabetic macular oedema at the time of cataract surgery - preliminary 6 month results.

To compare visual and anatomical outcomes between intravitreous bevacizumab (BVB, Avastin) and triamcinolone (TA, Triesence) when administered at the time of cataract surgery in patients with diabetic macular oedema (DME).

DiMECat Trial: A Prospective, Randomised Clinical Trial of Intravitreous Bevacizumab vs. Triamcinolone in Patients with Diabetic Macular Oedema at the Time of Cataract Surgery – Preliminary 6 Month Results

To compare visual and anatomical outcomes between intravitreous bevacizumab (BVB, Avastin) and triamcinolone (TA, Triesence) when administered at the time of cataract surgery in patients with diabetic macular oedema (DME).

IMPLICATION OF RECURRENT OR RETAINED FLUID ON OPTICAL COHERENCE TOMOGRAPHY FOR VISUAL ACUITY DURING ACTIVE TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION WITH A TREAT AND EXTEND PROTOCOL.

Purpose: Assess the correlation between optical coherence tomography findings and change in vision for patients receiving “treat and extend” protocol ranibizumab for neovascular age-related macular degeneration. Methods: Optical coherence tomography analysis and best-corrected visual acuity (BCVA) change: mild = 5 to 9 letters, moderate = 10 to 14 letters, and severe ≥15 letters. Results: A total of 103 eyes (99 patients, 63% female, 65–91 years) followed for 20.8 ± 4.9 months. By 12 months, there were 1.38 ± 0.59 instances of intraretinal fluid (IRF)/subretinal fluid recurrence on optical coherence tomography and 1.25 ± 1.00 instances of BCVA loss (≥5 letters) per patient. When BCVA was lost, IRF/subretinal fluid was present in 37.3% of cases. Occurrences of severe BCVA loss were less likely to recover vision than when BCVA loss was mild (5.9% vs. 75.6%, P = 0.001). New occurrence of IRF (33.9%) or subretinal fluid (29.6%) was more likely to lead to BCVA loss, compared with dry (16.6%) or persistent IRF (11.9%) or persistent subretinal fluid (14%, P < 0.001). With persistent fluid, any new loss of vision had a lower chance of recovery than when fluid was new in onset (64.3% vs. 85.3%, P = 0.04). Conclusion: During ranibizumab treatment, vision can decrease without signs of fluid. When fluid is present, IRF is associated with poorer vision. New occurrence of any fluid on optical coherence tomography is likely to lead to vision loss, but small amounts of persistent fluid can be tolerated without compromising vision.

Lessons learnt inform our approach to new antivascular endothelial growth factor treatments for neovascular age-related macular degeneration.

Antivascular endothelial growth factor treatment (anti-VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (nAMD). Ranibizumab (Novartis, Novartis Pharmaceuticals, Sydney, New South Wales, Australia), an affinity matured, humanized and monoclonal antibody fragment to VEGF, was first approved for use in 2006. In 2007, it was listed on the Pharmaceutical Benefits Scheme in Australia, for subfoveal nAMD. This followed the results of the pivotal anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization (CNV) in AMD and minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular AMD studies, which showed that monthly intravitreal ranibizumab was associated with a mean gain of +11.3 and +7.2 letters at 12 months ,and +10.7 letters and +6.6 letters at 24 months, in predominantly classic and minimally classic/occult lesions, respectively. To reduce the treatment burden of monthly injections, many clinicians have used less frequent dosing strategies. During 2006–2007, treatment in the retina clinics at the Royal Victorian Eye and Ear Hospital (RVEEH), the first public hospital in Australia to offer this treatment, was most often to perform three monthly injections and then use a pro re nata treatment regimen. The decision to re-treat was based upon signs of CNV activity, presence of new haemorrhage, loss of visual acuity (VA) and optical coherence tomography findings (increase in central macular thickness or the presence of either intraretinal fluid or subretinal fluid). Four to six weekly follow up was maintained throughout this period. An audit of the early results from RVEEH clinics analysed all patients with a diagnosis of subfoveal CNV secondary to AMD, who commenced intravitreal anti-VEGF treatment at the RVEEH from 2006 to 2007. In all cases, patients were treated with ranibizumab, although rarely bevacizumab was given as a single ‘one off’ dose, as an initial treatment to avoid any treatment delay while obtaining approval for ranibizumab treatment. The VA outcome of patients who commenced treatment in 2006 and 2007 cohorts, with the mean ± standard deviation change in VA after 3, 6, 12 and 24 months, was +4.0 ± 11.9, +1.6 ± 12.6, −3.4 ± 15.5 and −6.9 ± 17.8 letters, respectively. These disappointing results were achieved with the mean number of 4.2 ± 2.0 injections in the first 12 months, an extremely low number of injections that, in part, reflects that some cases were chronic, where treatment was offered without any real expectation of improved outcomes. When no benefit was gained, the treatment was ceased after just a few months. Industry-sponsored studies to determine if less frequent treatments would be as effective as monthly injections have reported similar, disappointing findings. The Efficacy and Safety of Ranibizumab in Subjects with Subfoveal CNV Secondary to AMD (EXCITE) studies investigated the 12-month efficacy of quarterly dosing of ranibizumab after three consecutive monthly injections. Both studies demonstrated that quarterly dosing regime was less effective than monthly treatment. Other approaches being trialled that were based not upon fixed dosing schedules, but around the individual patient responses guiding the treatment frequency were more successful. Results from the small Prospective Optical Coherence Tomography Imaging of Patients with nAMD Treated with intraocular Ranibizumab study suggested that a flexible dosing regimen, with the optical coherence tomography-measured central retinal thickness and VA being used as guiding criteria for re-treatment, may be as effective as monthly treatment. Similar results were also seen in the SUSTAIN study, where treatment outcome was similar to the monthly pivotal trials, although with a lower average number of re-treatments (mean of 5.6 injections over 12 months). A small loss in VA, however, was seen after the initial gain from three monthly loading doses.

Predictors of visual outcome and the role of early vitrectomy in streptococcal endophthalmitis: Streptococcal endophthalmitis outcomes

Streptococcal endophthalmitis has devastating sequelae. This study aims to identify factors which may be targeted to optimize patient outcomes.