Description of the condition
Sickle cell disease (SCD) is common genetic disorder affecting millions of people worldwide. It is most endemic in tropical regions, mainly sub-Saharan Africa, India and the Middle East (Weatherall 2001). It has become a global issue due to the migration of population from these areas to Europe and other parts of the world, particularly over the last few decades (Roberts 2007). Sickle cell disease includes sickle cell anaemia (Hb SS), sickle cell-haemoglobin C disease (Hb SC), sickle cell-β thalassaemia (Sβ0 Thal and Sβ+ Thal) and other less prevalent double heterozygous conditions (Serjeant 2001). It is a systemic disease that affects almost all the organs and leads to neurological, cardiac, pulmonary, hepatic, renal, ophthalmic, musculoskeletal and dermatological manifestations (Ballas 2010).
The main pathophysiology associated with ophthalmic manifestations in SCD is vaso-occlusion that occurs in any vascular bed of ocular structures including conjunctiva, anterior segment, choroid, retina and optic nerve with potential visual impairment (Emerson 2005). Sight-threatening problems in SCD are mainly due to proliferative sickle retinopathy (PSR), which is secondary to occlusion of the peripheral retinal vasculature, which in turn leads to retinal ischemia and proliferation of new blood vessels with characteristic sea fans appearance. The incidence of PSR is more common in Hb SC disease and sickle cell-β thalassaemia, being approximately 33% and 14% respectively, compared to 3% in Hb SS (Lutty 1994). The incidence of PSR increases with age, it is relatively common between 15 and 29 years of age (Condon 1972), but there were reported studies in which PSR was detected in children as young as 7 to 13 years (Abiose 1978; Condon 1974a; Erachulu 2006). The peak prevalence of PSR in the HbSC genotype occurs earlier than in the SS type between 15 to 24 years in men and 20 to 39 years in women (Elagouz 2010). Goldberg and colleagues developed a classification of PSR according to the severity of fundus changes (Table 1) (Goldberg 1971).
|Table 1:||Staging of proliferative sickle retinopathy (PSR)|
|Stage I||Peripheral arteriolar occlusion|
|Stage II||Vascular remodelling, formation of arteriovenous anastomoses|
|Stage III||Peripheral retinal neovascularization|
|Stage IV||Vitreous haemorrhage|
|Stage V||Retinal detachment|
Early stages of PSR may not need any intervention, as these early changes are quiescent or may even resolve due to auto-infarction. Spontaneous regression is seen in 32% of eyes with PSR without any blinding complications (Downes 2005). Regression of PSR is more common in the eyes of people with Hb SS disease, seen in 40% compared to 20% of Hb SC; and complete non-perfusion of PSR lesion is observed in 20% of SS and 7% of SC (Fox 1991). Although permanent visual loss is rare, incidence of visual loss among patients with SS and SC has been reported as 31 per 1000 eyes affected by PSR compared to 1.4 per 1000 eyes without PSR over a mean follow-up period of 6.9 years (Moriaty 1988). Visual loss in PSR is commonly due to vitreous haemorrhage and tractional retinal detachment (Moriaty 1988) and affects relatively younger patients indicating that early detection with timely effective treatment of stage III PSR is necessary to prevent such visual loss.
Description of the intervention
Various treatment options, such as diathermy, cryotherapy and transpupillary or transscleral diode laser photocoagulation, have been proven to be effective treatments of PSR (Condon 1974b; Goldbaum 1979; Seiberth 2001). Transpupillary laser photocoagulation is the safest and the preferred method among the available techniques, as cryotherapy is associated with adverse effects like retinal detachment (Goldbaum 1979). Transscleral diode laser coagulation is considered as an alternative in cases only when transpupillary laser coagulation is not applicable due to media opacities (Seiberth 2001).
