Salmaan Al‐Qureshi

Therapeutic targeting of the complement system in age‐related macular degeneration: a review

The last decade has produced pivotal change in our understanding of the molecular mechanisms underlying age-related macular degeneration (AMD), a leading cause of global blindness. In this time, the complement system has featured as a unifying theme for several elements of new evidence: initially, the discovery of complement proteins within drusen and subsequently, the association between AMD and mutations in various complement pathway genes, most notably complement factor H. Increasingly, a wealth of data are pointing towards a role for chronic local inflammation and complement activation in the patho-aetiology of AMD. These findings have paved the way for the exploration of a new paradigm of therapy in AMD management; targeting of specific molecular constituents in the complement pathway thus producing dampening or inhibition of the inflammatory response. Such an approach has the potential to intervene earlier in the disease process and ideally before vision is compromised. In this review we discuss the role of the complement system in AMD, novel therapies in preclinical evaluation and clinical trial, and whether these have a part to play in reducing the burden of disease.The last decade has produced pivotal change in our understanding of the molecular mechanisms underlying age‐related macular degeneration (AMD), a leading cause of global blindness. In this time, the complement system has featured as a unifying theme for several elements of new evidence: initially, the discovery of complement proteins within drusen and subsequently, the association between AMD and mutations in various complement pathway genes, most notably complement factor H. Increasingly, a wealth of data are pointing towards a role for chronic local inflammation and complement activation in the patho‐aetiology of AMD. These findings have paved the way for the exploration of a new paradigm of therapy in AMD management; targeting of specific molecular constituents in the complement pathway thus producing dampening or inhibition of the inflammatory response. Such an approach has the potential to intervene earlier in the disease process and ideally before vision is compromised. In this review we discuss the role of the complement system in AMD, novel therapies in preclinical evaluation and clinical trial, and whether these have a part to play in reducing the burden of disease.

Prevalence of optical coherence tomography-diagnosed postoperative cystoid macular oedema in patients following uncomplicated phaco-emulsification cataract surgery

Background:  Postoperative cystoid macular oedema is a complication of uneventful cataract surgery. Whereas improved surgical techniques have decreased the incidence of cystoid macular oedema, it remains a cause of unfavourable visual outcome following surgery. Fundus fluorescein angiography has been the ‘gold standard’ for diagnosing subclinical cystoid macular oedema; however, non‐invasive cross‐sectional imaging of the retina with optical coherence tomography may be equally effective at detecting the condition and offers the ability to quantify and repeat results over time.

Intravitreal injections: a review of the evidence for best practice

Intravitreal injection is a common procedure performed by ophthalmologists. It is a quick and targeted treatment for a number of ophthalmic conditions. Despite this, the potential to cause serious complications and patient discomfort cannot be ignored. This article presents the level of evidence in the scientific literature supporting common practices such as location of the procedure, anaesthetic choice, sterile procedure techniques, comparison of some common pharmaceutical agents and the use of antibiotics.Intravitreal injection is a common procedure performed by ophthalmologists. It is a quick and targeted treatment for a number of ophthalmic conditions. Despite this, the potential to cause serious complications and patient discomfort cannot be ignored. This article presents the level of evidence in the scientific literature supporting common practices such as location of the procedure, anaesthetic choice, sterile procedure techniques, comparison of some common pharmaceutical agents and the use of antibiotics.

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.

Diabetic retinopathy in pregnancy: a review.

The prevalence of diabetes in pregnancy is increasing. Pre‐existing diabetes is present in 1 in 167 pregnancies in Australia, divided equally between type 1 and type 2 diabetes. Diabetic retinopathy is a leading cause of blindness in women during their childbearing years, and pregnancy increases the short‐term risk of diabetic retinopathy progression. We examine the risk factors for progression of diabetic retinopathy during pregnancy including duration of diabetes, baseline level of retinopathy, level of glycaemic control and hypertension. We also examine current screening and management guidelines and their levels of evidence, current treatment options for diabetic retinopathy and avenues for further research.The prevalence of diabetes in pregnancy is increasing. Pre-existing diabetes is present in 1 in 167 pregnancies in Australia, divided equally between type 1 and type 2 diabetes. Diabetic retinopathy is a leading cause of blindness in women during their childbearing years, and pregnancy increases the short-term risk of diabetic retinopathy progression. We examine the risk factors for progression of diabetic retinopathy during pregnancy including duration of diabetes, baseline level of retinopathy, level of glycaemic control and hypertension. We also examine current screening and management guidelines and their levels of evidence, current treatment options for diabetic retinopathy and avenues for further research.

