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Systematic review of various laser intervention strategies for proliferative diabetic retinopathy Expert Rev. Med. Devices 12(1), 83–91 (2015)

Dawei Luo, Zhi Zheng, Xun Xu, Ying Fan, Bijun Zhu, Kun Liu, Fenghua Wang, Xiaodong Sun, Haidong Zou and Xin Xia* Department of Ophthalmology, Shanghai First People’s Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, China *Author for correspondence: Tel.: +86 021 6324 0090 Fax: +86 021 6306 7385 [email protected]

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Diabetic retinopathy (DR) is a common complication of diabetes. DR obstructs blood supply to the retina and has serious and long-lasting detrimental effects on quality of life. Panretinal photocoagulation, a laser surgical intervention, is advocated for early treatment of DR to prevent visual loss; however, results from studies reporting its efficacy vary markedly. In this review, we systematically conducted a database search of randomized controlled trials that investigated the safety and efficacy of different types of laser interventions, alone or in combination with adjunct intravitreal steroid utilization, in patients with DR. Data from 14 studies demonstrated that panretinal photocoagulation can be a safe and effective option for reducing visual loss and blindness in patients with DR. KEYWORDS: diabetes • diabetic retinopathy • panretinal photocoagulation • systematic review

Background

Diabetes is a lifelong, chronic metabolic condition, currently affecting more than 200 million people worldwide [1]. Although there has been little change in the prevalence of Type I diabetes in recent years, the rapid increase in obesity has boosted the incidence of Type II diabetes, causing many problems, especially among children and young adults [2,3]. Chronic diabetes results in multiple systemic complications with significant implications for healthcare. In particular, persistent hyperglycemia has potentially damaging consequences in many areas of the microvascular system, leading to neuropathy, nephropathy and retinopathy. Diabetic retinopathy (DR) is the primary cause of visual impairment and blindness in most developed countries, and it is estimated that 93 million people are subject to this common complication of diabetes [4]. The retinal vessel changes of DR occur in up to 80% of patients with diabetes and cause major disability. Recently, the results of the 25-year followup of The Wisconsin Epidemiological Study of Diabetics Retinopathy in Type I diabetes revealed that 13% of participants had some

10.1586/17434440.2014.953057

form of visual impairment; the incidence of visual impairment correlated with the degree of retinopathy and macular edema [5]. Diabetic retinopathy

The pathological changes in DR responsible for visual loss are the result of microvascular retinal changes, including capillary vessel occlusion, impaired retinal perfusion, retinal ischemia, macular edema and proliferative neovascularization. Non-proliferative diabetic retinopathy (NPDR) is characterized by the formation of microaneurysms, retinal ischemia and macular edema. During macular edema, plasma constituents leak across the blood–retina barrier and clinically manifest as retinal thickening. Proliferative diabetic retinopathy (PDR) is characterized by the formation of abnormal new blood vessels (neovascularization) at the back of the eye. These vessels are delicate, easily disrupted and can hemorrhage into the vitreous cavity. During the later stages of PDR, the vessels regress, leaving networks of avascular fibrous tissue adherent to the retina. This scar tissue shrinks, which leads to retinal tears and detachments.

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Expert Review of Medical Devices Downloaded from informahealthcare.com by University of Southern California on 03/13/15 For personal use only.

Review

Luo, Zheng, Xu et al.

The pathophysiology of DR is associated with hyperglycemia, the hallmark of diabetes; in fact, vascular occlusion and ischemia both stem from persistent hyperglycemia. Current consensus is that multiple interdependent biochemical pathways combine to contribute to DR. Causative biological dysfunctional mechanisms include the polyol pathway, protein kinase C, expression of growth factors, blood vessel pressures, increased glycation products and oxidative stress. Elevations in cell glucose levels lead to increased production of sorbitol and fructose in the polyol pathway. These by-products damage retinal cells due to osmotic pressure abnormalities, increased production of glycating agents and oxidative stress. Inflammation and capillary occlusion develop, and protein kinase C, VEGF and insulin-like growth factor-1 production and activity are increased. VEGF and other angiogenic factors mediate the development of macular edema and retinal neovascularization. Abnormally low concentrations of angiogenic inhibitors in the vitreous and retina advance the progression of macular edema and retinal neovascularization [6,7]. The retinal vessel endothelium is weakened, and hypertension, which typically occurs in patients with Type II diabetes, exacerbates vessel wall defects. Ultimately, retinal vessels bleed spontaneously, and visual impairment results [6]. Laser surgery intervention

Retinal photocoagulation using a xenon arc photocoagulator was introduced in 1959 [8]. Since then, panretinal photocoagulation (PRP) has been increasingly used to treat DR. The landmark studies – the Diabetic Retinopathy Study (DRS) and Early Treatment Diabetic Retinopathy Study (ETDRS) [9–12] –validated the efficacy, indications and parameters of PDR, which has become the gold standard for DR treatment. Nd: YAG and argon laser treatments are more commonly utilized in current clinical practice, while krypton lasers are rarely used today. The light energy from the laser is absorbed by melanin in the retinal pigment epithelium; as a result, the adjacent photoreceptors cannot survive this energy surge. Glial scars form as a reaction to the destruction of the retinal photoreceptors, and there is a reduction in oxygen consumption in the retina [13]. The glial scars also provide an oxygen diffusion pathway to the inner retina, which reduces the stimulation of VEGF subsequent to neovascularization, thereby preventing proliferative DR from developing [14]. The targeted effect of laser photocoagulation on retinal arteries creates vasoconstriction resulting in increased arteriolar resistance and reduced capillary hydrostatic pressure, thereby preventing macular edema [15]. Why it is important to do this review

The current clinical consensus is that laser surgery is the primary treatment option in the prevention of visual impairment due to DR. The incidence of diabetes and its complications are continuing to increase, and laser intervention for DR is being used with greater frequency. A systematic review assessing laser 84

intervention for RD with stringent inclusion criteria for RCTs has not been published to date. Therefore, it is important to undertake a comprehensive review of clinical study results. It is critical to assess laser surgery across available eligible studies to determine if it is a safe and effective intervention in all patients, and to consider potential negative consequences. Early observational studies have reported mild-to-moderate decline in visual function in those treated with panretinal laser surgery [9–12]. The aim of this systematic review is to pool the existing evidence from relevant RCTs and quantify the degree of clinical improvement in DR after laser photocoagulation. This review also assesses the type and frequency of adverse effects reported after laser surgery, as this may influence the decision to implement such therapy. Sub-group analyses of the type of laser and frequency of wavelength used for photocoagulation are reported in order to determine the presence of possible interactions of the treatment effect with those variables. Methods & materials Criteria for included studies

Inclusion criteria were: RCTs evaluating the efficacy and safety of laser surgical interventions for the treatment of DR; RCTs that included patients with Type I or Type II diabetes with fundoscopic evidence of NPDR or PDR; RCTs that reported laser photocoagulation as the treatment intervention for DR and RCTs comparing laser types and wavelengths. Types of outcome measures

The primary outcome measure was assessment of severe visual loss, as defined by visual acuity

Systematic review of various laser intervention strategies for proliferative diabetic retinopathy.

Diabetic retinopathy (DR) is a common complication of diabetes. DR obstructs blood supply to the retina and has serious and long-lasting detrimental e...
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