Given the favourable chances of spontaneous regression, indication for the treatment of PSR varies among clinicians. Treatment is usually indicated in cases with peripheral neovascularization of more than 60° of circumference. This is particularly the case in eyes with bilateral involvement, spontaneous vitreous haemorrhage, large and elevated sea fans, rapid progression of new blood vessels, or precious eye in which the fellow eye has been lost due to PSR (Emerson 2006). The aim of treatment is to induce regression in stage III PSR prior to complications to prevent visual loss (Goldberg 1983). The different types of laser mainly used to achieve these goals are white xenon arc or blue/green argon.
The specific methods of laser in PSR include feeder vessel coagulation and scatter laser coagulation, either localized or 360° peripheral scatter coagulation (Ballas 2012). Scatter laser photocoagulation is considered to be the preferred method for PSR (Castro 1999). There are two types of scatter laser photocoagulation, the first being sectoral or localised and the second being 360° or circumferential laser treatment. In sectoral ablation, laser burns are applied only to the localised area around new blood vessels whereas in circumferential or 360° scatter laser, burns are applied circumferentially to entire peripheral retina (Cruess 1983; Kimmel 1986). The latter is usually indicated in an unreliable patient (Ballas 2012). Laser therapy is most effective when peripheral lesions are diagnosed early before involving the central retina (Castro 1999).
How the intervention might work
Laser photocoagulation has been considered safe as well as effective in the treatment of PSR, as it maintains quality of life and preserves the vision by preventing vision-threatening complications in affected population (Goldbaum 1979; Goldberg 1983).
The mechanism of laser treatment in feeder vessel coagulation is to occlude the feeding vessels by applying direct, heavy laser burns to feeding arterioles leading to closure of neovascular fronds. Ocular media should be clear enough over the feeder vessels for successful photocoagulation (Goldbaum 1979). Both xenon arc and argon laser photocoagulation are used for feeder vessel coagulation; however, currently argon is more commonly used by clinicians as xenon has a higher complication rate compared to argon (Emerson 2005). Scatter laser coagulation has an indirect effect, as it destroys the ischemic retina responsible for production of vascular endothelial growth factor (VEGF) that triggers the proliferation of new blood vessels (Ballas 2012). This technique is primarily used to treat proliferative diabetic retinopathy. The fact that laser photocoagulation to ischemic retina results in regression of new blood vessels in eyes with proliferative diabetic retinopathy has led to this technique being adapted for treatment of PSR. To achieve this goal, blue/green argon laser burns are applied to the retina with laser setting of 500 um spot size and 0.1 second duration.
Studies have demonstrated that laser treatment for PSR has been accepted for several decades (Cruess 1983; Kimmel 1986; Rednam 1982). Timely, successful treatment avoids the need for surgical interventions with their potential complications and morbidities (Cohen 1986; Goldberg 1983).
Why it is important to do this review
Proliferative sickle retinopathy is a leading cause of visual impairment in patients with SCD. Cochrane systematic reviews of randomised controlled trials have been published for prophylaxis and treatment in other organs affected by SCD (Hirst 2012; Marti-Carvajal 2012), but none to date for ocular involvement. Cochrane systematic reviews evaluating the effects of laser photocoagulation in other proliferative retinopathies, such as neovascular age-related macular degeneration, have found that laser treatment slows the progression of visual loss in affected eyes (Virgili 2009). A Cochrane review for laser photocoagulation in diabetic retinopathy is currently ongoing (Dineen 2008). Despite the well-known clinical applications of laser photocoagulation in PSR, it is imperative to identify the treatment effect in people with SCD, given the potentially blinding complications of PSR if treatment is delayed.
Even though laser photocoagulation in PSR is a relatively simple and safe treatment, summarised safety and efficacy compared to placebo or other treatment options in patients with PSR is lacking. Furthermore, various techniques of laser photocoagulation have been practised among clinicians based on preference and facilities. It is therefore essential to perform a systematic review to evaluate the evidence for the effectiveness of different laser photocoagulation therapies in patients with PSR for preventing visual loss and ocular morbidity, along with their potential adverse effects.