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).

Intravitreous bevacizumab adult safety data: the evidence so far

Intravitreous bevacizumab has been used in Australia since November 2005 and used at the Royal Victorian Eye and Ear Hospital since June 2006, becoming the first hospital in the country to do so. During that period, it has been used to treat neovascular age-related macular degeneration, diabetic macular oedema, proliferative diabetic retinopathy, neovascular glaucoma as well as other conditions where the expression of vascular endothelial growth factor within the eye is thought to play a central role. The use of intravitreous bevacizumab has been off label, and given its well-known risks when given systemically, there has always been concern about its intraocular use. Two recent studies have given insight to systemic cardiovascular events in patients receiving treatment for neovascular age-related macular degeneration, the Medicare database study by Lesley Curtis and the Comparison of Age-Related Macular Degeneration Treatments Trial (CATT). Age-related macular degeneration itself is associated with an increased incidence of cardiovascular disease even in the absence of any intervention. This association is inconsistent and may be confounded by smoking. The Medicare data study examined the incidence of death, myocardial infarction, stroke and bleeding in patients receiving photodynamic therapy, pegaptanib, bevacizumab and ranibizumab. For those unfamiliar with US Medicare claims data, there is very little information on confounding treatment decision variables that may have led to the selection of a particular drug that could be included in a legitimate multifactorial analysis. Still, the annual incidence of death was 4.8% for pegaptanib (theoretically, the safer of all three drugs without pan-vascular endothelial growth factor inhibition), 4.4% for bevacizumab and 4.1% for ranibizumab and photodynamic therapy. There was a statistically significant difference between pegaptanib and ranibizumab but also between bevacizumab and ranibizumab. The authors, to their credit, understood the potential for selection bias between patients able to copay for ranibizumab and those for whom financial constraints meant that bevacizumab was the cheaper option. Briefly, those receiving bevacizumab were presumed quite correctly to be of a lower socio-economic rank with a higher incidence of cardiovascular disease and death from all causes. The authors adjusted for as many variables as was possible (race, co-morbidities, gender, age) but could not adjust for socio-economic rank. In a subgroup analysis limited to centres or doctors that used either ranibizumab or bevacizumab exclusively on all their patients; (thereby negating any difference in socioeconomic rank based on patient self-selection) there was NO statistical difference in cardiovascular outcomes (death, myocardial infarction and stroke). Of note, in the subgroup analysis, the mortality rates inverted at 4.7% for ranibizumab and 4.3% for bevacizumab. Perhaps it was the fewer numbers or, more likely, confounding that reduced the statistical power of the cohort calculations, or perhaps there is no additional cardiovascular risk between intravitreous bevacizumab and ranibizumab. Even disregarding the socio-economic health gradient hypothesis, the difference between ranibizumab and bevacizumab mortality is 0.3% (4.1% vs. 4.4%). The CATT trial has already generated discussion in previous editions of this journal. The authors correctly concluded that there was no difference in efficacy between monthly ranibizumab and bevacizumab, and that the study was insufficiently powered (and was never designed to) to detect a small difference in adverse events between the treatment arms. Despite this, debate has centred on the different incidence of adverse events between the bevacizumab-treated group (24%) and ranibizumab (19%). Because the trial was masked and randomized, and the pharmaceuticals provided free to all patients, there is no systemic confounder with regard to socio-economic rank. There are, however, two interesting points to note. The first is that the most significant difference that occurred between bevacizumab and ranibizumab groups; death from any cause; 16 versus 9, was due to a higher incidence of death in the pro re nata or ‘as needed’ bevacizumab group. There is no difference in mortality between monthly bevacizumab (1.4%), monthly ranibizumab (1.3%) and pro re nata ranibizumab (1.7%). If we were to accept (as Dr Beaumont and others have suggested), that intravitreous bevacizumab injections increase mortality when compared with ranibizumab, then a similar prima facie reading of the entire 12-month dataset

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).

Review of the role of refined dietary sugars (fructose and glucose) in the genesis of retinal disease

This review examines the current evidence of the relationship between sugar consumption and the development of retinal and other eye diseases including diabetic retinopathy, hypertensive retinopathy, age‐related macular degeneration, non‐arteritic anterior ischaemic optic neuropathy and cataract. Sucrose is comprised of fructose and glucose. Sugar consumption has increased five‐fold over the last century, with high quantities of sucrose and high‐fructose corn syrup found in processed food and soft drinks. This increased consumption is increasingly recognized as a central factor in the rapidly rising rates of obesity and type 2 diabetes. The body metabolizes fructose and glucose differently, with fructose appearing to have the greater propensity to contribute to the metabolic syndrome. This review examines the effect of high rates of dietary consumption of refined carbohydrates on the eye, including the effect of chronic hyperglycaemia on microvascular disease in diabetic retinopathy, and the pathophysiological changes in the retinal circulation in hypertensive retinopathy.This review examines the current evidence of the relationship between sugar consumption and the development of retinal and other eye diseases including diabetic retinopathy, hypertensive retinopathy, age-related macular degeneration, non-arteritic anterior ischaemic optic neuropathy and cataract. Sucrose is comprised of fructose and glucose. Sugar consumption has increased five-fold over the last century, with high quantities of sucrose and high-fructose corn syrup found in processed food and soft drinks. This increased consumption is increasingly recognized as a central factor in the rapidly rising rates of obesity and type 2 diabetes. The body metabolizes fructose and glucose differently, with fructose appearing to have the greater propensity to contribute to the metabolic syndrome. This review examines the effect of high rates of dietary consumption of refined carbohydrates on the eye, including the effect of chronic hyperglycaemia on microvascular disease in diabetic retinopathy, and the pathophysiological changes in the retinal circulation in hypertensive retinopathy.

Proliferative retinopathy in Duchenne muscular dystrophy and its response to bevacizumab.

We report the first case of proliferative retinopathy associated with Duchenne muscular dystrophy (DMD) treated with intra-vitreal bevacizumab. The patient is a 23-year-old quadriplegic male with ventilatory failure and cardiomyopathy requiring intermittent bilevel positive airway pressure for the past 12 months. The patient had complained of 2 weeks of loss of vision in the right eye associated with pain and photophobia. Visual acuity was 1/60 in the right eye and 6/12 in the left eye. Intra-ocular pressures were 36 mmHg on the right eye and 16 mmHg on the left eye. Examination of the right eye revealed iris neovascularization. The left anterior segment was normal. The right fundus eye displayed multiple deep intra-retinal haemorrhages and extensive neovascularization of the disc. The left fundus showed a pre-retinal and vitreous haemorrhage with disc neovascularization. Fundus fluorescein angiography was performed with an HRA2 (Heidleberg Engineering, Heidelberg, Germany). True colour fundus photographs were not available as we were unable to position the patient at the fundus camera adequately. The angiogram (Fig. 1) showed extensive retinal ischaemia and disc neovascularization. A full blood examination showed mild normocytic anaemia with a haemoglobin of 95 g/L. erythrocyte sedimentation ratio was 76 mm/h and C-Reactive protein was 14 mg/L. Clotting studies and blood glucose were normal. Bevacizumab 1.25 mg in 0.05 mL was injected into the vitreous cavity of the right eye at presentation. Rapid resolution of the iris neovacularization was observed the next day. Injections of bevacizumab in the left eye were performed 1 week and 5 weeks after presentation. Followup angiography at 8 weeks showed resolution of the microvascular abnormalities and regression of the neovascularization (Fig. 2) DMD is an X-linked recessive disorder characterized by progressive proximal myopathy. It is caused by a mutation of the dystrophin gene located on the short arm of the X chromosome at Xp21. A previous report in the literature discussed the various factors that may be involved in the pathogenesis of this florid proliferative retinopathy. It is likely that chronic hypoxia secondary to cardiomyopathy and ventilatory failure plays the predominant role. However, this degree of retinopathy is not seen in other patients with similar chronic hypoxia states such as chronic obstructive pulmonary disease, obstructive sleep apnoea and congestive cardiac failure. The comorbid mild anaemia would also have contributed to the retinal hypoxia but is also insufficient to explain the degree of retinopathy. The third factor that may be playing a significant role is the mutant dystrophin protein. Apart from muscle, it has also been shown that dystrophin is present in the retina in